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'MEDIA and NEWS 2000' a collection of Gene Therapy-related news updated January 12, 2001 |
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'MEDIA and NEWS 2000' a collection of Gene Therapy-related news updated January 12, 2001 |
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Catalogue of Entries 2000
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December 27, 2000 |
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December 21, 2000 |
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December 15, 2000 |
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December 13, 2000 |
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December 13, 2000 |
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December 7, 2000 |
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November 12, 2000 |
Doctor: U.S. Restores Heart Gene Therapy Trials |
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October 27, 2000 |
Parkinson-Krankheit |
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October 26, 2000 |
Gene therapy shown to protect and reverse the debilitating effects of Parkinson's disease in pre-clinical studies |
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October 18, 2000 |
Eingriffe in die Keimbahn: Weiterhin tabu? |
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September 18, 2000 |
Inheritable gene modification research should not proceed on humans without standards and oversight, AAAS report says |
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September 18, 2000 |
Science Group Opposes Inherited Gene Modification |
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September 5, 2000 |
Meilensteine und Rueckschlaege der Gentherapie |
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September 5, 2000 |
Von der Gentherapie zum Embryo-Design |
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September 5, 2000 |
"Gentherapie braucht einfach Zeit" - auch Raumfahrt hatte Misserfolge - Hintergrund |
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September 4, 2000 |
In letzter Sekunde - DNA-Serum gegen giftige Natternbisse |
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August 31, 2000 |
Bone-building therapies on the way, experts say |
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August 28, 2000 |
Gene Therapy Revives 'Dead' Heart Tissue - Study |
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Sept/Oct. 2000 |
Fundamentals of Gene Therapy |
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Sept/Oct. 2000
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The Last Word: Researchers React to Gene Therapy's Pitfalls and Promises |
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Sept/Oct. 2000 |
Human Gene Therapy: Harsh Lessons, High Hopes |
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August 9, 2000 |
Schnupfen-Virus gegen Krebs |
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August 7, 2000 |
Experten warnen vor zu grosser Hoffnung in |
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August 4, 2000 |
Forscher heilt Autoimmunkrankheiten |
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June 8, 2000 |
Gene therapy's trials |
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June 6, 2000 |
Researchers Sneak Gene Therapy Into Brain |
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May 17, 2000 |
Successful in Utero Gene Transfer Reported in Monkeys |
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May 16, 2000 |
Gene Therapy for Hearing Loss May Be Possible |
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April 28, 2000 |
Franzoesische Forscher erstmals mit Gentherapie erfolgreich |
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April 27, 2000 |
Premier succès pour la thérapie génique |
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April 27, 2000 |
Gene Therapy May Have Scored First Cure |
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March 10, 2000 |
Gene Therapy Panel Doesn't Vote |
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March 10, 2000 |
U.S. Experts Reject Halt to Gene Therapy |
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March 9, 2000 |
Parents' Plea Illustrates Gene Therapy Dilemma |
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March 7, 2000 |
Caution Over Gene Therapy Puts Hopes on Hold |
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March 7, 2000 |
FDA To Enforce Gene Therapy Safety |
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March 2, 2000 |
FDA Stops Researcher's Human Gene Therapy Experiments |
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March 1, 2000 |
Gene Experiment Helps Hemophiliacs |
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Feb 21, 2000 |
Gene therapy halts HIV in cell-based study |
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Feb 17, 2000 |
FDA Says No Contamination of Gene Therapy Viruses |
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Feb 11, 2000 |
Exposures Not Revealed in Gene Therapy Trial |
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Feb 11, 2000 |
Experiment May Have Exposed to AIDS |
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Feb 8, 2000 |
More Gene Therapy Experiments Are Suspended Hospital, Patient Groups Cite Safety Concerns |
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Feb 1st, 2000 |
Hundreds of gene therapy experiments failed |
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Jan 22, 2000 |
ANALYSIS-Gene therapists welcome trial suspension |
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Jan 22, 2000 |
Gentherapien nach erstem Todesfall gestoppt |
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Jan 14, 2000 |
Noch ein Rueckschlag fuer die Gentherapie |
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Jan 8, 2000 |
Erkenntnisdrang und Menschenwuerde |
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Neue Zuercher Zeitung, Jan 8, 2000 |
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Neue Zuercher Zeitung ZEITFRAGEN Samstag, 08.01.2000 Nr.6 94
Erkenntnisdrang und Menschenwuerde
Experimentelle Krebstherapien als ethische
Herausforderung
Von Irene Dietschi*
Patienten, die schwer an Krebs erkrankt sind, zeigen haeufig eine erhoehte Bereitschaft, sich fuer experimentelle Behandlungsmethoden zur Verfuegung zu stellen. Die medizinische Forschung sieht sich damit mit der Gefahr konfrontiert, allenfalls die Notlage eines Patienten auszunuetzen.
....
text truncated for copy-right reasons, please read the full text at: http://nzz.gbi.de/NZZ.ein
...
© AG fuer die Neue Zuercher Zeitung NZZ 2000
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Tages Anzeiger, Jan 14, 2000 |
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Noch ein Rueckschlag fuer die Gentherapie
Auch der Versuch, mit eingeschleusten Viren Menschen mit boesartigen Hirntumoren zu heilen, schlug fehl. Doch die Studie wurde nicht veroeffentlicht.
Von Michael Simm
Die weltweit groesste Studie zur Gentherapie ist erfolglos verlaufen. Den rund 300 Patienten, die in 45 Kliniken Europas und Nordamerikas wegen besonders boesartiger Hirntumoren (Glioblastome) behandelt wurden, "hat die Methode nichts gebracht", bestaetigt Rolf Seiler, Direktor der Neurochirurgischen Klinik am Inselspital Bern. Fuer die Gentherapie bedeutet das einen weiteren Rueckschlag. Erst im September war der 18-jaehrige Jesse Gelsinger, der an einer erblich bedingten Stoffwechselstoerung litt, an den Folgen einer Gentherapie gestorben (der TA berichtete).
30 Schweizer Patienten
Unter Seilers Leitung waren die meisten der rund 30 Schweizer Patienten behandelt worden, die in den Jahren 1996 bis 1998 an der Studie teilgenommen hatten. Die Nebenwirkungen seien zwar akzeptabel gewesen, die Ueberlebenszeiten der Krebskranken haetten sich aber nicht spuerbar verlaengert. Die gleiche Erfahrung hat man auch in der Neurochirurgie des Zuercher Universitaetsspitals gemacht, wo die uebrigen Schweizer Patienten behandelt wurden.
Die Untersuchung wurde schon vor einem Jahr abgeschlossen; seitdem sorgt der Fehlschlag fuer Gespraechsstoff - doch nur in Fachkreisen. Die Daten von 240 Patienten aus der entscheidenden Phase-III-Studie seien jedoch noch immer unveroeffentlicht, kritisiert Christian Ostertag von der deutschen Universitaetsklinik Freiburg. Der Pharmakonzern Novartis, der die Studie koordiniert und finanziert hat, will vorerst keine Zulassung beantragen, um die Gentherapie beim Glioblastom in die Praxis einzufuehren. "Die Studie ist beendet und wir haben viel gelernt", sagt ein Sprecher des Unternehmens. Bei gewissen Patienten habe man eine voruebergehende Wirkung gesehen, in der Gesamtbilanz koenne man jedoch nicht von einem medizinischen Erfolg reden.
Ziel der Gentherapie beim Glioblastom ist es, mit Hilfe bestimmter Viren "Selbstmordgene" in den Tumor einzuschleusen. Die fremde Erbinformation fuehrt dort zunaechst zur Bildung des Eiweisses Thymidinkinase. Anschliessend erhalten die Patienten eine Infusion der Arznei Ganciclovir, die von der Thymidinkinase im Tumor in ein starkes Zellgift umgewandelt wird.
Tierversuche weckten Hoffnungen
Theoretisch sollten damit nicht nur die virusinfizierten Zellen absterben, sondern auch Tumorgewebe in der direkten Umgebung. Schon 1992 war es den amerikanischen Gentherapie-Pionieren Kenneth Culver und Michael Blaese mit dieser Methode gelungen, Glioblastome bei Ratten und Maeusen vollstaendig zu heilen.
Nachdem man drei Jahrzehnte lang fast keine Fortschritte bei der Bekaempfung des aeusserst aggressiven Tumors gemacht hatte, weckten diese Versuche die Hoffnung, aehnliche Erfolge auch am Menschen zu erzielen, erklaert Manfred Westphal, kommissarischer Leiter der Neurochirurgie am Universitaetskrankenhaus Hamburg-Eppendorf. Westphal, der als Pruefarzt an der Novartis-Studie beteiligt war, verteidigt das Vorgehen des Konzerns: Der Druck der Oeffentlichkeit habe zum raschen Beginn der Studie im Jahr 1996 gefuehrt.
Im Durchschnitt ueberleben Glioblastom-Patienten ihre Diagnose trotz aller aerztlichen Bemuehungen nur etwa ein Jahr. Wie viele seiner Kollegen, hatte auch Westphal Hunderte Anrufe von verzweifelten Patienten und Angehoerigen erhalten. "Unter diesen Umstaenden war es gerechtfertigt, die Gentherapie auszuprobieren", betont der Mediziner. Allein im Raum Zuerich werden jaehrlich etwa 200 neue Faelle diagnostiziert.
Die fuer die Versuche an Krebskranken benoetigten Reagenzien, Viren und Maeusezellen, waren von der Novartis-Tochtergesellschaft Genetic Therapy Incorporated (GTI) im amerikanischen Gaithersburg produziert und tiefgekuehlt in fluessigem Stickstoff an die beteiligten Kliniken verschickt worden. "Dass die Logistik dieses Unternehmens geklappt hat, ist beeindruckend und ein grosser Schritt nach vorne", lobt Westphal.
Die Viren waren zu gross
Letztlich scheiterte der Versuch aber daran, dass die heilsamen Gene nur einen Bruchteil der Tumorzellen erreichten. Die von GTI bereitgestellten Viren waren zu gross, ihre Konzentration zu gering. Inzwischen wurde GTI einer weiteren Novartis-Tochter (Systemics) angegliedert und mit der Entwicklung besserer Genfaehren beauftragt.
Trotz des Rueckschlags hoffen die Forscher weiterhin, mit ihren Versuchen die Chancen von Glioblastompatienten zu verbessern. Sowohl in der Schweiz als auch in anderen Laendern Europas und den Vereinigten Staaten arbeiten Wissenschaftler derzeit an gentechnisch veraenderten Viren, von denen man sich bessere Resultate erhofft. Erprobt werden unter anderem Herpes,- Adeno- und dem Aids-Virus verwandte Lentiviren.
Ausserdem versucht man, mit dem Medikament Thalidomid (Contergan) den Hirntumoren die Nahrungszufuhr abzudrehen. In den Sechzigerjahren hatte der Gebrauch dieser Arznei waehrend der Schwangerschaft zu Missbildungen bei Neugeborenen gefuehrt. Nun berichteten Wissenschaftler aber auf der Jahrestagung der US-Krebsgesellschaft von einer Studie, bei der Thalidomid die Lebensqualitaet von Patienten mit fortgeschrittener Tumorerkrankung verbesserte. Nach einer im "New England Journal of Medicine" (Bd. 341, S. 1565) publizierten Studie wirkt Thalidomid auch bei boesartigen Wucherungen des Knochenmarks.
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DPA, Jan 22, 2000 |
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Gentherapien nach erstem Todesfall gestoppt
Washington (dpa) - Vier Monate nach dem weltweit ersten Todesfall durch eine Gentherapie hat die US-Behoerde FDA alle gentherapeutischen Versuche an der in den USA federfuehrenden Universitaet von Pennsylvania auf Eis gelegt.
Betroffen von der FDA-Maþnahme sind acht Studien. Fuenf davon sind laufende klinische Versuche mit Patienten, die an einer Reihe schwerer Krankheiten wie der zystischen Fibrose (Mukoviszidose) und Brustkrebs leiden, berichtete die ´New York Timesª am Samstag.
An dieser Universitaet war am 17. September der 18-jaehrige Jesse Geisinger aus Tuscon (Arizona) an Organversagen gestorben, nachdem die Aerzte sein Erbleiden genetisch zu behandeln versucht hatten. Geisinger erlag einer Immunreaktion auf das Schnupfenvirus, das das korrigierende Gen in seine Leberzellen schleusen sollte.
Bei einer Inspektion des der Uni angeschlossenen Instituts fuer Gentherapien am Menschen fand die Gesundheitsbehoerde "zahlreiche ernste Maengel" an den Vorkehrungen zum Schutz der Patienten. Das Institut ist das erste in den USA, das sich ausschlieþlich darum bemueht, Krankheiten genetisch zu kurieren.
In ihrem Bericht zitiert die Behoerde 18 Verstoeþe der Klinik gegen FDA-Bestimmungen, darunter unzureichend ausgefuellte Formblaetter. Neun der 18 Patienten, die an dem gleichen Experiment wie Jesse Gelsinger teilgenommen hatten, waren offenbar nicht wie vorgeschrieben ueber die Risiken des Experiments aufgeklaert und um ihre Zustimmung gebeten worden.
Die Entscheidung, laufende klinische Versuche auf Eis zu legen, ist in den USA hoechst ungewoehnlich. Die FDA kuendigte an, sie werde ihr Verbot nicht rueckgaengig machen, bis sie nicht davon ueberzeugt ist, dass sich das Institut in Philadelphia voll an die Vorschriften zum Schutz von Studienteilnehmern haelt.
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Reuters, Jan 22, 2000 |
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ANALYSIS-Gene therapists welcome trial suspension
By Maggie Fox, Health and Science Correspondent
WASHINGTON, Jan 22 (Reuters) - Gene therapists said on Saturday they welcomed the surprise suspension of gene therapy trials at a university where a teenager died during an experiment last month, saying it might help restore confidence in the field.
The U.S. Food and Drug Administration (FDA) said it had stopped eight trials at the University of Pennsylvania, where Jesse Gelsinger, 18, died last September during a gene therapy experiment aimed at correcting an inherited liver defect.
An FDA spokeswoman said an inspection had turned up ``deficiencies in the procedures for oversight and monitoring of the clinical trial,'' which was suspended immediately after Gelsinger's death. She said the agency was concerned other trials might have the same problems, so they were halted.
"It is clear that if violations have occurred, FDA can and should stop connected activities until these problems or issues are rectified," Inder Verma, a gene researcher at the Salk Institute in La Jolla, California, and one of the first gene therapists, said in an e-mail response to a question.
"I would have to guess that the FDA must have found some very serious breaches of regulations to warrant the action they took,'' agreed Richard Mulligan, a professor of genetics at the Howard Hughes Medical Institute at Harvard Medical School.
Gelsinger was the first person to die as a direct result of gene therapy, which doctors had considered a somewhat benign if not terribly effective approach. It uses altered genes to try to correct or cure an illness or condition.
The genes are carried into the body by a variety of means -- an altered virus, a fatty molecule, or just by themselves. With the viral approach there had always been the danger of an immune reaction, and the doctors who treated Gelsinger told a hearing at the National Institutes of Health last month that he had suffered a huge revolt of his immune system. It destroyed his liver and spleen, and badly damaged other organs.
PROCEDURES WERE VIOLATED
With the scrutiny that followed it soon became clear that the researchers had failed to follow some of the procedures that regulate gene therapy trials.
For instance, Gelsinger's admission to the trial, led by Dr. James Wilson and Dr. Mark Batshaw, was out of order.
Wilson's team treated their volunteers in batches of three. The defect they were treating, ornithine transcarbamylase deficiency (OTC), usually causes worse symptoms in males than females, so the first two patients in each batch were supposed to be women with few or no symptoms but who carried the defective gene.
Only after three patients were administered one dose safely were they supposed to raise the dose for the next batch of three. But Gelsinger was the second patient in his batch, and got the highest dose of virus in the trial.
Also, the researchers had failed to immediately notify the FDA and the Recombinant DNA Advisory Committee (RAC) at the NIH when volunteers in previous batches showed toxic reactions.
OTC causes ammonia to build up in the liver and just before he got the gene therapy Gelsinger's levels went above those allowed in the experiment, but he was treated anyway.
And in a last-minute change, Wilson's team administered the gene therapy mixture in a direct infusion to a liver artery instead of giving it intravenously.
The researchers admitted to some of the violations and apologized for them, but said they did not think they had contributed to Gelsinger's death.
Nonetheless, the FDA and the RAC, which both have authority over gene therapy trials, are proposing tighter restrictions on researchers. In addition, a hearing is scheduled next week before Sen. Bill Frist, a Tennessee Republican who chairs the Senate public health subcommittee.
SCRUTINY MAY RESTORE CONFIDENCE
Mulligan said he did not think the scrutiny endangered the field. "Although I have been involved in the very early development of gene transfer technology, and have always been a firm believer in the promise of gene therapy, I have always been concerned that the conduct of gene therapy research has not always appeared to be subject to the same rigorous standards that are generally applied to the conduct of most other scientific and medical fields of research," he said. "If there can be any positive outcome of the recent tragic events that have occurred, it may be that the field may be finally forced to address this criticism head-on."
Pharmaceutical companies that sponsor gene therapy research oppose any tightening of the rules. The Biotechnology Industry Organization (BIO) has expressed fears that trade secrets could be revealed if scientists have to make public every twist and turn of their experiments.
But Michael Werner, director of federal government relations for BIO, said the FDA's action might reassure critics that the field is properly regulated. "I think the public will have more confidence if they know the FDA will enforce the rules," Werner said in a telephone interview.
Werner said about 300 gene therapy trials had been organized since the first one in 1990. They are only just now starting to show any real efficacy.
One team has helped heart patients grow tiny blood vessels that act as heart bypasses, and another has helped three patients with hemophilia by giving them a gene that controls creation of the blood clotting agent Factor IX.
"For the hundreds of thousands or millions of people in America who suffer from genetic diseases, gene therapy is the one of the most promising types of treatment," Werner said. "Despite what happened at Penn, which obviously is a tragedy, it is important for the research and technology to go forward."
Copyright 2000 Reuters Limited
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BBC News, Feb 1st, 2000 |
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Hundreds of gene therapy experiments failed
Hundreds of failed gene therapy experiments, including a number of deaths, have been revealed in the US. The US National Institutes of Health (NIH) has confirmed that only 39 of the 691 "serious adverse events" now logged had been reported to them "immediately", as required by federal regulations.
The late reports have flooded in since the death of a teenager undergoing gene therapy last year. This prompted the NIH to send stern letters to researchers reminding them of their duty to report problems.
Financial damage
One prominent US researcher said he was worried that poor results were being kept secret because of the financial damage they could cause to the funding companies.
Professor Stuart Newman, at the New York Medical College, said: "Because of the commercialisation of this research there really is an incentive to keep secret anything that reflects badly on the progress of the work."
Gene therapy is an experimental treatment for serious diseases including cancer. DNA is inserted into the patient's cell, usually through the action of an infectious virus. Despite much research effort, no successful gene therapy treatment has yet been developed.
Fevers and paralysis
The newly-revealed failures, detailed in the Washington Post newspaper, show that many patients suffered fevers, clotting abnormalities and serious drops in blood pressure.
Problems were also caused by the medical procedures used to deliver the genetic material. Needle damage in patients being treated for brain tumours has apparently led to partial paralysis and speech impairment.
In one study taking place in a Boston hospital, three of the six patients involved died. But chief researcher Richard Junghans, of Harvard Medical School, blames the problems on tragic coincidences mostly unrelated to the gene therapy, according to the Washington Post.
Rule violations
The NIH committee is supposed to help decide the cause of any deaths or illnesses "so that appropriate measures can be taken by other researchers to safeguard the health of other patients". Because so many reports had not been properly filed, it is not now clear whether 18-year-old Jesse Gelsinger, who died in September 1999, really was the first person to lose his life as a result of gene therapy or merely the first the federal government knew about.
Gelsinger was treated and died at the University of Pennsylvania and on 21 January the Food and Drug Administration (FDA) shut down all its gene therapy experiments because of numerous violations of federal research rules.
Researchers are supposed to report problems to both the NIH and the FDA but the FDA keeps most information secret, whereas the NIH makes everything public.
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Washington Post, Feb 8, 2000 |
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More Gene Therapy Experiments Are Suspended Hospital, Patient Groups Cite Safety Concerns
By Deborah Nelson, Washington Post Staff Writer
A Harvard-affiliated medical center and two patient advocacy groups have temporarily halted gene therapy experiments because of concerns raised by the September death of a Tucson teenager undergoing treatment at the University of Pennsylvania.
Beth Israel Deaconess Medical Center in Boston decided last week to suspend its gene therapy program, while the Cystic Fibrosis Foundation and Muscular Dystrophy Association have placed a hold on three human gene experiments they are sponsoring.
Representatives of all three institutions cited general safety concerns about gene therapy that surfaced in the months following the death of Jesse Gelsinger at Penn, rather than any specific problems with their own experiments.
"The reason that we decided to temporarily hold our clinical trials is that we put patient safety first," Michael Rosenblatt, interim president of Beth Israel Deaconess, said yesterday. "We want to benefit from the national discourse."
Gelsinger's was the first death attributed to gene therapy, a 10-year-old science that has attempted--so far without success--to treat cancer, AIDS and inherited diseases by altering people's genetic makeup.
Since then, the Food and Drug Administration temporarily suspended Penn's gene therapy program after uncovering numerous safety lapses in the clinical trial that killed Gelsinger; the National Institutes of Health discovered that gene therapy researchers elsewhere had failed to promptly report more than 600 illnesses and deaths among gene therapy volunteers to the agency as required; and Sen. Bill Frist (R-Tenn.) initiated hearings last week on whether the federal government's oversight of gene therapy is adequate.
The decision by Beth Israel Deaconess came less than a week after The Washington Post reported that the hospital had failed to immediately notify the NIH about three deaths and one serious illness among the first seven volunteers in another gene therapyexperiment involving terminally ill cancer patients. Both Rosenblatt and the researcher said they did not know they were supposed to notify the NIH, which makes such information public, in addition to the FDA, which does not.
Federal regulations require researchers to report all deaths and serious illnesses among gene therapy volunteers to the NIH regardless of whether they are caused by the gene therapy, the underlying illness or something else. In this case, the lead researcher decided that earlier health problems caused the three deaths shortly after treatment, but that the therapy likely caused high fever and severe heart problems in a surviving volunteer. The medical center suspended the experiment following the serious illness last summer and had planned to restart it this month with an improved protocol.
Now, however, Rosenblatt said, the experiment won't resume until he gets some sort of signal from the FDA and the NIH that they consider gene therapy safe and will continue to support it. In addition, he said, he has stopped the one other gene experiment at the medical center, involving hemophilia patients, even though there have not been any deaths and only one serious but unrelated illness eight months after treatment.
NIH and FDA officials are exploring whether they need to improve the way gene therapy experiments are approved and conducted, as well as whether they should change the way adverse events are reported to the public.
"What we will be looking for is a reaffirmation of the commitment [to gene therapy] from these agencies," Rosenblatt said.
Representatives of the Muscular Dystrophy Association and Cystic Fibrosis Foundation also said they are waiting to see what comes out of regulators' discussions and the Senate hearings before proceeding.
The Muscular Dystrophy Association stopped an experiment it is sponsoring at Ohio State University that used a genetically engineered virus manufactured at Penn. The study was the first, long-awaited gene experiment on people with muscular dystrophy.
The FDA action against Penn had already stopped one of the two gene experiments sponsored by Cystic Fibrosis Foundation that used the same type of altered virus that killed Gelsinger. Ronald Crystal of Cornell University Medical College suspended the other one at the request of the Cystic Fibrosis Foundation.
© Copyright 2000 The Washington Post Company
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The Associated Press, Feb 11, 2000 |
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Experiment May Have Exposed to AIDS
WASHINGTON -- A gene therapy experiment may have inadvertently exposed more than two dozen young cancer patients to the virus that causes AIDS, The Washington Post reported.
Researchers at St. Jude Children's Research Hospital in Memphis and Baylor College of Medicine in Houston discovered the accidental exposure in December, but did not inform federal regulators until last week, the Post said Friday. The researchers began contacting patients and their parents about the possible infections Thursday.
The newspaper reported that researchers and federal officials said early testing of the gene-based medicine may have been contaminated with HIV-1, the virus that causes AIDS, and HCV, which causes hepatitis C.
Two subsequent tests found no contamination, indicating that the first results might have been false. The Food and Drug Administration is now conducting more reliable tests and is looking into possible laboratory problems and the timing of the reporting, the Post said.
While testing continues, researchers have ended the study.
Deidre Malone, St. Jude's public relations director, would not comment on the Post report other than to say the hospital would have a statement Friday.
Laura Bowman, the study's principal investigator at St. Jude, was quoted by the Post as saying that all of the volunteer cancer patients were near death and only a handful of the 20 patients she treated are alive today, the rest having died from their cancer.
The National Institutes of Health was already investigating St. Jude for its handling of patient deaths in a different study, the Post said.
The cancer patients suffered from neuroblastoma, a brain cancer that is the second most common childhood malignancy. The experimental therapy involved removing a patient's own tumor cells and inserting an immune system gene with a gene-altered virus. The modified cells were put back in the patient to galvanize the immune system to fight the cancer.
Bowman said she discovered last fall that the two most recent volunteers a child and a teen-ager treated a year ago received viruses that had been processed incorrectly and could have been contaminated.
She said she could find no evidence that the original batch of cells from 1995 used to grow the viruses had been properly screened for contamination. In November, she sent cells from the original batch for testing at an outside lab, which sent back results that twice showed the presence of DNA from HIV and HCV.
She said she decided to contact the FDA last week when further test results were slow to arrive.
Malcolm Brenner, who initiated the study while at St. Jude and continued the work at Baylor, told the Post he doubted the initial test results, but if the contamination was real it could have been caused by HIV-infected blood in the laboratory being accidentally splashed on the viruses.
The surviving volunteers would probably only need AIDS testing if further tests confirm the contamination, Bowman said.
© Copyright 2000 The Associated Press
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Washington Post, Feb 11, 2000 |
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Exposures Not Revealed in Gene Therapy Trial
By Rick Weiss and Deborah Nelson, Washington Post Staff Writers
Researchers discovered in December that they may have accidentally exposed more than two dozen young cancer patients to the virus that causes AIDS in a gene therapy experiment, but did not inform federal regulators until last week.
Only when it became clear that the potential problem was about to become public yesterday did the researchers at St. Jude Children's Research Hospital in Memphis and Baylor College of Medicine in Houston start contacting patients and their parents about the possible infections.
Preliminary tests on the gene-based medicine that was administered to young volunteers suggest that the treatment may have been contaminated with HIV-1, the virus that causes AIDS, and HCV, which causes hepatitis C, the researchers and federal officials acknowledged yesterday.
Although two successive tests have so far found evidence of contamination, scientists and government officials emphasized yesterday that the scare might prove to be a false alarm. The tests that have been performed so far are extremely sensitive and prone to giving "false positive" results on the kinds of samples used. New and more reliable tests are now being conducted by the Food and Drug Administration. In the meantime, the study has been terminated.
In the wake of several other recent revelations about the failure of several gene therapy research institutions to report patient deaths and illnesses properly, the incident again raises questions about the fledgling field's ability to protect patients adequately and comply with federal regulations.
In January, the FDA shut down the University of Pennsylvania's prestigious gene therapy program after an agency investigation uncovered multiple serious lapses in patient protections that may have contributed to the death of an 18-year-old volunteer - the first death attributed to gene therapy. National Institutes of Health officials subsequently revealed that hundreds of deaths and other "adverse events" in gene therapy trials had gone unreported to that agency, despite federal rules that require such events to be reported immediately.
The new case also adds to St. Jude's troubles with the National Institutes of Health, which was already investigating the medical center for its handling of patient deaths in a different clinical study and which has had problems with bacterial contamination of some bone marrow preparations.
Scientists involved in the new case described a series of oversights and mistakes dating to 1995 that led to the current alarm. The treatment was designed for patients with neuroblastoma, a brain cancer that is the second most common childhood malignancy. It called for a patient's own tumor cells to be removed and enhanced with an immune system gene inserted by a gene-altered virus. Those cells were then reinjected into the patient in an effort to rally the immune system against the cancer.
Laura Bowman, the study's principal investigator at St. Jude, said she was reviewing the laboratory's quality control program last fall when she discovered that the two most recent volunteers - a child and a teenager treated a year ago - received genetically engineered viruses that had not been processed correctly. That lapse could increase the odds of contamination with foreign viruses.
Bowman looked for documentation showing that the original, 1995 "master batch" of cells, in which the engineered viruses were grown, had been properly tested for contaminating viruses, such as HIV. She could not find any evidence that those tests had been performed as required.
In November, she sent some of the lab's gene-altered viruses grown from that "master batch" of cells to an outside laboratory for testing. Twice those tests indicated the presence of DNA from HIV and HCV. When further test results were slow in coming, she said, she decided to contact the FDA last week.
Both Bowman and Malcolm Brenner, who initiated the study while at St. Jude and has continued the work at Baylor, said tests on viruses for contaminating viruses are notoriously prone to false positives, and they doubt the results are accurate. More accurate follow-up tests are being conducted on the cells upon which the viruses were grown.
If the master batch does prove to be contaminated with deadly viruses, Brenner said, it may be that some HIV-infected blood in the laboratory somehow got accidentally splashed on the viruses. Alternatively, Bowman said, some contaminating viruses may have become mixed with the study viruses when the immune system gene was first inserted.
All the volunteers were close to death from recurrences of their cancers, Bowman said. Only a handful of 20 patients she treated are alive today, Bowman said. Of six treated at Baylor, four remain alive. All the deaths were from cancer, the researchers said.
Bowman said AIDS testing of surviving patients would probably be recommended only if further tests confirm the contamination. But she and Brenner said that when researchers found out yesterday that The Washington Post had learned of the problem, they decided to contact patient families immediately.
FDA officials yesterday said that in addition to conducting tests on the viruses, the agency is looking into the possible laboratory problems and the timing of the reporting.
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FDA Says No Contamination of Gene Therapy Viruses
WASHINGTON (Reuters) - Government tests on a batch of viruses used to make an experimental gene therapy treatment given to children at a Memphis hospital showed no signs they were contaminated with the AIDS or hepatitis C viruses, officials said on Thursday.
Scientists at St. Jude Children's Research Hospital had feared they may have accidentally exposed 17 children to HIV and hepatitis C when tests suggested the batch of master cells they used were contaminated.
Researchers reported the findings to federal authorities this month but cautioned that their tests were especially sensitive and could have provided a false alarm.
The FDA used tests that were newer and more reliable than the ones St. Jude's used. An FDA spokesman said Thursday the agency's tests were negative.
"We've finished our analysis. It turned out negative for both HIV and hepatitis C", the spokesman said, adding that the agency had no further comment.
St. Jude's original test results came to light as part of the intense scrutiny on gene therapy, in which researchers aim to treat or cure diseases with healthy genes. New attention to the decade-old field has come since the September death of 18-year-old Jesse Gelsinger, the only person believed to have died from gene therapy.
Federal officials have since found researchers were underreporting so-called adverse events in gene therapy trials and have urged scientists to come forward with the information promptly. St. Jude discovered possible contamination in December and reported it in February.
Dr. Laura Bowman, who led the St. Jude study, said last week she worried that making incidents available to the public too quickly, before they could be fully understood, might scare people from volunteering for studies. Industry groups and scientists have expressed similar concerns. Bowman was not immediately available for comment Thursday.
In the St. Jude study, researchers were trying to treat a brain cancer called neuroblatoma by injecting a virus combined with an immune system gene that they hoped would rouse the body to fight tumors. All of the patients were close to death from cancer at the time, and only four are still alive.
The trial was stopped in January after Bowman's tests on a "master batch" of viruses showed possible contamination by HIV, the virus that causes AIDS, and the virus that causes hepatitis C, a liver disease.
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Gene therapy halts HIV in cell-based study
NEW YORK, Feb 21 (Reuters Health) -- Brandishing a new weapon in the war against HIV/AIDS, researchers say they have used gene therapy to interrupt the replication of the virus in cells taken from infected patients.
``These results suggest that, with further work, this technique may keep HIV-infected patients free of disease symptoms,'' said study senior author Dr. Wenzhe Ho of The Children's Hospital of Philadelphia, in Pennsylvania. The findings are published in the journal Gene Therapy.
In gene therapy, genetic material is introduced into a patient's cells to take over the function of a faulty or missing gene.
According to a statement issued by the hospital, Ho's team focused their efforts on HIV's 'tat' gene, essential for the replication of the virus within cells.
The researchers developed an 'antitat' gene, designed to disable proper tat function. In experiments conducted in the laboratory, they then used a (harmless) mouse retrovirus to 'piggyback' antitat into HIV-infected laboratory-cultured cell lines, as well as immune cells taken from HIV-infected patients.
The result? ``The antitat gene inhibited HIV activation and replication'' in both the cultured cell lines and the patients' immune cells, according to the hospital statement. The gene therapy also bolstered the survival of CD4+ T lymphocytes, important immune cells that are also the favorite target of HIV.
While the technique worked in cells in the lab, the Philadelphia team stresses that much more work needs to be done to see if it can successfully suppress HIV activity in humans. And study co-author Dr. Stuart E. Starr noted that ``since potential safety issues exist with gene therapy, the next step will be to test the antitat strategy in animal models.''
Still, the research could signal the advent of a whole new method of treating HIV. Today, many -- but not all -- patients infected with the virus can reduce their viral load to near-undetectable levels using powerful combination drug therapies. These therapies are very expensive, however, and carry a risk of side effects. Furthermore, HIV usually rebounds to pre-treatment levels once patients go off their medication.
In contrast, ``the antitat gene offers the possibility of prolonging the (viral suppression) period indefinitely without the need for long-term antiretroviral treatment,'' Starr said. He also noted that ``early indications are that the antitat gene does not affect uninfected cells or cause toxic side effects.''
SOURCE: Gene Therapy February, 2000.
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Gene Experiment Helps Hemophiliacs
By JOSEPH B. VERRENGIA AP Science Writer
Amid controversy over the risks of gene therapy, scientists reported that an experimental gene-replacement procedure appears to improve blood clotting in hemophiliacs without triggering complications.
Researchers at Children's Hospital of Philadelphia and Stanford University cautioned that their success in treating hemophilia B, a relatively rare form of the illness, was encouraging but preliminary.
Just three patients participated in the experiment, in which researchers injected patients with a healthy gene to stimulate production of a blood-clotting protein. An expanded trial with more patients and higher doses is under way.
If the method continues to work, it would be one of the few successful genetic treatments of any disease since the approach was introduced a decade ago.
The new gene's effect is ``modest, but measurable,'' said Stanford geneticist Mark A. Kay, who led the study. ``It changes from severe disease to moderate, which really increases the quality of life for the individual.''
The hemophilia study appears in the March issue of Nature Genetics amid a public backlash against gene therapy. The outcry was prompted by the death last September of a Phoenix teen-ager who had volunteered for a different gene experiment.
Jesse Gelsinger, 18, was the first person believed to die as a direct result of a genetic experiment. Researchers at the University of Pennsylvania had infused his liver with a gene therapy aimed at reversing a rare metabolic disease. The procedure triggered an extreme immune-system reaction that caused multiple-organ failure.
In recent weeks, several leading scientists, including Caltech president and Nobel laureate David Baltimore, have questioned whether gene therapy is too risky. And the National Institutes of Health, which funds gene therapy research, is evaluating 400 trials conducted with more than 4,000 patients.
Other geneticists said the hemophilia B study in Nature Genetics, while not conclusive, is a confidence-builder.
``What I like is that it was a very low-risk study,'' said Baylor College of Medicine geneticist Arthur Beaudet. ``There is a lot of uncertainty in the field now. It's reassuring to see some positive studies.''
About 5,000 Americans suffer from hemophilia B. They produce insufficient levels of a clotting protein known as Factor IX. As a result, blood leaks into their joints. Many patients are disabled by age 30.
Researchers believe hemophilia B is suitable for gene therapy because the factor IX gene is small and a healthy copy can be easily substituted.
Also, levels of factor IX as low as 1 percent of normal can improve blood clotting, so the new gene does not have to work perfectly to be effective.
Researchers injected a healthy factor IX gene into the patients' thigh muscles. The gene had been incorporated into a low dose of a simple virus that has never been associated with human disease. As the virus spread, it copied the healthy gene into the patients' cells.
Tthe healthy gene was producing effective levels of factor IX in two patients within 12 weeks. Their reliance on clotting medication was reduced 50 percent 80 percent. The third patient showed no improvement.
In Gelsinger's death, Penn researchers used a different virus - one that was known to stimulate a more vigorous response from the immune system. Also, they injected a higher dose directly into the youth's bloodstream.
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FDA Stops Researcher's Human Gene Therapy Experiments
By Deborah Nelson and Rick Weiss, Washington Post Staff Writers
The Food and Drug Administration has halted four human gene therapy experiments conducted by a leading researcher who was trying to grow new blood vessels in patients with heart disease and other circulatory problems.
Neither the FDA nor the company sponsoring the experiments would provide a detailed explanation of why the agency had stopped the experiments, which were led by Jeffrey Isner of Tufts University School of Medicine and St. Elizabeth's Medical Center in Boston.
The move comes on the heels of disclosures that Isner failed to promptly report the deaths of two volunteers to the National Institutes of Health as required by federal rules. Isner has said the deaths were not related to the treatment. But Vascular Genetics of Durham, N.C., a company founded by Isner to commercialize the technology, recently acknowledged that one of those deaths remains unexplained.
The FDA's move against Isner's research marks the second time in two months that the agency has put human gene experiments on hold. In January, the agency suspended the University of Pennsylvania's high-profile gene therapy program after a federal investigation into a teenage patient's death there uncovered scientific and regulatory lapses.
The field of gene therapy, in which researchers give patients new genes in an effort to cure cancer or other disorders, has been roiled with controversy since the September death of that youth, Jesse Gelsinger--the first death directly attributed to gene therapy. In the weeks after Gelsinger's death, The Washington Post revealed that Isner and another gene therapy researcher, Ronald Crystal of Cornell University Medical Center in New York, had not reported patient deaths in compliance with NIH rules.
A subsequent inquiry from Congress revealed that other gene therapy researchers had similarly failed to report hundreds of "adverse events," including many deaths, prompting both the FDA and the NIH to start developing strategies for increasing compliance with federal research rules. Meanwhile, some researchers have begun to wonder openly whether the fledgling field, which has failed to produce a single cure in 10 years of efforts on thousands of patients, can survive much more airing of its problems.
The latest action involves two experiments in which scientists gave new genes to patients with coronary artery disease in an effort to help them grow fresh vessels to increase blood flow to their hearts, and two experiments for patients with painful vessel problems in their limbs. Unlike the Penn study, which used potentially toxic viruses to deliver new genes to patients, Isner's studies infused raw, or "naked" DNA into patients' vessels. The approach has been touted by some as being safer than those using viruses.
John Cumming, president of Vascular Genetics, said researchers in three of those four studies had recently enrolled and treated their final volunteers. But he was told by the FDA last week that the company must stop enrolling or treating patients in its large, ongoing heart study, which was taking place at medical centers around the nation. That study was the one in which the unexplained death occurred last May, less than 24 hours after the gene infusion.
Cumming would not talk about the FDA's specific concerns except to say that the agency had requested additional data relating to the fate of the gene in patients' bodies. He said he did not think that the FDA's action reflected any agency concerns that the treatment might have caused any of the patient deaths (a third death, in one of the limb vessel studies, occurred and was promptly reported last fall). Rather, he said, the move reflected generic concerns about the study that the company was already addressing.
"We're putting together a full presentation for the FDA," Cumming said. "Our philosophy is to err on the side of thoroughness. We are very comfortable with the data."
Cumming said the company had hoped to use the heart study's results to gain FDA approval for a larger and final "pivotal" study, which could lead to eventual marketing approval of the treatment. With only about three-quarters of the intended volunteers enrolled to date, he said, and no clues about whether or when the FDA might eventually allow the study to continue, it was not clear whether the company would succeed in getting that study approved this year.
FDA officials said it is the agency's policy not to comment when it puts an experiment on "clinical hold," the technical term for the open-ended suspension order imposed on the Isner experiments.
Inder Verma, a gene therapy researcher at the Salk Institute in La Jolla, Calif., and president of the American Society for Gene Therapy, said yesterday he had not heard about the FDA's action against the Isner study but that the field of gene therapy badly needed to regain a level of public trust. "If people have not done the right thing," he said, "then they need to be held responsible."
Vascular Genetics is being heavily underwritten by Human Genome Sciences Inc., a Rockville biotechnology company that owns patent rights on the gene, called VEGF-2, being studied in all four closed experiments. William Haseltine, chairman and chief executive of Human Genome, said he did not foresee major problems from the delay.
"Basically it's routine," he said. "It's a request for more and better pharmacology to measure blood levels of VEGF-2. We think there's going to be no trouble complying."
Staff writer Justin Gillis contributed to this report.
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FDA To Enforce Gene Therapy Safety
By LAURAN NEERGAARD AP Medical Writer
WASHINGTON (AP) - The Food and Drug Administration will begin forcing scientists to monitor patient safety better during gene therapy experiments and conduct surprise inspections to make sure researchers follow the rules.
The FDA made the announcement Tuesday amid growing criticism of lax government oversight of gene therapy experiments, including one that killed an Arizona teen-ager last fall.
Federal regulations already require that researchers establish patient-safety monitoring systems before putting experimental treatments to the test. But the FDA acknowledged Tuesday it has not enforced the rules for gene therapists.
Indeed, in the University of Pennsylvania experiment that killed 18-year-old Jesse Gelsinger, ``there were deficiencies in the monitoring,'' said FDA gene therapy chief Dr. Kathryn Zoon.
Pennsylvania researchers didn't have a formal patient monitoring system, something FDA said it discovered only when it inspected the hospital's gene therapy lab after Gelsinger died.
Under FDA's new initiative, all gene therapy researchers must appoint someone not directly involved with their experiments to monitor patient safety. The monitors could comprise contract research organizations or other scientists at a hospital or university.
The monitors are not truly independent - the gene therapists hire them.
But the FDA pledged to ensure gene therapy monitors are working and know the law requires them to report patient-safety problems to the government - and to conduct random, surprise inspections to make sure.
Experiments that don't comply can be halted.
``We believe these are important steps ... to ensure patient safety,'' Zoon said.
The initiative sparked a mixed reaction.
``They were supposed to be doing that already,'' said bioethicist George Annas, a Boston University professor of health law. ``FDA has let this get out of hand. ... They don't inspire a lot of confidence.''
He questioned whether FDA inspectors had the time or expertise to oversee how more than 350 gene therapy experiments now under way are conducted.
But another critic welcomed the change.
``The patient-safety monitoring is the most important element that's been missing in all of this,'' said Abbey Meyers, president of the National Organization for Rare Disorders and a former National Institutes of Health gene therapy adviser.
Today, gene therapists can conduct experiments for years without anyone checking how their patients fared, Meyers said. So FDA inspections are vital, but the agency lacks the money and people, she said.
``The FDA's budget has been raped, absolutely raped, over the last 10 years,'' Meyers said. ``Congress has got to give them the money to do this job right.''
The FDA employs between 150 and 200 clinical trial inspectors, but they never have been asked to judge patient-safety monitoring in early-stage experiments or to focus on gene therapy instead of the many other types of human experiments now under way.
Gelsinger's death is the only one so far blamed directly on gene therapy, among experiments on about 5000 patients in 10 years.
This new field has not cured anyone yet. And the NIH has discovered hundreds of adverse reactions patients suffered that researchers delayed reporting to government experts who oversee the experiments' safety.
Thus, some critics say gene experiments should temporarily be halted until closer oversight is established.
``We're doing a lot of premature human experimentation here that's more trial-and-error than hypothesis testing,'' Annas said. ``This is very important research. I don't want to see it tarnished in the public's view'' because it was done wrong.
Also Tuesday, the government announced it will bring together the nation's most experienced gene therapists to debate how best to ensure patient safety. And the FDA said it is preparing a new regulation to force disclosure of serious side effects so the public understands the risks.
On the Net: FDA statement at http://www.fda.gov/bbs/topics/NEWS/NEW00717.html
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Caution Over Gene Therapy Puts Hopes on Hold
By Rick Weiss,Washington Post Staff Writer
Like most 2-year-olds, Max Randell is a bundle of exuberance, gaining new mastery over the world with every passing day. But unlike most children his age, Max has just about reached the prime of his life.
Max has Canavan disease, a rare inherited disorder that destroys young brains, dragging toddlers into a near coma by age 4 and typically killing them before the age of 10. The Chicago-area boy's parents believe that his only hope for any semblance of a childhood is an experimental gene therapy developed at Jefferson Medical College in Philadelphia, now under federal review.
But given gene therapy's many troubles of late--including a teenage patient's death in Philadelphia and revelations of numerous research lapses at other sites around the country--Max's doctor and parents fear that officials will demand extraordinary evidence that the Canavan treatment is ready for human testing, and perhaps withhold a go-ahead until it's too late for Max.
"I hate that all this happened right now," said Max's mother, Ilyce, speaking of the current wave of negative attention on gene therapy. "We don't have the luxury of waiting."
That urgency infuses an emotional debate that has drawn federal regulators, scientists and patients into what amounts to a rare public tribunal over an entire branch of experimental medicine. At stake is gene therapy's scientific credibility, and perhaps even its economic future, in what experts are calling the "post-Gelsinger era." The term refers to Jesse Gelsinger, whose September death at Penn marked the first death attributed to a gene therapy experiment and a turning point in public confidence in the field.
On one side are those who believe that gene therapy has become something of a rogue branch of medical science in which patients, their families and even some doctors have become deluded by unrealistic hopes--and by hype from gene therapy's growing cadre of scientist-investors and venture capitalist backers.
With the decade-old field still lacking a single cure and facing numerous questions about financial conflicts of interest, some critics are even calling for a temporary halt to gene therapy pending further studies in animals and a review of ethics rules.
"No one seems ready to start saving lives, and it's too valuable an area of research to not do it right and to lose the public confidence," said George Annas, a professor of health law and bioethics at Boston University. "I say take a voluntary moratorium."
On the other side are many scientists, patients and family members who acknowledge that the field has had a few mishaps but who believe it's been unfairly tarnished by overly close news media scrutiny and by activists opposed to genetic research. If the negative rhetoric doesn't stop soon, these supporters warn, the field may get curtailed just as it's about to produce results.
"The controversy has gotten so overblown," said Carl Feldbaum, president of the Biotechnology Industry Organization. "That could hurt the very people we're trying to help."
Both views will be aired at a three-day National Institutes of Health meeting beginning tomorrow at which officials will consider the Canavan treatment along with broader questions about how best to regulate gene therapy.
Few experts believe that NIH will endorse a moratorium on gene therapy. But there is evidence that the past six months' events may already be taking a toll on the beleaguered specialty's supply of volunteers. A gene therapy experiment for cystic fibrosis at Johns Hopkins University School of Medicine, for example, has now gone several months with no patients, said Pamela Zeitlin, a professor of pediatrics who is running the study.
Zeitlin had no trouble attracting volunteers for an earlier version of the study, and she had planned to start the new version in December. But because of trouble finding willing patients, the first volunteer will be treated just this month. Meanwhile, many asked about Gelsinger's death and never returned.
"We've had many more potential volunteers with concerns about risk," Zeitlin said, "or who planned to start and then had second thoughts and didn't enroll."
Scientists at other gene therapy centers said it's too soon to say whether the current climate of distrust is slowing enrollment. Indeed, some noted, if some patients are thinking twice about getting new genes, others are responding to gene therapy's crisis in just the opposite way: by scrambling to get into studies before a feared crackdown occurs.
When a Boston research hospital last month responded to all the attention on the field by temporarily halting its hemophilia gene therapy experiment, for instance, patients with the bleeding disorder seethed with anger. Beth Israel Deaconess Medical Center said it suspended the study to make sure that no potential risks to patients had been overlooked. But the study had already been fully approved and had experienced no problems, suggesting to angry critics that the shutdown, which was reversed two weeks later, represented a capitulation to a mere wave of fear.
"It sent a very bad message, a terrible message," said Michael Coyne, a Pittsfield, Mass., board member of the National Hemophilia Foundation whose 9-year-old son, Conor, has the clotting disorder. "If a trial is going to be shut down, it should be shut down for medical rationale, not political rationale."
That reaction miffed hospital officials, who complained that all the hoopla surrounding gene therapy had left them trapped between competing pressures.
"What if we say, 'Damn the torpedoes, full speed ahead, everything is fine!' And what if something had happened to someone in those two weeks?" asked Michael Rosenblatt, Beth Israel's interim president. "Would patients still support the hospital then?"
Abbey Meyers, president of the National Organization for Rare Disorders, was equally upset with hemophilia patients' desperate demands for access--but for a very different reason.
"These people are disappointed that this is going to delay their treatment, but they don't understand there has been a betrayal here," said Meyers, a former member of the NIH gene therapy oversight committee, which is meeting this week in Bethesda.
"They haven't been told the truth," Meyers said, about how unlikely it is that they will be helped, or about the risks of participating. "We've got to get some rules around this to make sure it's being done properly."
Biotechnology industry representatives have already said they are willing to impose upon themselves new rules to allay public concerns. And a recent letter to medical research leaders from Jordon Cohen, president of the Association of American Medical Colleges (AAMC), said the association would embark upon several initiatives to reverse the "erosion of public trust" that had been prompted by recent events.
But some critics are concerned that the proposed changes may prove more cosmetic than substantial. One federal health official, speaking on condition of anonymity, was especially critical of the Feb. 18 AAMC letter, calling it a blueprint for "damage control" instead of a proposal to more thoroughly protect medical volunteers.
The letter describes plans for a conference call among the deans of medical centers recently targeted by the FDA, with the goal of learning how federal investigators conducted their inquiries. That information should be used to develop a "strategic response plan," the letter said, to help other institutions develop more effective public communications in the event they come under similar scrutiny.
Moreover, the letter stated, the association had scheduled a meeting with The Washington Post's editorial board, and would help coordinate "other media outreach activities as appropriate."
"I wouldn't call it 'damage control,' it's just about good communication," Cohen said in an interview last week, noting that the letter also describes planned efforts to educate scientists about federal regulations. "We need to get the facts out there so people are not operating on rumors or bad information."
But if the facts are that gene therapy is not working and may even cause harm, then those facts are not likely to emerge from a young field that is under growing financial pressures to succeed, Meyers and other critics said.
Perhaps, some said, that explains why so much was made last week of some very preliminary findings from a gene therapy study of hemophilia, published in the journal Nature Biotechnology.
Results of the study, which involved only three patients, rained upon news organizations in the form of faxes and repeated phone calls made by a public relations company hired by Avigen, a California biotechnology company that sponsored the research. According to a company news release, "even the lowest dose is effective."
Yet the amount of clotting factor found in the gene-treated patients' blood was barely detectable, outside scientists said. And the measure of clinical effectiveness used in the study--essentially patients' personal assessments that they were feeling less pain--was all but invalid, experts said, because the patients knew they'd received a new treatment. Volunteers who know they've received a new drug predictably report feeling better, because of the so-called placebo effect.
Declarations of the treatment's "efficacy," said the University of Michigan's Randy Kaufman, a hemophilia expert who cloned the gene involved in the most common form of the disease, are "a lot of hype."
Still, experts said, it's difficult to ignore the wishes and demands of patients and their family members, including Ilyce Randell, who want their personal shot at the latest that medicine has to offer.
The experiment that Randell craves would involve an injection of genetically engineered viruses directly into Max's brain. It has never been tried in people, and the goal for now is just to see if it causes damage, not to see if it can actually protect dying brain cells.
Randell said she understands that distinction, and that participation in this kind of study is really for the good of future patients. But her words also illustrate how difficult it can be for a patient or parent to stop hoping.
"We're at the point where Max is almost 2 1/2, and soon he's going to start losing ground," Randell said. "He can't wait until winter to be treated."
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Parents' Plea Illustrates Gene Therapy Dilemma
By Maggie Fox, Health and Science Correspondent
BETHESDA, Maryland (Reuters) - A desperate, emotional plea on Thursday from the parents of a brain-damaged daughter who say gene therapy is her only hope illustrated the dilemmas facing government advisers.
Lindsay Karlin, now 5, suffers from a genetic disorder known as Canavan disease. She has been a patient in several experimental gene therapy trials and her parents, Dr. Roger Karlin and his wife, Helene, of New Fairfield, Connecticut, believe the experiments have helped her.
Given a chance to speak at a meeting of National Institutes of Health (NIH) advisers who were meeting to discuss a proposed new gene therapy experiment for Canavan disease, they pleaded for speedy approval.
``Our children have an ethical right to this treatment as long as it is safe,'' Helene Karlin, a child psychologist, told the Recombinant DNA Advisory Committee (RAC). ``If you do not pass this protocol, you are giving them a death sentence.''
Scientists are used to hearing such pleas from desperate parents. But the Karlins say they are different from many of the families of volunteers in experimental trials.
Karlin is himself a doctor, a specialist in internal medicine. He and his wife say they are entirely familiar with the scientific method and understand why research often proceeds so slowly and carefully.
But that very deliberation, they say, could cost their daughter her life.
Canavan disease, also known as Canavan's leukodystropy, is relatively rare, affecting about one in 6,000 births. It is caused by a defect in the gene controlling the enzyme aspartoacyclase.
This enzyme breaks down N-acetylaspartic acid. When N-acetylaspartic acid builds up in the brain, it damages brain cells. Children usually die of it by the age of 5.
There was no treatment until researchers tried out gene therapy. Paola Leone and colleagues at Thomas Jefferson University in Philadelphia are applying for permission to start a new trial using a virus to carry new copies of the aspartoacyclase gene into patients' brains.
The RAC is one of the groups that advises the government on whether to approve such trials.
At the same time, the RAC is talking about ways to strengthen government oversight of such trials. Since the death last September of Jesse Gelsinger, 18, in a gene therapy trial, the field has been under fire and government regulators have said they planned to tighten enforcement of safety rules.
Some trials have been suspended, and several teams of investigators have voluntarily stopped or suspended trials while they double-check procedures.
To some scientists, the obvious answer is for researchers to report everything that goes wrong, immediately, so it can be discussed and decided whether the gene therapy is to blame.
But private corporations, who sponsor many of the trials, fear that releasing such information would not only confuse people, but would give away valuable clues.
``One phrase they used was that deaths of patients was a trade secret ... proprietary information,'' Ruth Macklin, a bioethicist at Albert Einstein College of Medicine in New York, who heads a subcommittee discussing the issue, said.
She said there is ``sharp disagreement'' over what should be reported and to whom. Currently, scientists say they are confused about what they should report to the Food and Drug Administration (FDA), what they should tell the NIH, and when.
``This is a first step toward trying to harmonize reporting to the NIH and the FDA and to lay out a framework for what should be reported,'' Macklin said in an interview.
This week's meeting would not lead to any final decision, she said. ``Whatever happens here is one piece of the puzzle.''
Meanwhile, for families like the Karlins, the clock is ticking.
``Every day we wait, their brain cells are deteriorating,'' Karlin said.
Lindsay started showing symptoms of the condition when she was 2 or 3 months old, Karlin said. ``One of the things was being out of it, being stoned almost,'' he said.
She lost the ability to lift her head or to track objects with her eyes.
But after the first gene therapy treatment, which used liposome or little fatty capsules to carry the new gene into her brain, she showed a dramatic improvement. ``She became a new child. This happened within a month of gene therapy,'' Karlin said.
But the treatment gradually wore off.
Each time Lindsay got a new treatment, the Karlins noticed marked changes. Physical changes could be seen in her brain, too, Karlin said.
Karlin said he had studied information about the new adeno-associated virus vector, and he believed it offered a much more effective way of getting the corrective gene into the brain. ``The risk-benefit ratio here is incredible,'' he said.
``My daughter can hold her head up,'' Helene Karlin added. ''My daughter has been helped by the gene, and had she not had the gene, I believe she would be dead now.''
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U.S. Experts Reject Halt to Gene Therapy
By Maggie Fox, Health and Science Correspondent
WASHINGTON (Reuters) - Scientists and other experts who advise the federal government on gene therapy issues rejected calls for a moratorium on experiments on Friday, but also warned researchers and patients against placing undue faith in the field.
Gene therapy has been under fire since the death last September of a teen-ager in an experiment, and subsequent revelations about researchers who have broken rules about protecting patients and reporting ``adverse events'' to regulators.
Jeremy Rifkin, a writer and president of the Foundation on Economic Trends, who has campaigned against many aspects of biotechnology, on Friday urged the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health to vote for a temporary halt of gene therapy experiments.
``It's now time to reevaluate a field of research that's run amok before any more people die needlessly,'' he said in a written submission to the panel.
``The fact is, after 10 years of human trials, adverse effects continue to mount, more patients are dying, more questions about safety and toxicity are being raised, and many researchers acknowledge that they are no closer to finding the answers.''
Experts in gene therapy say they have been unable to document any cure from the treatment -- which involves infusing new genes into the body to treat disease. But several experiments have shown what appear to be positive effects, especially in treating hemophilia and heart disease.
However, Rifkin said researchers do not fully understand the risks involved in using viruses to carry new genes into the body.
``In the final analysis, biotech research will be better served if we implement a ... moratorium on the use of viral vectors in ... gene therapy trials,'' he said.
A subcommittee of the RAC rejected Rifkin's arguments. The RAC has been meeting this week to consider proposals for new gene therapy experiments and discuss possible way to make the filed safer.
``The working group does not consider the proposal from the Foundation for Economic Trends to be necessary or helpful to the goals of improving safety and strengthening oversight in gene transfer research at this time,'' the group, headed by bioethicist Ruth Macklin of Albert Einstein College of Medicine in New York, said in a statement.
But the RAC agreed that monitoring of gene therapy should be tightened and warned that many people have inappropriate faith in a field that is still in its ``adolescence''.
``It is important for investigators and oversight bodies in gene transfer research to resist the temptation to exaggerate the potential for benefit and to overlook excessive risk out of the desire to help desperately ill patients, because at present the possibility of benefit from this novel technology is, on the whole, still too uncertain,'' Macklin's group said.
Earlier this week the Food and Drug Administration (FDA) said it would tighten scrutiny of the monitors that are supposed to keep an eye on gene therapy trials involving people, and the NIH said it was starting a series of symposiums to help gene therapists exchange information about safety issues.
Several patients taking part in gene therapy trials, or the parents of patients, pleaded with the RAC to press to keep experiments moving, saying that for many patients, gene therapy was the only hope.
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Gene Therapy Panel Doesn't Vote
By PAUL RECER, AP Science Writer
WASHINGTON (AP) - An advisory committee to the National Institutes of Health debated a proposal calling for a moratorium on human gene therapy experiments, but then adjourned without taking a vote.
The proposal, formally presented to the committee Friday by a Washington activist group, called for a halt to gene therapy experiments except as a ``last resort for life threatening illness.''
The motion by the Foundation of Economic Trends cited the death last fall of a Tucson teenager, along with hundreds of reported adverse reactions among patients enrolled in gene therapy as reasons to ``impose an immediate moratorium'' on gene therapy experiments.
Committee member Nancy King of the University of North Carolina, Chapel Hill, said the idea was flatly rejected by a subcommittee that studied the proposal.
The full committee adjourned without ever presenting the proposal for a vote. The committee has no power to block gene therapy, but its recommendations are closely monitored by the Food and Drug Administration which has approval authority for such human experiments.
In her report, King said the part of the proposal suggesting experimentation could continue for those with life threatening illnesses ``comes perilously close to saying terminally ill patients are expendable.''
King said the subcommittee felt it was possible to increase the safety and oversight of gene therapy experiments, while advancing the science. To shut down the gene studies, she said, ``would halt or postpone at least some demonstrably low-risk, but potentially valuable research.''
Jeremy Rifkin, president of the group that presented the proposal, repeatedly cited the death of Arizonian Jesse Gelsinger, 18, who died four days after starting a gene therapy experiment at the University of Pennsylvania. Gelsinger's death last September is the first known to have been caused by gene therapy.
``Are you waiting for a second Jesse Gelsinger?'' Rifkin asked.
He also said that researchers have an inadequate understanding of the effects of engineered viruses used to deliver genes to the cells of patients. And Rifkin said that no patient has been cured by the new therapy.
Additionally, Rifkin said that researchers have a financial interest in gene therapy companies and, thus, have an economic disincentive to report bad news from gene therapy experiments.
``There is greed here,'' said Rifkin. ``The process is so flawed that I am skeptical we will find the best way to treat patients.''
A cancer patient, Charles Rogers of Houston, however, strongly supported the benefits of gene therapy, saying an experiment has almost cleared his lung of cancer.
In testimony that followed Rifkin's comments, Rogers said he was diagnosed with cancer in both lungs in 1995. Conventional chemo and radiation therapy put his disease into remission, he said, but it reappeared in his right lung.
Last August, said Rogers, he enrolled in an experiment in which he received three infusions of genes that prompted his body to attack the cancer. Within months, he said, his cancer was in full retreat.
``If you wonder about gene therapy, look at me,'' said Rogers. ``I had a tumor in my right lung that was 31/2 inches long and 11/2 inches wide.''
Now, he said, ''98 percent of the tumor melted away and it is still getting smaller.''
Copyright © 2000 The Associated Press
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Gene Therapy May Have Scored First Cure
By Maggie Fox, Health and Science Correspondent
WASHINGTON (Reuters) - In what some experts are calling the first true gene therapy success, French researchers said on Thursday they had treated two infant boys for a rare, inherited immune system disorder.
The boys have human severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. Patients usually live out their short lives in sterile ''bubbles'' because any infection would overwhelm them.
Dr. Alain Fischer of the Necker Hospital in Paris and colleagues said they had managed to restore their immune systems using gene therapy. ``Both enjoy normal growth and psychomotor development. No side effects have been noted,'' they wrote in their report, published in the journal Science. Although they do not know how long the new genes will last and continue to provide an immune system for the boys, the researchers said their results ``pave the way'' for the same approach to be used in other genetic diseases. ``I think this is the first evidence ever that gene therapy does anything,'' said Dr. David Nelson, an expert in inherited immune diseases at the National Cancer Institute in Bethesda, Maryland, said in a telephone interview. ``This is really good stuff.''
Missing Master Control Gene Replaced
SCID X1 patients are missing a master control for the immune system, a cell receptor that turns on the different immune system cells, including T-cells that flag and destroy invaders and natural killer cells. Attempts to introduce an improved version of the gene into patients' bodies have not worked, so Fischer's team tried a new approach, using stem cells. Stem cells are nursery cells, found in this case in the bone marrow. They give rise to all the different kinds of blood cells, including the immune system cells. Fischer's team took bone marrow cells from the two boys, aged 8 and 11 months at the time, and purified out the stem cells. They nursed these cells along in a special cocktail of compounds meant to help the stem cells thrive and multiply, and also to make them more amenable to genetic engineering. Added into the mix was a virus carrying a healthy version of the gene the boys needed. After three days, the mixture was purified and the infected cells put back into the boys.
Results Within 15 Days
Within 15 days the researchers saw results. The boys started producing immune cells and chemicals. One boy who had suffered from diarrhea and skin lesions had his symptoms clear up and both went home after three months. The researchers think the stem cells carrying the new and improved gene had a survival advantage over the defective immune cells. They worked better, so they thrived. Each boy has been home for nearly a year without treatment. They have normal levels of T, B, and natural killer immune cells and have been successfully vaccinated against tetanus, diphtheria, and polio -- vaccinations that would not have worked for the boys before. Fischer said a third patient had also gone through the treatment and looked healthy after four months.
Dr. William French Anderson of the University of California Los Angeles, who performed the first-ever gene therapy experiment in 1990, said Fischer's work is pivotal. ``If it hadn't worked, it would have been extremely depressing,'' he said in a telephone interview. ``SCID is unique ... if you can't successfully treat SCID you are not going to be able to treat anything else.''
Plans To Try Similar Method In U.S.
Most gene therapy has not worked because so few cells take up the new genes and produce the needed protein. But with SCID, the faulty gene is one that causes many different cells to proliferate, so a strong effect can be seen quickly. ``If you get a few corrected cells in the body, the body will amplify those and basically replace the blood system with the corrected cells,'' Anderson said. Many researchers are now looking at using stem cells to help deliver gene therapy to the body. Anderson said he intends to try it with the very first gene therapy patient, Ashanthi DeSilva, who is now 13. Anderson's gene therapy treatment of DeSilva partly corrected her immune disorder, known as ADA deficiency. ''Although she is holding up beautifully, that is not a full correction,'' Anderson said. ``We plan to go in and give her gene-corrected stem cells this summer. Once you have got stem cells in a patient, if it's a high enough level, then the patient should be corrected for life.''
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Premier succès pour la thérapie génique
Grave déficit immunitaire soigné chez des "bébés bulles"
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Paris (ats/afp) La thérapie génique a connu son premier succès. Grâce à ce nouveau mode de traitement, des médecins parisiens ont pu soigner un grave déficit immunitaire chez des nourrissons. Cette infection oblige les bébés à vivre dans une bulle stérile pour éviter les microbes. Les deux premiers "bébés bulles", traités à 8 mois et 11 mois, ont pu rentrer chez eux sans aucun traitement. Ils jouissent depuis plus d'une année "d'un système immunitaire normal, sans effets secondaires indésirables", explique Alain Fischer, co-auteur de l'étude, dans la revue américaine "Science" de vendredi.
Première preuve tangible
Cette restauration du système immunitaire a été confirmée par les vaccinations contre la diphtérie, la poliomyélite et le tétanos: les nourrissons ont réagi normalement en produisant des anticorps contre ces maladies. L'équipe prévoit de traiter six autres bébés cette année et s'intéresse à des maladies similaires.
Ce succés apporte la première preuve tangible de l'efficacité de la thérapie génique. Au total, cinq bébés ont bénéficié du traitement, dans quatre cas avec succès. Pour le dernier cas, les chercheurs sont dans l'attente et refusent pour l'heure de se prononcer.
"Jamais jusque là une correction complète des anomalies de la maladie n'avait été obtenue pour d'autres maladies", ajoute le professeur Fischer. Les enfants "devront être surveillés toute leur vie pour s'assurer de leur bonne santé et contrôler le succès à long terme du traitement", relève-t-il toutefois.
Maladie rare
L'immunodéficience combinée sévère est une maladie rare, caractérisée par l'absence totale de cellules de défense. Elle laisse le malade à la merci de la moindre infection, provoquant sa mort en l'absence de greffe de moelle osseuse ou de l'abri en chambre stérile.
Le traitement consistait à introduire un gène "sain" dans des cellules sanguines, afin de corriger le défaut génétique. Les cellules modifiées ont proliféré rapidement, ce qui a permis de reconstituer le stock de globules blancs, de lymphocytes T et d'autres cellules de défense de l'organisme.
(SDA - ro/fd/4/c4fra sozm for/000427 1722)
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Franzoesische Forscher erstmals mit Gentherapie erfolgreich
Erstmals in der Geschichte der Gentherapie scheint eine solche Behandlung erfolgreich zu sein. Franzoesische Forscher und Aerzte haben eine Methode entwickelt, um Patienten mit erblicher, schwerer Immunschwaeche gentherapeutisch zu helfen. Zwei Kinder, die zuvor nur unter sterilen Bedingungen im Krankenhaus ueberleben konnten, haben jetzt, gut zehn Monate nach der Behandlung, ein weitgehend funktionsfaehiges Immunsystem und leben ohne Nebeneffekte zu Hause. Auch das Krankheitsbild eines dritten Patienten, der erst vor vier Monaten behandelt wurde, stimmt optimistisch.
Die zwei betreffenden Kinder, 8 und 11 Monate alt, leiden an einer erblichen Form der Immunschwaeche, genannt X-SCID (severe combined immunodeficiency). Diese Krankheit hiess frueher Agammaglobulinaemie Schweizer Typ. Durch einen Defekt in einem Gen auf dem X-Chromosom sind viele Zellen des Immunsystems, die sogenannten T-Lymphozyten und neutrophile Killerzellen, nicht funktionsfaehig. Daher sind X-SCID-Patienten hochgradig anfaellig fuer Infektionen. Der Gendefekt bei X-SCID liegt in der Bauanleitung fuer einen Teil eines Rezeptors, der die noch nicht spezialisierten Stammzellen anregt, sich zu differenzieren und zu vermehren
Das Forscherteam um Alain Fischer vom Kinderkrankenhaus Necker in Paris entnahm den Patienten Knochenmark, worin sich die lahm gelegten Vorlaeuferzellen der Immunzellen, die Stammzellen, befinden. Diese Stammzellen wurden in Kultur drei Tage lang mit Retroviren inkubiert, die intakte Versionen des betreffenden, defekten Gens enthielten. Anschliessend wurden die Stammzellen den Patienten wieder injiziert.
Bereits nach 15 Tagen fanden Fischer und seine Kollegen neue, voll funktionsfaehige Immunzellen im Blut der Patienten. Inzwischen, rund 10 Monate nach der Therapie, haben die beiden Patienten ein aehnlich gut funktionierendes Abwehrsystem wie Gesunde. Die Patienten konnten sogar erfolgreich gegen Tetanus, Diphtherie und Kinderlaehmung geimpft werden - Vorraussetzung dafuer ist ein intaktes Immunsytem.
Fischer glaubt, dass der Erfolg dieser Gentherapie nicht "in der Technik, sondern in der Krankheit selber liegt." Denn bei X-SCID-Patienten scheint es so zu sein, dass die funktionsfaehigen, mit dem intakten Rezeptorgen versehenen Immunzellen einen Wachstumsvorteil haben vor den defekten Zellen. "Das bedeutet, dass selbst bei einer nur wenig effizienten Gentherapie-Technik - eine, bei der zur wenige Zellen das korrekte Gen erhalten - als Behandlung wirksam sein kann", erklaert Fischer.
Lesen Sie auch einen Beitrag zur Gentherapie im aktuellen Heft (5/2000) "bild der wissenschaft".
[Quelle: Karin Hollricher und Science 288, S. 669 - 671]
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Gene Therapy for Hearing Loss May Be Possible
By Penny Stern, MD
NEW YORK (Reuters Health) - Loss of tiny hair cells in the inner ear, such as after exposure to loud noise, can result in irreversible hearing loss and problems with balance. In an unexpected finding, researchers at Genentech, Inc. have demonstrated that they can induce production of inner ear hair cells in rats, something once thought impossible to achieve after birth.
The researchers hope that their finding may one day lead to gene therapy to treat hearing and balance impairments.
Drs. Wei-Qiang Gao and J. Lisa Zheng present their findings in the June issue of Nature Neuroscience.
Hair cells, located in the part of the inner ear called the cochlea, are part of the hearing apparatus. They are electromechanically sensitive, responding to both sound and motion. Gao explained to Reuters Health that ``hair cell regeneration occurs spontaneously in post-embryonic and mature bird and lower vertebrate ears,'' but was not thought possible in mammals.
The San Francisco, California investigators showed that a specific gene, called Math1, associated with hair cell production during early embryonic life, could be induced to produce new hair cells much later, suggesting that ``mammalian inner ears retain the competence to produce new hair cells even after birth,'' Gao said. In addition, the team successfully ''identified...cell types which can differentiate into new hair cells in the inner ear,'' the researcher noted.
In Gao's view, these findings hold the potential for significant therapeutic importance ``because hair cell loss due to loud sounds, aging, and drugs (toxic to the ear), is one of the major causes of hearing loss (affecting) millions of people.''
The ability to replace hair cells damaged or lost with new cells through gene therapy would represent a great ``benefit (to) those suffering from hearing and balance disorders,'' Gao explained.
Future research efforts for the team will include determining whether hair cell growth can be induced in adult mammals. ``It should be recognized that our work is done in postnatal rat cochleae which are still immature,'' Gao stressed. ``Similar experiments need to be performed in mature mammalian cochleae before any clinical trials can be considered.''
SOURCE: Nature Neuroscience 2000;3:580-586.
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Successful in Utero Gene Transfer Reported in Monkeys
By Karla Harby
BOSTON (Reuters Health) - The first successful fetal gene transfer in a species with a gestational course closely resembling that of the human--the rhesus macaque--suggests that gene transfer can be accomplished in utero without causing genetic malformations in the offspring, according to a report.
The finding holds out the hope that gene therapy can be safely administered in utero to human fetuses to treat genetic diseases, although such experiments are years away, said Dr. Bruce A. Bunnell of Children's Hospital, Columbus, Ohio.
Bunnell directly injected 14 macaque fetuses with a fluorescing marker gene, derived from jellyfish, and incorporated into two retroviral vectors. These were the murine leukemia virus (MLV), a commonly used in research, or the HIV-1 virus.
HIV-1 was chosen because MLV integrates only rapidly dividing cells, whereas HIV-1 reaches the cells of such organs as the liver and brain that are less likely to divide, Bunnell said. Although selected proteins were deleted from the HIV-1 virus to enhance safety, he noted that the use of HIV-1 remains controversial.
All of the monkeys were carried to term and delivered by cesarean section. At their births, Bunnell found that all 14 primate infants were healthy and normal, except that they expressed the marker gene in every cell of their bodies. For the most part, the dams (mother monkeys) did not express the gene, as maternal circulation was bypassed by using a long needle to inject the foreign genetic material directly into fetal circulation.
However, after about 1 month the infants stopped expressing the marker gene. No one knows why this happens, Bunnell said, but it may be that the infants mounted an immune response to the foreign protein. Until this limitation is understood and overcome, fetal gene therapy cannot have long-term success, he added.
"The macaque fetal development is very similar to the human, except that it occurs in a little more compressed time frame," Bunnell said. For this reason, although the macaque model is more difficult to study, the data are more relevant to human genetic disease than data from rodents, sheep or other species, he said.
The study findings were presented this week at the combined annual meeting of the Pediatric Academic Societies and the American Academy of Pediatrics.
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Researchers Sneak Gene Therapy Into Brain
By Maggie Fox, Health and Science Correspondent
WASHINGTON (Reuters) - Using protective balls of fat and precisely targeted antibodies, researchers said on Monday they had found a way to sneak gene therapy into the brain in a new approach they hope could be used against a range of diseases from Alzheimer's to brain cancer.
They said their new method might also be used in general as a safe and effective technique for gene therapy of all kinds. And, although they did their work in rats, they think their technique might be ready to be tested in humans within months.
Dr. William Pardridge, a professor at the University of California Los Angeles School of Medicine, said gene therapy has not worked well in the past and attempts to make it work in the brain have been especially unsuccessful. "The reason all pharmaceutical companies have given up on gene therapy of the brain is it requires drilling a hole in your head -- that's expensive, invasive and it doesn't work," Pardridge said in a telephone interview. "The gene only goes to a part of your brain the size of a pin head. The second problem is they uniformly use viruses, either adenoviruses or herpes viruses, and we all have a pre-existing immunity to either virus."
The idea behind gene therapy is to correct disease or genetic defects by introducing new genes into the body. It is still highly experimental and the field suffered a setback last year when one patient died, apparently because his immune system revolted against the virus used to carry the genes.
Writing in the Proceedings of the National Academy of Sciences, Pardridge's team said they had taken another standard gene therapy route, using capsules of fat known as liposomes. To target the liposomes, they attached antibodies, which are immune system compounds that can seek out and attach to specific cells, as well as viruses and bacteria. "This enables us one, to have widespread distribution and expression of the gene through the brain following a simple intravenous injection and two, no use of viruses," Pardridge said. "The DNA is encapsulated from the liposome so it is fully protected from all the enzymes that are there to chew it up." But just injecting DNA is no good, because it does not know where to go. That is where the antibodies come in.
Pardridge's team used as their target the transferrin receptor, which is a molecule found on brain cells and on cells in certain other organs such as the liver. When injected into rats, it carried the DNA -- in this case simply an experimental "marker" gene that could easily be traced -- into brain and liver cells. Gene therapy in the brain might be used to treat or even cure Parkinson's disease, brain cancer and genetic disorders such as Tay-Sachs and Gaucher's disease. Pardridge thinks the approach could be used against a range of other disease, too. "You can deliver anything you want to cells," he said. "It opens up an entirely new approach to pharmaceutics." But what was especially intriguing about this approach, he said, was it was able to get past the "blood-brain barrier" -- a molecular system that keeps many drugs from getting into brain cells. "Now we have found a way to ferry genes across the barrier by exploiting natural receptors in the brain." Pardridge hopes his team can move ahead quickly. "The next step is usually you say three to five years before studies in humans," he said. "That isn't the case here." He said his team had a project that could move into human beings within five months. But, he said, no drug companies were interested. "All of the components are available off the shelf now, but who is going to invest in this?" he asked. "It's a problem. You mention blood-brain barrier to venture capitalists and their eyes get glazed over."
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Gene therapy's trials
One major laboratory has closed because of a clinical trial's tragic outcome. But others need publicly to review their roles.
When Jesse Gelsinger, an 18-year-old Arizona man, died during a gene-therapy experiment last autumn, the scientific community first rallied to find out what went wrong. Then politicians and bureaucrats started looking for someone to blame.
Fault has come to rest on the University of Pennsylvania's Institute for Human Gene Therapy (IHGT), whose clinical-trials programme has now been terminated. The IHGT had failed to inform the US Food and Drug Administration (FDA) of adverse events experienced by other patients treated before Gelsinger, according to an FDA letter to the university. But other institutions, agencies and individuals may share some moral culpability: when oversight breaks down, everyone involved in it must examine their role.
The sense that this process is far from settled emerged at a recent Senate hearing. When officials from the Department of Health and Human Services, National Institutes of Health (NIH) and FDA were asked whether recommendations made in 1998 about clinical-trial oversight had been implemented, none responded definitively. Weeks earlier, the health department's Office of Inspector General pointed out that the 1998 recommendations had been largely ignored. Those recommendations spoke directly to many of the problem areas in the Gelsinger trial: informed consent, adverse-events reporting and clinical-trial oversight. The agencies' failure to address issues raised years earlier may have indirectly contributed to the trial's tragic outcome.
Adverse-events reporting may be the clearest example of this. Hundreds of previously unreported adverse events poured in to the NIH once it asked for them following Gelsinger's death. Many gene-therapy researchers privately object to filing adverse-events reports either to the FDA, where they remain confidential, or to the NIH, where they are made public. But, in retrospect, having more public records on adverse events associated with the vector used in Gelsinger's trial would have been useful. Perhaps if enough data on immune responses associated with the vector had been made public before his death, rather than after, the trial would never have been launched.
So whose fault is it that many gene-therapy investigators didn't report their adverse events earlier? The answer is hard to determine, but the NIH leadership may have sent an inadvertent message that reporting to the Recombinant DNA Advisory Committee (RAC) isn't compulsory when in 1996 they tried to reduce the committee's scope.
And although IHGT investigators didn't notify the FDA of all adverse events immediately, they did notify them of similar immune responses. In each case, the FDA let the trial resume. The IHGT and FDA changed the route of vector administration, from intravenously to directly into patients' livers, without notifying the RAC. While that adjustment was intended to limit the vector to the liver, Gelsinger's autopsy showed that it had the opposite effect.
Clearly, the IHGT's closure does not obviate the need for other institutions, agencies and individuals to assess their roles in the tragedy and to make their conclusions public.
Nature © Macmillan Publishers Ltd 2000
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Forscher heilt Autoimmunkrankheiten
(ExpeditionZone) - Mit Hilfe von DNA Injektionen koennten in Zukunft Patienten, die an Autoimmunerkrankungen leiden, geheilt werden.
In ersten Versuchen gelang dem israelischen Forscher Dr. Nathan Karin vom Technion-Israel Institute of Technology eine Heilung von Ratten.
Die neuartige Gentherapie soll vor allem Patienten, die an Multipler Sklerose (MS) oder Arthritis leiden, helfen. Bei beiden Krankheiten attackiert sich der Koerper selbst und erzeugt so Entzuendungen.
Bei MS etwa, wird die Myelin Schicht um die Nerven zerstoert, waehrend bei Arthritis Gelenke und Knorpel attackiert werden. Verursacht werden die Schaeden durch proentzuendliche Peptide (Zytokine und Chemokine), die in zu hohem Ausmaþ gebildet werden.
Ein Weg um diese Krankheiten unter Kontrolle zu bringen, ist die Patienten mit neutralisierenden Antikoerpern, die gegen eines oder mehrere der proentzuendlichen Peptide gerichtet sind, zu immunisieren, so Forschungsleiter Dr. Nathan Karin. Tatsaechlich haben wir das bereits gemacht.
Bei der neuartigen Methode injizierte Karin leicht veraenderte DNA in den Koerper, die fuer die Zytokine kodiert sind. Der Koerper erkennt die nach dieser Vorlage hergestellten Zytokine als "fremd" und bildet Antikoerper. "Dadurch werden auch die ueberschuessigen koerpereigenen Zytokine aus dem Verkehr gezogen und das Immunsystem dazu veranlasst selbst gegen die Stoerenfriede vorzugehen", meint Karin. Der Patient heile sich dann sozusagen von selbst, so der Arzt.
Die Ergebnisse wurden kuerzlich im Journal of Clinical Investigation veroeffentlicht.
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DPA, August 7, 2000 |
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Experten warnen vor zu grosser Hoffnung in Gentherapie
Hannover (dpa) - Auf dem Weltgesundheitskongress in Hannover haben Mediziner am Montag vor zu grossen Hoffnungen auf einen schnellen Einsatz der Gentherapie gewarnt. Zwischen theoretischem Wissen ueber das Erbgut und der praktischen Anwendung klaffe eine groþe Luecke. Erfolg versprechend seien jedoch Gentests zur Krankheitsdiagnose, die eine gezieltere Therapie ermoeglichen.
Nach Auskunft von Prof. Felix Mitelman von der Universitaet Lund in Schweden sind etwa 600 verschiedene Erbgutfehler bekannt, bei denen ein Gen oft ohne erkennbare Ursache an einen falschen Ort gelangt ist und dadurch Krebs ausloest. ´Und das ist nur die Spitze des Eisbergs.' Besonders oft sei das bei Leukaemie (Blutkrebs) diagnostiziert worden. ´Jeder Tumor hat eine spezielle Genveraenderung.' Wenn der Arzt diese kennt, koennte er, so die Hoffnung, genau das Eiweiss angreifen, das bei diesem Krebs zu haeufig oder in falscher Form produziert wird. Bei einer Art der chronischen myeloischen Leukaemie seien damit schon erste Erfolge erzielt worden.
Einen Einsatz der Gendiagnose bei Brustkrebs nannte Jonathan Knowles, Forschungsdirektor bei Hoffmannn-La Roche in Basel. So sei das Mittel Herceptin nur bei einer ganz speziellen Genveraenderung wirksam, die einen Typ des Tumors ausloest.
Bob Williamson vom Royal Children's Hospital in Melbourne sprach sich dafuer aus, klinische Versuche erst zu beginnen, wenn genuegend Grundlagenforschung geleistet sei. Sonst koennten sie falsche Hoffnungen wecken. In den vergangenen zehn Jahren habe es etwa 400 bis 500 Versuche der Gentherapie am Menschen gegeben, jedoch erst einen wirklichen Erfolg. Vor kurzem hatte das Fachjournal ´Science' eine Studie mit drei Kinder praesentiert, die von einen vererbten Immundefekt befreit wurden. Diese Kinder, deren Abwehrkoerper nicht reifen konnten, waren alle unter ein Jahr alt. Nun muesse man jedoch auch hier noch abwarten, ob die Therapie dauerhaft erfolgreich ist, sagte Williamson.
Die weitgehende Entzifferung des menschlichen Erbmaterials brachte den Forschern eine Reihe neuer Probleme: ´Die Gene darauf zu finden, ist schwieriger als wir dachten', bekannte Jean Weissenbach vom Nationalen Zentrum fuer Gensequenzierung in Evry (Frankreich). Nach neuesten Schaetzung einiger Forscher hat der Mensch nicht rund 100 000 sondern nur 25 000 Gene, etwa doppelt so viele wie die Fruchtfliege Drosophila. Der Unterschied zwischen dem Mensch und diesen Tieren liege wahrscheinlich vor allem in der Steuerung der Gene, sagte Weissenbach. Sie sei beim Menschen wesentlich vielfaeltiger, aber noch kaum verstanden.
Der Kongress parallel zur Expo dauert noch bis 20. August. Das fuer Dienstag geplante Tagesforum zum Thema Krebs wurde abgesagt.
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Aus "Morgen Welt", August 9, 2000 |
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Schnupfen-Virus gegen Krebs
Ein gentechnisch veraendertes Schnupfen-Virus haben Mediziner gegen Kopf- und Nacken-Tumore eingesetzt, berichtet das Magazin ´MorgenWelt'. Das Virus sei direkt in die Tumoren gespritzt worden. Gleichzeitig erhielten die Patienten eine konventionelle Chemotherapie. Den Angaben der Wissenschaftler zufolge seien die Ergebnisse der kombinierten Behandlung aeusserst ermutigend gewesen: Bei neunzehn von dreissig Patienten seien die behandelten Tumore geschrumpft. Acht Tumore seien sogar komplett verschwunden. Aufgrund dieser Ergebnisse wollen die Forscher demnaechst eine Studie mit vierhundert Probanden durchfuehren, schreibt das Wissenschaftsmagazin.
Laut ´MorgenWelt' setzten die Wissenschaftler ein Adenovirus namens Onyx-015 ein. Dieses Virus verursache normalerweise Erkaeltungen. Um Zeit fuer seine Vermehrung zu gewinnen, blockiere es das Selbstmord-Programm von befallenen Zellen mit Hilfe eines speziellen Gens. Dieses Virus-Gen haetten die Forscher aber ausser Kraft gesetzt. Daher konnte sich das Virus nur noch in Zellen vermehren, deren Selbstmord-Programm ohnehin nicht mehr funktionierte. Dies sei bei bis zu 70 Prozent aller Kopf- und Nacken-Tumore der Fall.
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FDA Consumer magazine, sept/oct 2000 |
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Human Gene Therapy
Harsh Lessons, High Hopes
By Larry Thompson
A 4-year-old girl named Ashanthi DeSilva from the suburbs of Cleveland lay on crisp white hospital sheets with a needle stuck in a vein. She didn't mind; this happened all the time in her chronically sick childhood. At the other end of the intravenous hookup hung a clear plastic bag of very special cells: her own white blood cells, genetically altered to fix a defect she inherited at birth. (See related commentary in "The Last Word.")
A strikingly thin middle-aged doctor stared anxiously at the tiny figure. W. French Anderson, M.D., and his colleagues R. Michael Blaese, M.D., and Kenneth Culver, M.D., all then working at the National Institutes of Health, crossed a symbolic threshold with Ashanthi DeSilva that day, becoming the first group to begin a clinical trial in the new frontier of medical treatment: human gene therapy.
The reason for the excitement was simple: Most diseases have a genetic component and gene therapy holds the hope of curing, not merely treating, a broad range of ailments, including inherited diseases like cystic fibrosis and even chronic conditions like cancer and infectious diseases like AIDS.
At least, that's the theory.
In the 10 years since that first genetic treatment on Sept. 14, 1990, the hyperbole has exceeded the results. Worldwide, researchers launched more than 400 clinical trials to test gene therapy against a wide array of illnesses. Surprisingly, cancer has dominated the research. Even more surprising, little has worked.
"There was initially a great burst of enthusiasm that lasted three, four years where a couple of hundred trials got started all over the world," says Anderson, now at the University of Southern California in Los Angeles. "Then we came to realize that nothing was really working at the clinical level."
Abbey S. Meyers, president of the National Organization for Rare Disorders Inc., an umbrella organization of patients' groups, is much more blunt. "We haven't even taken one baby step beyond that first clinical experiment," Meyers says. "It has hardly gotten anywhere. Over the last 10 years, I have been very disappointed."
And then things got worse.
In September 1999, a patient died from a reaction to a gene therapy treatment at the University of Pennsylvania's Institute of Human Gene Therapy in Philadelphia. Jesse Gelsinger, an exuberant 18-year-old from Tucson, Arizona, suffered from a broken gene that causes one of those puzzling metabolic diseases of genetic medicine. An optimistic, altruistic Gelsinger went to Philadelphia to help advance the science that might eventually cure his type of illness. Instead, the experiment killed him.
In the aftermath of his death, there has been a flurry of activity to minimize the chance of future accidental deaths. The Food and Drug Administration, along with the National Institutes of Health, launched several investigations of the University of Pennsylvania studies and others. The inquiries provided disappointing news: Gene therapy researchers were not following all of the federal rules requiring them to report unexpected adverse events associated with the gene therapy trials; worse, some scientists were asking that problems not be made public. And then came the allegations that there were other unreported deaths attributed to genetic treatments, at least six in all.
"Probably the clearest evidence of the system [to protect research subjects] not working is that only 35 to 37 of 970 serious adverse events from [a common type of gene therapy trial] were reported to the NIH" as required, says LeRoy Walters, the recently retired head of the Kennedy Institute of Ethics at Georgetown University and former chairman of NIH's Recombinant DNA Advisory Committee. "That is fewer than 5 percent of the serious adverse events."
The news hit the clinical trial community like a thunderclap. The consequences have been immediate and wide-ranging, and may threaten future research.
"Participation in gene therapy trials is way down because the public is not sure what to make of this," says Philip Noguchi, M.D., director of the Cellular and Genetic Therapy Division in FDA's Center for Biologic Evaluation and Research (CBER). "They want to know what the government is doing to help restore the confidence in this field."
Responding to the Crisis
The federal government moved quickly to do just that. FDA immediately shut down the trial in which Gelsinger had volunteered, and all clinical gene transfer trials at the University of Pennsylvania in January. The university went on to severely restrict the research of its once-high-flying gene therapy institute director James Wilson, M.D., announcing in May that all his work would be confined to animal and laboratory experiments and that he would be barred from conducting studies in people.
FDA also suspended gene therapy trials at St. Elizabeth's Medical Center in Boston, a major teaching affiliate of Tufts University School of Medicine, which sought to use gene therapy to reverse heart disease, because scientists there failed to follow protocols and may have contributed to at least one patient death. FDA also temporarily suspended two liver cancer studies sponsored by the Schering-Plough Corporation because of technical similarities to the University of Pennsylvania study.
Moreover, as nervousness spread through the field in the months after revelations about Gelsinger's death, some research groups voluntarily suspended gene therapy studies, including two experiments sponsored by the Cystic Fibrosis Foundation and studies at Beth Israel Deaconess Medical Center in Boston aimed at hemophilia. The scientists paused to review their studies and make sure they learned from the mistakes made at the University of Pennsylvania.
In March, the Department of Health and Human Services announced two initiatives by FDA and NIH. The Gene Therapy Clinical Trial Monitoring Plan is designed to ratchet up the level of scrutiny with additional reporting requirements for study sponsors. A series of Gene Transfer Safety Symposia was designed to get researchers to talk to each other, to share their results about unexpected problems and to make sure that everyone knows the rules.
In addition, FDA launched random inspections of 70 clinical trials in more than two dozen gene therapy programs nationwide and instituted new reporting requirements. "We see the need to get the concept across that this is for keeps," says FDA's Noguchi. "You can be sloppy when you are dealing with a scientific paper, but you can't be sloppy when you are dealing with a human. Everything matters."
So far, the inspections only suggest that one other program appears to be in trouble, he says, but by the fall, "We should be able to say accurately [what is] the state of the art of gene therapy and where it needs to improve."
Meanwhile, President Clinton announced more "new actions designed to ensure that individuals are adequately informed about the potential risks and benefits of participating in research ... and steps designed to address the potential financial conflicts of interest faced by researchers." In addition, the President said in May, "We are also sending the Congress a new legislative proposal to authorize civil monetary penalties for researchers and institutions found to be in violation of regulations governing human clinical trials." If the legislation passes, FDA will, for the first time for drugs and biologics, have the power to essentially fine researchers and their institutions, up to $250,000 and $1 million respectively.
"This is a clear message," HHS Secretary Donna E. Shalala, Ph.D., said in May, "that we intend to get serious."
A History of Special Concern
Genetic engineering has always worried the general public.
When scientists first learned to clone genes in the mid-1970s, public reaction ranged from antipathy to hostility. Opponents, fearing that genetically engineered bacteria might escape from a laboratory, shut down the research at Harvard University and the Massachusetts Institute of Technology for months. Twenty-five years ago, in response to public concern, American scientists organized a voluntary moratorium on certain types of gene engineering experiments until safety questions could be resolved.
To help assuage public concern, NIH created its Recombinant DNA Advisory Committee, the RAC--which most simply call the "rack"--to provide a forum for genetic engineering debates to take place in public. As a result, the general opposition subsided.
But the RAC could do little if scientists didn't follow the rules. The promise of gene therapy, the glory of being the first to cure human ills, led at least one very smart scientist to make a very questionable decision. In 1980, an ambitious hematologist at the University of California at Los Angeles tested his gene therapy ideas on patients in Israel and Italy after being denied permission to perform the tests in Los Angeles. The experiments, conducted by Martin Cline, M.D., failed to help his subjects, and they violated federal rules designed to protect research subjects, leading to severe censure of the California scientist.
Ethical issues aside, the bigger problem for gene therapy has been basic biology. It's difficult to get new genes into billions of target cells within the body. Once inserted, the new genes need to function. Frequently, the body suppresses gene expression, essentially turning the new genes off, or destroys the transplanted genes. Although techniques have improved, today's scientists still face these challenges. To solve the problems, independent researchers have sometimes devised their own remedies of unknown safety. FDA began paying careful attention to these laboratory constructs when researchers began to request permission to test them in people under Investigational New Drug applications.
"Early investigators were more mom and pop operations," Noguchi says. "They were individual investigators making their own products ... Almost all of them went on clinical hold because there was a lack of product information." Before FDA could allow them to proceed, technical questions about safety had to be answered, and that took time.
Typically, scientific questions are answered in laboratory and animal studies, but, with gene therapy, clinicians have been anxious to test their ideas in people. Once the NIH physicians treated their tiny patient in 1990, researchers rushed to get into the game with human trials. At the halfway point in the decade, the field was not progressing well. Then-NIH Director Harold Varmus, M.D., himself critical of the gene therapy trials in people, created a committee to review NIH's investment in the field. Varmus wanted to know whether NIH should continue to invest so heavily in the new technology.
The committee's conclusions were bleak:
"While the expectations and the promise of gene therapy are great, clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol, despite anecdotal claims of successful therapy and the initiation of more than 100 ... approved protocols," concluded the ad hoc committee co-chairmen Stuart H. Orkin, M.D., of Harvard Medical School and Arno G. Motulsky, M.D., of the University of Washington in Seattle in December 1995. While they saw promise, they also saw challenges. "Significant problems remain in all basic aspects of gene therapy. Major difficulties at the basic level include shortcomings in all current gene transfer vectors and an inadequate understanding of the biological interaction of these vectors with the host."
To transfer a repair gene into a patient, the researchers must go through several steps (see "Fundamentals of Gene Therapy"). First, they must isolate the disease-related gene. Then it must be packaged in a vector, usually a disabled virus that cannot reproduce and cause disease, but that can act like a delivery truck to transport the gene inside the patient's cells. Once inside the body's cells, the new gene can begin to function and restore health.
But building an effective delivery truck hasn't been easy. Scientists started by using a type of mouse virus as a vector, engineered so that it cannot replicate itself, that easily infects human cells and integrates the new genes into the cell's chromosomes (structures in the cell that hold the genes). These mouse vectors, however, only infect dividing cells, so researchers switched to adenovirus, a type of human virus that causes the common cold. Because the adenovirus's own genes to reproduce itself have been removed, the remaining viral container is unable to cause an illness.
At least, that's the idea.
The Gelsinger Case
When Orkin and Motulsky reported on the technical limitations of gene transfer techniques five years ago, they virtually predicted problems in the clinic. During that same December meeting at which Orkin and Motulsky made their disheartening report, the RAC approved the University of Pennsylvania gene therapy trial for ornithine transcarboxylase deficiency (OTCD). FDA, too, allowed the study to proceed.
The treatment idea was fairly straightforward. OTCD occurs when a baby inherits a broken gene that prevents the liver from making an enzyme needed to break down ammonia. With the OTCD gene isolated, the University of Pennsylvania researchers packaged it in a replication-defective adenovirus. To reach the target cells in the liver, the Philadelphia scientists wanted to inject the adenovirus directly into the hepatic artery that leads to that organ. Some members of the NIH RAC objected, fearing that direct delivery to the liver was dangerous. Nonetheless, after a vigorous public discussion with the University of Pennsylvania researchers, the RAC voted for approval of the study.
At age 18, Jesse Gelsinger was in good health, but was not truly a healthy teenager. He had a rare form of OTCD that appeared not to be linked to his parents, but the genetic defect arose spontaneously in his body after birth. During his youth, he had many episodes of hospitalization, including an incident just a year before the OTCD trial in which he nearly died from a coma induced by liver failure. But a strict diet that allowed only a few grams of protein per day and a pile of pills controlled his disease to the point where he appeared to be a normally active teenager. With the encouragement of his father, Paul Gelsinger, Jesse volunteered for the study, and when he was initially evaluated, his medical condition qualified him to participate.
Gelsinger received the experimental treatment in September 1999. Four days later, he was dead. No one is really sure exactly why the gene therapy treatment caused his death, but it appears that his immune system launched a raging attack on the adenovirus carrier. Then an overwhelming cascade of organ failures occurred, starting with jaundice, and progressing to a blood-clotting disorder, kidney failure, lung failure, and ultimately brain death.
In its investigation, FDA found a series of serious deficiencies in the way that the University of Pennsylvania conducted the OTCD gene therapy trial, some more serious than others. For example, researchers entered Gelsinger into the trial as a substitute for another volunteer who dropped out, but Gelsinger's high ammonia levels at the time of the treatment should have excluded him from the study. Moreover, the university failed to immediately report that two patients had experienced serious side effects from the gene therapy, as required in the study design, and the deaths of monkeys given a similar treatment were never included in the informed consent discussion.
FDA's discussions with the university remain ongoing.
Signs of Progress
Not all the news about gene therapy is bad. It's true that dramatic cures have not been seen to date, but there are tantalizing signs that important advances may be just around the corner.
Ashanthi DeSilva, the girl who received the first credible gene therapy, continues to do well a decade later. She suffered a type of inherited immune disorder called Severe Combined Immune Deficiency, or SCID (pronounced skid), that left her susceptible to every passing microorganism. Without gene therapy, DeSilva would be living like David, the Boy in the Bubble, who had a similar disorder. Instead, the NIH researchers inserted a normal copy of the broken gene into some of her white blood cells, healing them, helping them function normally to restore her immune system. Cynthia Cutshall, the second child to receive gene therapy for the same disorder as DeSilva, also continues to do well.
Scientists, however, have discounted the benefit of the first gene therapies because the girls began receiving a new drug treatment that replaces the missing enzyme just before receiving the genetic therapy. And they continue to receive the drug after the genetic treatment, though gene therapy pioneer Anderson argues that since the drug dose has remained the same while their bodies have grown substantially over the decade, it makes a negligible contribution to their well being.
In April, French scientists reported convincing evidence that they successfully treated a different form of SCID (X-linked severe combined immune deficiency, the type suffered by the boy in the bubble) with gene therapy. Four of the first five babies treated by Alain Fischer, M.D., of the Necker children's hospital in Paris have had "a complete or near complete recovery" of their immune systems after the treatment.
Meanwhile, researchers at Children's Hospital of Philadelphia, Stanford University and Avigen, Inc., a biotech company in Alameda, Calif., have reported promising results in hemophilia B patients. The team packaged a gene for Factor IX, a blood clotting protein, in a defective adeno-associated virus (AAV). They then used the AAV to insert the gene into patients who suffered abnormal blood clotting because they lack Factor IX. Normally, these hemophilia patients needed to inject Factor IX to prevent uncontrolled bleeding. In June, the researchers reported treating six patients with the Factor IX gene therapy. Even though the dose of the gene therapy was so low that no one expected it to help, it reduced the number of injections of Factor IX that these patients used on an ad hoc basis.
"The hemophilia studies are looking promising," says FDA's Noguchi, "but will need further study to know whether it is an effective product."
These two studies suggest the power of genetic treatments.
"We do seem to have turned the corner," says Anderson, "and there are a number of clinical trials that are starting to show success."
Even as FDA increases its scrutiny of the field to ensure patient safety, there is a sense of advancement. "There is good progress being made," Noguchi says. "FDA thinks that gene therapy will work, but we don't know for which disease. The recent events in France show that if you have the right disease, and can insert the right gene, you can obtain good results."
Larry Thompson is the editor of FDA Consumer.
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FDA Consumer magazine, Sept/Oct. 2000 |
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The Last Word
Researchers React to Gene Therapy's Pitfalls and Promises
By Savio L.C. Woo, Ph.D.
The possibility of correcting human genetic disorders by gene therapy caught the imagination of the scientific community as well as that of the public long before the first clinical gene transfer experiment was launched ten years ago. During the ensuing decade, however, the extraordinarily high level of expectation has proven to be grossly optimistic. This prompted Dr. Harold Varmus, then Director of the National Institutes of Health, to appoint two separate committees in the mid-1990s to evaluate the field of gene therapy. The committees independently concluded that clinical applications of gene transfer could not possibly succeed without adequate scientific and technological support, as well as sufficient preclinical studies in relevant animal models of human disease to validate treatment efficacy.
The scientific community has taken these constructive criticisms to heart during the past few years, and dramatic progress has been made in the basic science of viral and non-viral vector development used to transfer genes into patients. As a result, some approaches appear to be working. The Hemophilia B trial currently being conducted at the Children's Hospital of Philadelphia and Stanford University employs intramuscular delivery of the gene expressing human Factor IX, a protein involved in blood clotting. Patients in this trial have exhibited much improved whole blood clotting times for months after the gene treatment. Children in Paris with X-linked SCID, an inherited disorder that destroys the immune system, are able to live at home normally after genetic treatment of bone marrow stem cells. While both trials are in early phases, the encouraging results do provide proof of the scientific principle that human genetic disorders can be corrected by gene transfer.
In September 1999, clinical experiments in gene transfer research suffered their first patient loss as a direct consequence of the gene treatment itself. The patient was a 19-year-old male with a metabolic disorder who received a high dose of a genetic treatment directly into his liver at the University of Pennsylvania. He died from multi-organ failure induced by an adult respiratory distress syndrome secondary to a systemic inflammatory response to the method used to deliver the new gene.
Initial public response to the tragic incident was rather mild, as it is understood that medical research is not without risks. But public perception of clinical gene therapy took a precipitous turn for the worse after the FDA cited the University of Pennsylvania investigators in December 1999 for multiple protocol violations in the trial. In addition, NIH revealed that only 6 percent of all serious adverse events observed in patients during past and current clinical gene transfer studies were reported to the NIH as required. These findings triggered a series of corrective actions by the relevant federal regulatory agencies including the FDA and the NIH, with the full cooperation and enthusiastic support of the American Society of Gene Therapy (ASGT). The Board of Directors of ASGT has accordingly adopted a policy that calls for all of its members to rigorously adhere to federal regulations and institutional guidelines in clinical gene transfer studies. This policy was published in the January issue of Molecular Therapy, the official scientific journal of the Society.
Another revelation that further shook the public's confidence in clinical gene transfer studies at its roots was that some investigators apparently have significant financial interests in the outcome of the clinical research they are conducting. To ensure the public that clinical gene transfer research will be performed with high ethical standards and without financial conflicts in the future, the ASGT Board of Directors adopted a second policy published in the May issue of Molecular Therapy. It prohibits investigators and team members from direct participation in the recruitment and clinical management of trial patients or in gaining participants' informed consent if they have financial interests in companies sponsoring the trial.
While the recent advances in clinical gene transfer to treat Hemophilia B and X-linked SCID show that gene therapy is indeed an immensely powerful technology that can be developed into novel treatments for a wide variety of human diseases, it is critically important for the scientific community to rise to the occasion and restore full confidence in the public's mind that clinical gene transfer research will be conducted by investigators in a responsible manner and free from financial conflicts. Only then can the full potential of using genes as medicines to treat human disease be realized, which will have a major impact on medicine and health in the 21st century.
Savio L.C. Woo, Ph.D., is the director of the Institute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine in New York, where he is a professor, and is the immediate past president of the American Society of Gene Therapy.
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Fundamentals of Gene Therapy
You look a little like your mother and a little like your father because of the genes they gave to you. Genes, those conceptual units composed of deoxyribonucleic acid-DNA, carry the information needed to make proteins, the building blocks of our bodies. The body buries genes deep in the heart of every cell, the nucleus, and organizes them in the chromosomes that hold the DNA. But when your DNA is damaged, it no longer makes all the needed proteins and disease results.
To reverse disease caused by genetic damage, researchers isolate normal DNA and package it into a vector, a molecular delivery truck usually made from a disabled virus. Doctors then infect a target cell -usually from a tissue affected by the illness, such as liver or lung cells-with the vector. The vector unloads its DNA cargo, which then begins producing the missing protein and restores the cell to normal.
Recently, French researchers reported dramatic results in treating a disease called severe combined immune deficiency (SCID), the disorder suffered by David, The Boy in the Bubble. A broken gene eliminates the production of an enzyme essential for the development of a normal immune system. Scientists isolated the normal copy of the gene and packaged it into a vector. In the laboratory, they then used the vector to transport the gene into the patient's own bone marrow cells. Bone marrow cells create the immune system. The treated bone marrow cells are then given back to the patient in a germ-free isolation room, where they reconstitute a normal, functioning immune system, freeing the patient from the need to remain in isolation.
FDA/Office of Public Affairs
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Reuters, August 28, 2000 |
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Gene Therapy Revives 'Dead' Heart Tissue - Study
By Maggie Fox, Health and Science Correspondent
WASHINGTON (Reuters) - Gene therapy may work not only to help patients grow their own heart bypasses, but to revive heart tissue that appeared to be dead, researchers said on Monday.
They said their study, published in the American Heart Association journal Circulation, boosted evidence that gene therapy could help patients with heart disease.
The gene therapy not only made patients feel better, but was shown on scans to increase blood flow to the heart, said Dr. James Symes of Tufts University in Boston.
"It seems to work," Symes said in a telephone interview.
"We have to recognize that we are still talking about a very small number of patients, but it is very clear to me, as the surgeon who injected this into most of these people, that it does clearly have the ability to modify the objective tests that we used to measure how much blood flow was going into certain areas of the myocardium (heart muscle)."
The team, headed by Dr. Jeffrey Isner at Tufts, had been testing gene therapy on 30 very ill heart disease patients.
All had severe angina, or chest pain, and all had undergone heart bypasses or angioplasties that had blocked up again and failed. None were able to have any more such operations and all were so seriously ill that they could barely perform daily activities such as shaving.
Growth Factor Injected
Isner's team injected the gene for vascular endothelial growth factor (VEGF-2), one of the proteins involved in the growth of new blood vessels, into the hearts of the patients.
They reported earlier that two-thirds of the patients felt significantly better afterwards. Symes said the study reported on Monday came as a surprise.
"It was only partway through study that we acquired the technology to do the mapping and became sufficiently good at it," Symes said.
So they scanned 13 patients -- eight men and five women -- to see if the heart muscle was responding.
They used single-photon emission CT-sestamibi (SPECT) imaging, which involves injecting a tiny amount of a radioactive substance, stressing the patient's heart with exercise or a drug, then scanning the heart to see where the substance goes.
A second scan is done a day or so later, when the patient is resting, to see which parts of the heart ``recover'' after stress.
They also were given NOGA left ventricular electromechanical mapping tests (EMM), which involves threading a device into the left ventricle, the heart's main pumping chamber, to measure the heart's electrical activity. A computer produces three-dimensional maps showing areas of live heart muscle and bits that are not moving
"If the heart muscle does not recover at rest, we assume the muscle is dead," Symes said.
"But in fact, some of that myocardium was not actually dead. Some of areas that appeared to be irreversible were in fact reversible."
"Dead" Tissue Revived
After the gene therapy treatment, nearly all the patients had tissue that looked dead before that recovered afterward.
Symes said it appears the areas of ``hibernating'' muscle were getting a little blood, but not enough to allow the cells there to beat. "You just have to bump up the oxygen supply or blood supply by a certain small percentage," he said.
The study adds to several reported by the team, who believe their gene therapy technique initiates the growth of new blood vessels, a process known as angiogenesis.
"There has been great concern about whether gene therapy works. This is very solid evidence that it does," Isner said in a statement.
Isner's team has been in trouble over its experiments.
In May the U.S. Food and Drug Administration (FDA) warned Isner of failing to properly report the death of one patient in gene therapy trials, and accused him of putting a cancer patient at risk.
Symes said the team had addressed the FDA's concerns and was waiting for the go-ahead to start a Phase II clinical trial, with more patients, using VEGF.
Copyright © 2000 Reuters Limited
The FDA has been cracking down on gene therapy researchers since the death last September of Jesse Gelsinger, 18, during a gene therapy experiment.
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Reuters Health, August 31, 2000 |
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Bone-building therapies on the way, experts say
By Merritt McKinney
NEW YORK (Reuters Health) - The latest research on the make-up of bones paves the way for potential new therapies for osteoporosis and other bone diseases, several bone experts report in the September 1st issue of the journal Science.
Each day we depend on our bones to be steady and firm as we move around, but bones are actually changing continually. New bone cells are constantly being formed to replace old cells in a process called bone remodeling.
As we age, the regulation of bone growth can go awry and the formation of new bone cells cannot keep up with bone destruction, or resorption, as happens in the brittle-bone disease osteoporosis.
Two major types of cells are involved in maintaining bones. Osteoblasts construct bone cells, while osteoclasts destroy old ones to make way for the new.
According to Dr. Gerard Karsenty and colleagues at Baylor College of Medicine in Houston, both cell types are important, but the osteoblast is the key to reversing bone disease that often accompanies the aging process.
"In terms of osteoporosis, it is the most important cell type," Karsenty told Reuters Health in an interview. "What you want is to build bone, not to destroy it."
During the past five years, researchers have identified substances that transform normal cells into osteoblasts, according to Karsenty. Learning more about the bone-building cells ``opens the way to new treatments,'' he said, noting that the more is known about the bone-building process, the easier it is to design drugs to boost bone formation.
Recently, Karsenty and his colleagues discovered that the hormone leptin seems to be involved in regulating the formation of osteoblasts. Mice that are deficient in this hormone, which has been shown to be involved in regulating weight, have two to three times more bone mass than normal mice. Though leptin is unlikely to be the only hormone involved in regulating bone formation, the discovery highlights the potential for hormone-targeted drug therapy to increase bone mass, Karsenty explained.
In another review article, Dr. Steven L. Teitelbaum, of Washington University School of Medicine in St. Louis, Missouri, points out that even though the role of osteoclasts in the bone resorption process is understood for the most part, less is known about how to stop the destruction of bone cells.
Several types of treatments, including estrogen, selective estrogen receptor modulators (SERMs) like raloxifene and drugs called bisphosphonates, are already available to slow down the resorption process, according to Teitelbaum.
But advances in the study of genes will make it easier to develop drugs that more accurately target molecules that control osteoclasts, he told Reuters Health in an interview.
"With our ability to do genetic engineering, instead of testing drugs randomly, we can actually identify molecular targets within the cells,'' he said. ``We are going to pinpoint molecules that are important."
By age 40, the scales of bone remodeling begin to tip towards osteoclasts, as bone destruction begins to out pace bone formation, according to the authors of a third article, Drs. Gideon A. Rodan, of Merck Research Laboratories in West Point, Pennsylvania, and T. John Martin, of St. Vincent's Institute of Medical Research in Melbourne Australia.
New treatments will hopefully restore the balance of the bone remodeling process, they write.
One treatment approach already in the works is a protein called OPG, which limits the formation and activity of bone-destroying osteoclasts. Injections of the protein prevent bone loss in rats, according to the report.
But the protein has to be given in high doses, and it may affect other parts of the body besides bones, Rodan and Martin point out.
Another promising treatment for bone loss is parathyroid hormone, according to the authors. Daily injections of the hormone have been shown to improve bone density in men and women with osteoporosis, they note.
The authors explain that cholesterol-lowering drugs called statins encourage bone formation in rats. Even if the statins already on the market turn out to be unsuitable for building bones in people, studying the activity of the drug may lead to new treatment approaches, Rodan and Martin write.
Finally, advances in genetics may lead to improved prevention and treatment of bone loss, the authors state.
Since osteoporosis probably has at least some genetic component, it may be possible to identify people with a genetic risk of the disease, who would be good candidates for prevention, according to the report.
Gene therapy may be another way to treat osteoporosis, the authors suggest. And identifying genes responsible for bone loss may make it easier to develop drug therapies.
"Recent understanding of bone cell function and of the pathophysiology of bone diseases has led to the availability of new therapeutic agents to treat these diseases," the authors write.
"There are clearly additional opportunities for developing new inhibitors of bone resorption, as well as effective stimulators of bone formation, so far a major unmet need."
"We are certainly closer than when we didn't know which way to look," Karsenty added.
SOURCE: Science 2000;289:1501-1514.
Copyright © 2000 Reuters Limited
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"Gentherapie braucht einfach Zeit" - auch
Raumfahrt hatte Misserfolge
Hintergrund
Von Gisela Ostwald, dpa
New York (sda/dpa) Nach Jahren der Trippelschritte und schweren Fehlschlaege sah es bis vor kurzem schlecht aus um die Gentherapie. Mehr als 420 Studien an 4000 Patienten in aller Welt liessen keinen Durchbruch erkennen.
Als Anfang 2000 dann auch noch der erste Patient den Folgen eines gentherapeutischen Experiments erlag, glaubten manche Experten an das Ende einer vielversprechenden, aber viel zu frueh bejubelten neuen Technologie.
Doch kurz vor ihrem zehnten Jubilaeum am 14. September wendete sich das Blatt und der Forscher, der als ihr Pionier gilt, triumphierte erleichtert: "Wie jedes andere Verfahren braucht die Gentherapie einfach ihre Zeit zur Entwicklung", bilanzierte French Anderson von der Universitaet von Suedkalifornien.
Auch Antibiotika und Organtransplantationen haetten Jahre zum Ausreifen benoetigt. Selbst beim bemannten Mondflug habe es "Schlappen und Enttaeuschungen gegeben", erinnert Anderson.
Erster Sieg
Grund fuer Zuversicht gibt den Spezialisten der erste klare Sieg franzoesischer Gentherapeuten im April dieses Jahres. Einem Team um Alain Fischer und Marina Cavazzana-Calvo am Necker Kinderspital in Paris gelang es, das Leben mehrerer Babys zu retten, die sonst vermutlich einer schweren Stoerung des Immunsystems erlegen waeren.
Nur drei Monate nach ihrer Behandlung konnten die ersten beiden Jungen, einer acht und der andere elf Monate alt, erstmals bei ihren Familien sein. Ein gutes halbes Jahr spaeter galten sie als geheilt. Babys mit ihrer Krankheit, schweres kombiniertes Immunversagen oder SCID genannt, feiern selten den ersten Geburtstag.
Nur das isolierte Dasein unter einer sterilen Glocke oder alternativ eine Rueckenmarkstransplantation mit weniger als 60 Prozent Aussicht auf Erfolg hatte sie bisher am Leben halten koennen.
Kenner raeumen ein, dass sich SCID "perfekt" fuer eine Gentherapie eignet. Die Zellen, die zur Heilung der Krankheit ein neues Gen brauchen, sind im Rueckenmark angesiedelt und damit relativ leicht zu erreichen. Die genetisch korrigierten Zellen breiten sich mit Hilfe der Koerperhormone schnell aus und ersetzen die Zellen mit defekten Genen.
Gentherapien gegen ein gutes Dutzend andere Krankheiten, kardiovaskulaere Leiden, die Alzheimer Krankheit, Hypercholesterinaemie (Ueberproduktion von Cholesterin) und vor allem Tumore, sind weitaus komplizierter und daher noch nicht so weit fortgeschritten.
Noch keine Hilfe bei Krebs
Nach einer Aufstellung des "Wiley Journal of Gene Medicine" vom Juni 2000 versuchen Forscher in aller Welt derzeit in 279 Studien an 2459 Patienten, Krebs mit Hilfe intakter Gene zu bekaempfen. Keiner der Versuche hat bisher zum langfristigen Erfolg gefuehrt.
Gentherapien fuer Leiden, die durch ein einziges defektes Gen verursacht werden (monogenetische Stoerungen), werden in weiteren 55 Studien an 306 Patienten erprobt, und Infektionskrankheiten in 33 Untersuchungen an 412 Kranken.
Die USA sind laut dem Journal der Schrittmacher auf dem gentherapeutischen Feld mit 310 Studien (72,9 Prozent), gefolgt von Europa mit 97 Studien (22,8 Prozent) und Asien mit neun Versuchen (2,1 Prozent). In Australien laufen drei Studien und in Afrika eine.
(SDA - mt/vm/4/c1 for/000905 0510)
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Von der Gentherapie zum Embryo-Design
Gespraech
Philadelphia (sda/dpa) In absehbarer Zeit, so glaubt der US-Bioethiker Arthur Caplan, werden reiche Paare ihren Nachwuchs nach dem Katalogverfahren kreieren: mit blonden Haaren oder schwarzen, Talent zum Malen, Klavier- oder Fussballspielen, sanft oder bestimmt.
Dass es moeglich ist, neue Gene in die Zellen des Menschen einzupflanzen, wissen Forscher seit Beginn der Gentherapie-Versuche am Menschen vor zehn Jahren. Bisher setzen sie das Verfahren nur gegen schwere Erbleiden ein, die durch ein defektes Gen verursacht werden.
Doch genauso lassen sich im Prinzip Aussehen, Verhalten und Intelligenz eines ungeborenen Menschen korrigieren. "Der Weg ist vorgezeichnet", sagt Caplan, der das namhafte Zentrum fuer Bioethik an der Universitaet von Pennsylvania leitet, im Gespraech. "Es ist nur eine Frage der Zeit".
Selektion
Schon jetzt werden Embryos in zwei US-Fruchtbarkeitskliniken und einem Institut in Grossbritannien nach ihren Anlagen selektiert. Die "guten" kommen in die Gebaermutter, die "schlechten" Embryos in den Gefrierschrank, berichtet Caplan. "Schlecht" ist, wenn ein weiblicher Embryo die muetterliche Veranlagung fuer Brustkrebs traegt. "Gut" ist ein Embryo ohne dieses mutierte BRCA-Gen.
"Mit der Zahl neuer genetischer Tests wird die Zahl der Elternpaare wachsen, die ihren Kindern ein krank machendes Gen ersparen wollen", sagt Caplan. Fuer ihn ist das aus ethischer Sichts nichts anderes, als ein mit Herzfehler geborenes Baby zu operieren.
Caplan bekuemmert jedoch die Tatsache, dass die Selektion des gesunden Embryos oder die Gentherapie beim Embryo ein Privileg betuchter Eltern bleiben wird.
Ausgefeiltes Verfahren
Der Zukunft gehoert nach seiner Meinung einem weiter ausgefeilten Verfahren, mit dem bisher nur experimentiert wird: Dem biotechnologischen "Engineering" von Samen- und Eizellen. Dabei wird eine Samenzelle durch Injektion einzelner Gene nach Wunsch "verbessert" und dann mit einer entsprechend verfeinerten Eizelle in der Laborschale vereint.
Die US-Regierung wird nach Auffassung von Caplan nur wenig oder gar nichts unternehmen, um diese Entwicklung zu stoppen. Selbst Kirchen duerften keine Einwaende erheben, wenn die genetische Manipulation am Samen oder am Embryo ein gesuenderes Kind mit besserem Gehoer und uneingeschraenkter Sicht produziert.
Dahingegen wuerden Eingriffe in die Keimbahn zur kosmetischen Korrektur, das heisst, zur Veraenderung des Aussehens und vielleicht der Intelligenz, mit Gewissheit den Protest von Geistlichen provozieren.
Doch kirchliche Einwaende werden die Entwicklung nicht aufhalten, glaubt Caplan. Ausser den USA wird nach seiner Einschaetzung auch Asien in den kommenden Jahrzehnten von diesen Moeglichkeiten der Biotechnologie Gebrauch machen.
(SDA - mt/vm/4/c1 for/000905 0515)
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In letzter Sekunde - DNA-Serum gegen giftige Natternbisse
Serum gegen Schlangengift wird immer knapper: Doch Anti-Serum soll bald mit moderner DNA-Technologie hergestellt werden - und so unzaehlige Leben retten.
Seit hundert Jahren helfen grosse Tiere, meist Pferde, bei der Herstellung von Antiserum. Ihnen injiziert man das Schlangengift in langsam steigenden Dosen, bis ihr Immunsystem Antikoerper produziert, die aus dem Blut isoliert werden. Diese Methode ist allerdings nicht wirtschaftlich, inzwischen spricht man von einer weltweiten Krise in der Antiserum-Produktion, besonders in Afrika.
In herkoemmlichen Antiseren sind zudem viele Antikoerper ueberfluessig, weil sie sich gegen harmlose Bestandteile des Giftes richten. Auch kann das Serum die so genannte "Serumskrankheit" oder einen anaphylaktischen Kreislaufschock ausloesen. Diese Nebenwirkungen fallen weg, wenn den Tieren statt des "Gift-Cocktails" der Schlange nur die Erbinformation der giftigen Bestandteile injiziert werden, erklaert Rob Harrison von der Liverpool School of Tropical Medicine.
Sein Team isolierte das Gen eines Enzyms aus dem Gift der Brasilianischen Lanzenotter Jacaraca (Bothrops jararaca), das innere Blutungen ausloest. Die Wissenschaftler brachten das Gen in groesseren Mengen auf mikroskopisch kleine Goldkuegelchen auf, und "schossen" sie in die Haut von Maeusen. Die Hautzellen der Maeuse stellten aus dem Gen das Enzym her, und der Organismus der Maeuse produzierte daraufhin Antikoerpern gegen das Enzym. Zwar richten sich diese Antikoerper nur gegen einen einzigen Bestandteil des Schlangengiftes, doch verhindern mehr als 70 Prozent der Blutungen, so Harrison.
Jetzt arbeitet die Gruppe an einem Gegengift fuer die Schlangenart Echis, auch Sandrasselotter genannt. "Diese Schlange ist fuer mehr Todesfaelle verantwortlich als jede andere Schlange der Welt", sagt Harrison. Er will menschliche Antikoerper herstellen, die im Koerper keine schaedlichen Nebenwirkungen hervorrufen. Dazu injiziert sein Team die Gift-Gene in genetisch veraenderte Maeuse, deren Immunsystem menschliche Antikoerper produziert. Dann wollen die Wissenschaftler die Zellen, die diese Antikoerper herstellen, isolieren und Zellkulturen verbinden, die sich im Reagenzglas wachsen - eine unerschoepfliche Gegengift-Quelle, ohne das jemals wieder Tiere verwendet werden.
[Quelle: Doerte Saþe und NewScientist]
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Meilensteine und Rueckschlaege der Gentherapie
In den vergangenen zehn Jahren hat es weltweit rund 500 Versuche zur Gentherapie am Menschen gegeben. Trotz einiger Erfolge gilt bislang keiner der beteiligten Patienten als wirklich geheilt. Folgend einige bedeutende Fortschritte und Rueckschlaege der Gentherapie.
1968: Der US-amerikanische Mediziner French Anderson reicht beim "New England Journal of Medicine" die Arbeit "Gegenwaertige Moeglichkeiten zur Behebung genetischer Defekte" ein. Sie wird als viel zu spekulativ abgelehnt.
1985: Die vom Bundesforschungsministerium eingesetzte "Benda- Kommission" segnet die Gentherapie in Deutschland verfassungsrechtlich ab. Die Keimbahntherapie wird hingegen abgelehnt.
1989: Die Uebertragung fremder Gene in einen Menschen mittels Retroviren ist in den USA erstmals gelungen. Es handelt sich jedoch nur um ein Markergen ohne therapeutischen Zweck.
1990: Der 14. September 1990 gilt als Start der Gentherapie. In den USA beginnt der erste klinische Versuch an einem Menschen. Patientin ist ein vierjaehriges Maedchen, das an der schweren, erblich bedingten Immunschwaechekrankheit, dem ADA-Syndrom, leidet.
1990: Verabschiedung des deutschen Embryonenschutzgesetzes. Es verbietet die kuenstliche Veraenderung menschlicher Keimbahnzellen.
1991: US-Forscher erproben erstmals die Gen-Therapie, um eine Krebserkrankung (Hautkrebs) zu bekaempfen.
1992: In Europa beginnt die erste gentherapeutische Studie. Der Mailaender Claudio Bordignon versucht, das ADA-Syndrom zu heilen.
1993: Drei an Zystischer Fibrose (Mukoviszidose) erkrankten Patienten wird mittels Adenoviren das intakte Gen in Zellen der Nasenschleimhaut eingeschleust. Das Krankheitsbild bessert sich allerdings nur fuer wenige Wochen.
1994: Erstmals wird die Gentherapie auch in Deutschland (Freiburg und Berlin) erprobt und zwar bei Krebserkrankungen.
1994: In den USA gelingt es, eine an einem erblich bedingten erhoehten Cholesterinspiegel (Hypercholesterinaemie) leidende Frau mit einer Gentherapie laengerfristig erfolgreich zu behandeln. Noch zwei Jahre nach der Erbgutmanipulation im Juni 1992 lag der Cholesterinwert der Frau 20 Prozent unter dem davor gemessenen Wert.
1995: In den USA schlagen Gentherapien zur Behandlung von zwei schweren Erkrankungen, Mukoviszidose und Muskelatrophie, fehl. In Tierversuchen waren die Verfahren zuvor vielversprechend verlaufen.
1999: Im September stirbt der 18-jaehrige Jesse Gelsinger aus Arizona. Er gilt als das erste Todesopfer der Gentherapie. Der junge US-Amerikaner hatte sich freiwillig gemeldet, um anderen zu helfen. Er selbst hielt sein Stoffwechselleiden mit einer besonderen Diaet und Medikamenten unter Kontrolle.
April 2000: In Paris gelingt eine Gentherapie bei Kleinkindern, die am ADA-Syndrom leiden. Nach zehn Monate nach der Behandlung fuehren die kleinen Patienten ein normales Leben.
Mai 2000: Nach einer Gentherapie stirbt ein Mann, dem in den USA das Gen fuer einen Blutgefaesswachstumsfaktor injiziert wurde. Ein direkter Zusammenhang mit der Gentherapie ist jedoch unklar.
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Science Group Opposes Inherited Gene Modification
WASHINGTON (Reuters) - The modification of human genes that can be passed to future generations is not safe at this time and should not be undertaken, the world's largest federation of scientists reported on Monday.
In a long-awaited report on human inheritable genetic modifications, known as IGM, the American Association for the Advancement of Science (AAAS) said no human trials of this kind of gene therapy should occur until standards and stringent oversight are in place.
The idea behind such research would be to free families of inherited genetic disorders, but by modifying inheritable genes -- those in a patient's sperm or eggs -- the therapy could introduce new genetic problems that would in turn be passed along to new generations.
The report noted that researchers have been successful in some cases with somatic gene therapy, which deals only with genes that cannot be inherited. But what works in somatic gene therapy will not now work to treat inherited genetic ills.
"IGM utilizing current methods for somatic gene transfer cannot presently be carried out responsibly to humans," Dr. Mark Frankel, the report's co-author, said in a statement.
Aside from strictly medical questions, the issues of ethics and religion come into play on this matter, the report said.
"GM might change attitudes toward the human person, the nature of human reproduction, and parent-child relationships," the scientists reported.
"IGM could exacerbate prejudice against persons with disabilities. The introduction of IGM in a society with differential access to health care would pose significant justice issues and could introduce new, or magnify existing inequalities," the report said.
If there is ultimately "a societal decision" to go ahead with IGM research, "The ethical and social issues are sufficiently compelling to justify government oversight in this case," Frankel said.
There should also be "a meaningful dialogue" with the American public, the scientists reported.
Copyright © 2000 Reuters Limited
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Inheritable gene modification research should not proceed on humans without standards and oversight, AAAS report says
Washington, DC - September 18, 2000 - Modifying human genes that can be transmitted to offspring is neither safe nor responsible at this time, according to a special report issued today by the American Association for the Advancement of Science (AAAS). The report identifies technological obstacles, the complexity of the ethical and religious implications and the absence of public oversight as issues that must be addressed before further research or application of technologies is undertaken. The report calls for the immediate appointment of a public body to oversee current research and development that can alter the human germ line.
The report reflects two-and-a-half years of study by a working group of scientists, ethicists, theologians and policy analysts convened by AAAS and funded by the Greenwall Foundation. Since the project began, studies involving animals have made it clear that scientists are improving the technical capacity to manipulate genetic material for transmission to future generations.
The panel looked at both the potential benefits of human inheritable gene modification (IGM) and the significant concerns about it. Recently, researchers announced credible success in improving patient health through somatic (non-inheritable) gene therapy, signaling that years of research are about to bear fruit. Theoretically, modifying genes that are transmitted to future generations could prevent and possibly decrease the incidence of certain inherited diseases, according to the report.
Currently, however, neither the safety nor efficacy of such genetic interventions has been determined, nor are they likely to be for the foreseeable future, due to technical obstacles. According to Dr. Mark S. Frankel, director of AAAS's Scientific Freedom, Responsibility and Law Program and co-author of the report, "IGM utilizing current methods for somatic gene transfer cannot presently be carried out responsibly on humans." Consequently, the AAAS report recommends that human trials of inheritable genetic changes should not be initiated until reliable techniques for gene correction or replacement are developed that meet agreed upon standards for safety and efficacy.
Serious ethical and religious issues also must be addressed as research policy is formulated, according to the report. IGM, for instance, raises questions of justice and the allocation of resources. Will IGM be a technology that only the wealthy and advantaged are able to access? What safeguards are necessary to prevent unequal access? IGM also could potentially affect our relationships with future generations, raising "major ethical concerns about the attitudes toward the human person, the nature of human reproduction, and the parent-child relationship," the report states.
According to Dr. Audrey R. Chapman, director of AAAS's Program of Dialogue on Science, Ethics and Religion and co-author of the report, "IGM for enhancement, meaning applications to produce improvements in human form or function, would be particularly problematic."
The report recommends that if a societal decision is made to proceed with IGM research, "comprehensive oversight mechanisms should be put in place to review and approve all IGM protocols for research and applications in both the public and private sectors." "The ethical and social issues," according to Frankel, "are sufficiently compelling to justify government oversight in this case."
Chapman also noted that a way must be found to hold an informed conversation with the American public to educate and empower them in the debate. "A meaningful dialogue on such an important topic can't be left solely to experts. It needs public deliberation."
AAAS, the world's largest federation of scientists, works to advance science for human well-being through its projects, programs and publications. With more than 146,000 members and 275 affiliated societies, AAAS conducts many programs in the areas of science policy, science education and international scientific cooperation. AAAS publishes the prestigious peer-reviewed journal Science, as well as a number of electronic features on the World Wide Web.
Contact: Cate Barnett Alexander
calexand@aaas.org
202-326-6431
http://www.aaas.org/spp/dspp/sfrl/germline/main.htm
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Eingriffe in die Keimbahn: Weiterhin tabu?
Amerikanische Expertengruppe empfiehlt ein Moratorium
Ein von der American Association for the Advancement of Science zusammengerufenes Expertenteam kommt zum Schluss, dass es zum jetzigen Zeitpunkt unverantwortlich sei, die Ei- oder Samenzellen von Menschen gentechnisch zu veraendern. Mit dem soeben veroeffentlichten Bericht verfolgt die Organisation das Ziel, eine oeffentliche Diskussion ueber die ethisch umstrittene Keimbahntherapie in Gang zu bringen.
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text truncated for copy-right reasons, please read the full text at: http://nzz.gbi.de/NZZ.ein
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Copyright © 2000 Neue Zuercher Zeitung AG
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Rush Presbyterian St. Luke's Medical Center, October 26, 2000 |
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Rush Presbyterian St. Luke's Medical Center
Gene therapy shown to protect and reverse the debilitating effects of Parkinson's disease in pre-clinical studies
Researchers at Rush-Presbyterian-St. Luke's Medical Center, Chicago, and Lausanne, Switzerland, have successfully used gene therapy to reverse the anatomical, cellular changes that occur in the brains of primates with Parkinson's disease. The researchers also report success in preventing the disease from progressing and reversing functional deficits or symptoms associated with the disease in monkeys displaying early signs of Parkinson's disease.
Results of the research are published in the Oct. 27 issue of the journal Science.
Rush scientists used a special virus (lenti-GDNF), which was developed by colleagues in Switzerland to deliver the gene for glial-derived neurotrophic factor (GDNF) directly to the brain cells of monkeys.
GDNF is a nutrient that strengthens and protects brain cells that would normally die in this disease. GDNF also increases production of the chemical neurotransmitter dopamine, which sends signals in the brain that enable people to move smoothly and normally. The loss of dopamine in the brain causes the symptoms of Parkinson's disease.
"The lentiviral vector delivery system was effective in getting GDNF to the specific sites needed to rescue the cells and enhance the production of dopamine. By giving GDNF, we can stimulate dopamine production and prevent both the structural and functional consequences of cell degeneration that are characteristic of Parkinson's disease," said Jeffrey H. Kordower, PhD, the principal author of study. He is professor of neurological sciences and director of the Research Center for Brain Repair at Rush-Presbyterian-St. Luke's Medical Center in Chicago. Study collaborators at the Lausanne University Medical School are Patrick Aebischer, MD, PhD, and Nicole DÈglon. PhD.
Two groups of monkeys were involved in the research. The first group was studied to determine if and how the lentivirus delivery system affected the anatomy of the aged brain cells. The second group was studied to identify whether the lentivirus treatment had any affect on the behavior or functional problems associated with Parkinson's disease.
The first group in the study involved eight, aged monkeys (approximately 25 years old) whose brains displayed specific cellular changes associated with early Parkinson's disease. In this stage of the disease, the brain cells remain intact but either stop making dopamine, or make less dopamine than normal. They received six injections of the lenti-GDNF into the brain.
Before treatment, the monkeys' brains were analyzed using positron emission tomography (PET). After three months of treatment, their brains were extensively analyzed using PET as well as neuroanatomical, neurochemical and molecular biological techniques. The results showed a dramatic increase in the production of dopamine, similar to levels of dopamine found in the brains of young monkeys.
The second group included 20 young monkeys with no symptoms of Parkinson's disease. To evaluate any changes on function or behavior during the course of the study, each monkey was trained to perform consistently on a hand-reach task requiring them to pick-up food treats out of recessed wells. They were also analyzed on a Parkinsonian clinical rating scale (CRS), an observational assessment of movement analogous to one used by neurologists to assess patients with Parkinson's disease. The CRS assessment and the hand-reach task training indicated that they did not have any symptoms of Parkinson's disease.
The monkeys then received the chemical MPTP, which has been shown to initiate a Parkinson's disease-like state in monkeys and humans. A week later they were tested again using the hand-reach test and the CRS. The monkeys exhibited great difficulty in performing the hand-reach task, and the CRS analysis also verified the presence of Parkinson's symptoms.
The animals were then injected with the lenti-GDNF. One week later, a three-month re-testing period was begun using the hand-reach task and the CRS. As a result of the lenti-GDNF treatment, performance on the hand-reach test improved to near normal, similar to how they performed prior to injection of MPTP. Scores on the clinical rating scale also improved significantly.
The monkeys in this second group also received a PET scan, and their brains were extensively analyzed. Results showed that the treatment completely prevented degeneration of the dopamine system: brain cells and their fibers were preserved, and increased levels of dopamine were produced.
As a control for the study to insure that it was not the injections themselves that resulted in improvements but rather the lenti-GDNF, half the monkeys in each group received injections of a control lentivirus, lenti-þGal. The monkeys receiving the lenti-þGal virus displayed robust expression of þGal, indicating the effectiveness of the lentivirus delivery system. However, as expected, the delivery of the lenti-þGal had no effect on the structure and anatomy of the brain cells and did not improve the impaired behavior of the Parkinsonian monkeys.
A third group of normal monkeys received lenti-GDNF and was allowed to survive for eight months. High levels of GDNF were found in these animals, demonstrating long-term gene expression using this delivery system.
"The study suggests a new approach to forestall disease progression in newly diagnosed Parkinson's disease patients by delivering potent trophic factors with effects that are long-term and non-toxic," Kordower noted.
He anticipates that clinical testing in humans of the lentiviral delivery system for GDNF will begin in Switzerland and the U.S. in less than five years following review in this country by the Food and Drug Administration.
The research was supported by grants from the U.S. Department of Defense; the Swiss National Science Foundation; and the Swiss National Program in Neurological Diseases.
Parkinson's is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson's disease that includes: resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs; and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.
Parkinson's disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. While there is currently no cure for Parkinson's disease, progressive treatments allow many patients to maintain a high level of function throughout their lifetimes. It is not a fatal illness.
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Parkinson-Krankheit
Neue Erkenntnisse dank Gentherapie
Lausanne/Chicago(sda/dpa) Eine Gentherapie koennte in Zukunft Parkinson-Kranken helfen. Das geht aus Tierversuchen hervor, die eine internationale Forschungsgruppe gemacht hat. Ihre Arbeit wurde am Freitag im US-Wissenschaftsmagazin "Science" veroeffentlicht.
Die Forschungsgruppe, an der sich auch Forscher der Universitaeten Lausanne und Genf beteiligten, schaffte es durch eine Gentherapie bei Rhesusaffen, die Degradation der Zellen und das Fortschreiten der Krankheit zu bremsen.
Die Mediziner injizierten hirngeschaedigten Rhesusaffen Lentiviren mit dem Gen fuer den menschlichen "neurotrophen Faktor GDNF" direkt in die zerstoerten Hirnareale. Derartige Faktoren steuern die Arbeitsweise von Nervenzellen, die auch an der Kontrolle der Muskeln beteiligt sind.
Noch keine klinischen Tests
Bevor klinische Tests begonnen werden, seien aber noch einige Huerden zu ueberwinden, schreibt "Science". So schoss die eigentlich erwuenschte Steigerung der Dopamin-Konzentration in den behandelten Hirnarealen ueber das erwartete Mass hinaus. Statt zu wenig produzierten die Nerven zu viel Dopamin.
Der Botenstoff Dopamin spielt im Gehirn eine Schluesselrolle bei der Parkinson-Krankheit. Ist zu wenig Dopamin in einigen Bereichen des Gehirns vorhanden, wird die Signaluebertragung zwischen den Nervenzellen gestoert. Die Kontrolle ueber die Muskeln nimmt ab, es kommt zu der als Schuettellaehmung bekannten Parkinson-Krankheit.
Jaehrlich mehr als eine Millionen Menschen
Laut der Weltgesundheitsorganisation WHO erkranken weltweit jaehrlich mehr als eine Million Menschen an der Parkinson-Krankheit. Allein in der Schweiz sind gegenwaertig rund 15 000 Menschen davon betroffen.
Im Laufe der Krankheit sterben im Gehirn Nervenzellen ab. Klassische Symptome sind Zittern, Verlangsamung, Versteifung der Muskulatur und Gleichgewichtsstoerungen.
(SDA - kn ucst rs/vm/5/vd ge c1 sozm for comm/001027 1401)
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Doctor: U.S. Restores Heart Gene Therapy Trials
By Maggie Fox, Health and Science Correspondent
NEW ORLEANS (Reuters) - Gene therapy trials suspended in a government crackdown after a teen-age patient died have been allowed to start again and will be up and running next week, the researcher in charge said on Sunday.
Dr. Jeffrey Isner of Tufts University and St. Elizabeth's Hospital in Boston, who had been conducting three separate gene therapy trials aimed at helping patients grow new blood vessels to alleviate diseases of the heart and artery, said he hoped to re-start them this week.
"We are now, as of this coming week, able to resume our trials of gene therapy," Isner told a news conference at a meeting of the American Heart Association.
"All the issues that were raised have been satisfactorily addressed," Isner added in an interview later.
Isner has been working to try to help patients grow their own heart bypasses by giving them genes that make new blood vessels grow. One group is getting a gene called vascular endothelial growth factor-1 (VEGF-1) and a second group has been getting VEGF-2.
Isner's team has reported some success with the treatments, with patients saying they have less chest pain and other evidence of improved blood flow, which Isner believes suggests they have grown tiny new blood vessels.
A third group of patients got VEGF in clogged arteries in the legs and they also reported improvements.
The successes were among the first chalked up for gene therapy, an experimental new field that shows promise in theory but which scientists have found harder to make work in real patients.
In September of last year, 18-year-old Jesse Gelsinger died during a gene therapy experiment aimed at correcting an inherited liver disorder. His was the first death directly attributed to gene therapy.
The National Institutes of Health (NIH) and Food and Drug Administration (FDA) responded by investigating all gene therapy trials. In May, the FDA suspended Isner's program and issued a strongly worded letter accusing him of failing to report the death of one patient and saying he showed a ``serious lack of knowledge'' about his duties.
Isner has since said 16 of the FDA's 21 findings were in error and said on Sunday he had resolved the rest.
Researcher Says Fda Overreacted
Isner, who thinks his approach may be a way to help the most severely ill heart disease patients, who cannot be helped with bypass surgery, said he is keen to resume his work.
"Much of the hysteria has died down," he said. "The atmosphere has been a lot more positive."
"Whenever someone young, in the prime of life dies ... that is a horrendous tragedy. I think some of the reaction to it was understandably severe (but) quite frankly an overreaction."
Isner's trials are sponsored by Vascular Genetics Inc. of Durham, North Carolina, a company he helped found in 1997.
He is one of many researchers who stand to gain financially from their own work. The American Society of Gene Therapy says this poses a potential conflict of interest, but Isner and St. Elizabeth's, which also has a stake in the work, say it does not influence the research.
Also on Sunday, Isner said a whole new line of research, involving the use of immature versions of the endothelial cells that line blood vessels, may also help grow bypasses.
Copyright © 2000 Reuters Limited
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Reuters, December 7, 2000 |
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New Gene Therapy Approach May Treat Diabetes
By Maggie Fox, Health and Science Correspondent
WASHINGTON (Reuters) - Gene therapists might be able to retrain cells in the stomach and intestine to produce insulin and treat diabetes, scientists said on Thursday.
They said they had genetically engineered gut cells in mice to produce human insulin. The genetically engineered mice survived without developing diabetes even after their pancreatic cells, which normally produce insulin, were destroyed, the researchers said.
Their report, published in the journal Science, is the second in as many months to suggest that gene therapy might be used to treat or even cure diabetes, which affects 16 million people in the United States alone.
The idea is to replace the insulin produced by pancreatic beta cells by genetically altering cells that make similar substances in the body. In type I, or juvenile, diabetes, the beta cells in the pancreas are destroyed and in type II, or adult-onset, diabetes the body is no longer able to use insulin effectively.
Tests on human patients are a long way off, said Timothy Kieffer, a researcher at the University of Alberta in Edmonton, Canada who helped lead the study.
"The approach that we took in this study is clearly not applicable to treat human patients, so what we need to do now is develop a suitable delivery system to get into humans," he said in a telephone interview.
Kieffer, Anthony Cheung and colleagues used cells in the gut called K cells, which are similar to beta cells.
K cells secrete the hormone GIP, which works with insulin, which in turn helps the body use fats and glucose effectively.
"The role of GIP is to tell the pancreatic beta cells that there is food in the intestine containing glucose," Kieffer said. He said if they could be made to produce insulin, the body would probably handle it better than it handles the injected insulin used by diabetics.
They took K cells from mice and inserted the human insulin gene. They injected this new gene into mouse embryos and found when the mice were born, they produced human insulin in the small intestine and stomach.
K-Cell Insulin Prevented Diabetes
"This insulin protected the mice from developing diabetes," the researchers wrote. They tested this by destroying the beta cells of the mice. Normal mice died of diabetes but the genetically engineered mice survived.
This could be a useful approach for gene therapy for diabetes, the researchers said.
"There are many features of the upper gastrointestinal tract that make it an attractive target for gene therapy," they wrote. It is easy to get to without surgery, using tools such as endoscopes, so it would be easy to deliver gene therapy directly to the area.
Kieffer said it might even be possible to deliver the new genes orally, in a pill or perhaps using liposomes, little balls of fat, encased in food or some other carrier.
And the gut is full of stem cells -- the immature master cells that can give rise to many other types of cells, which are again preferred targets of gene therapy. Kieffer said if stem cells could be genetically changed, instead of mature cells, the effects will last much longer.
Theirs is the second report in as many months on gene therapy and diabetes. In November, teams at the University of Calgary and Yonsei Medical School in Seoul used genetic engineering to make mice produce human insulin in their livers.
In February a team at Ariad Pharmaceuticals Inc. said they genetically engineered mouse muscle cells to produce extra insulin when "told" to do so by a drug given orally.
And Canadian researchers reported in August that they had transplanted pancreatic islet cells into patients to treat their diabetes.
Kieffer thinks a gene therapy approach may work better than transplants, because the immune system will attack any transplanted cells. Thus patients who get transplants have to take immune-suppressing drugs.
"A potential feature of the gene therapy approach is that by making another cell in the body take over the production of insulin, we hope this would ameliorate the requirement for immunosuppression," he said.
Kieffer, whose work was paid for by the Juvenile Diabetes Research Foundation, the Heritage Foundation and the Canadian Diabetes Association, said he and Cheung had formed a company under the auspices of the University of Alberta, called enGene, to help move the research along.
Copyright © 2000 Reuters Limited
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Washington Post, December 13, 2000 |
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Gene Research Rule Proposed
By Rick Weiss, Washington Post Staff Writer
Fifteen months after the field of gene therapy was roiled by the death of a teenage volunteer and by revelations that many researchers had failed to tell regulators about complications in their own gene therapy studies, the Clinton administration yesterday proposed a new system for tracking dangerous side effects of the experimental treatments.
A proposed federal rule, published in yesterday's Federal Register, seeks to resolve conflicts between patient advocates who have called for full public disclosure of all ill effects in gene therapy volunteers, drug companies that hope to profit from the nascent field of medicine but are accustomed to keeping the details of their studies confidential, and researchers who have complained about being overburdened with regulations.
It attempts to achieve middle ground by loosening old requirements that had demanded immediate reporting of all serious complications, while at the same time beefing up federal attention to those complications when they're reported.
Representatives of groups that would be affected by the change quickly found fault with various aspects of the proposed rule. It remained unclear yesterday whether that meant the rule was a good compromise or was doomed to political oblivion.
At issue are so-called serious adverse events, including deaths, life-threatening episodes or significant incapacities that occur in volunteers getting gene therapy, an experimental approach that seeks to cure diseases by giving people new genes.
For the past 10 years the National Institutes of Health has demanded that all serious adverse events occurring in gene therapy volunteers be reported to that agency immediately, whether they seem to have been caused by the treatment itself or were probably a normal outcome of the patient's underlying condition.
That standard is more strict than the Food and Drug Administration's rule that immediate reporting is required only when researchers believe the problem may have been caused by the treatment itself--a difference that reflects NIH's longstanding concern that researchers might not be able to tell if a problem was caused by the novel treatment or not.
Three events last fall triggered a review of the NIH policy. First, several gene therapy companies submitted adverse-event reports with demands that the data be kept confidential, in violation of NIH's policy of public access. Second, a nationwide review indicated that many researchers were not even reporting adverse events to the NIH as required. And third, Tucson teenager Jesse Gelsinger became the first person to die as a clear and direct result of gene therapy.
The newly proposed rule reaffirms that all adverse events should be made public. But it calls for researchers to immediately report to the NIH only those serious adverse events believed to have been possibly caused by the treatment. That standard is in harmony with FDA's rules, a simplification that researchers said they applauded. But some patient advocates criticized the change, saying researchers cannot be expected to be unbiased when it comes to deciding whether their treatment has caused a problem.
"It's very disturbing that they are going to do something like this, where everyone can decide for themselves," said Abbey S. Meyers, president of the National Organization for Rare Disorders in New Fairfield, Conn.
Under the rule, problems deemed unrelated to the treatment must be submitted in annual summary reports--which a new NIH subcommittee would analyze, along with other reports, to watch for worrisome trends.
Paul Gelsinger, Jesse's father, said he favored the extra oversight the new committee would bring and didn't mind if some adverse-event reports got submitted annually instead of immediately--as long as it would encourage better reporting overall. "Remember," he said, "some of these guys weren't reporting adverse events at all before."
But Carl Feldbaum, president of the Biotechnology Industry Organization, criticized those aspects of the new rule, saying they would allow too much public access to commercial data he believes should be confidential. Moreover, he said, the NIH subcommittee's duties would be redundant with the FDA's.
"It usurps FDA's regulatory authority and turns the death of Jesse Gelsinger into some kind of a turf battle," he said.
The NIH is accepting comments on the proposed rule through Feb. 10.
© 2000 The Washington Post
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Frankfurter Allg. Zeitung, December 13, 2000 |
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Noch sind unendlich viele Krankheiten nicht zu beherrschen
Noch sind unendlich viele Krankheiten nicht zu beherrschen
Deutsche Bank: Biotechnik waechst jaehrlich um 20 Prozent bis
2010
Qiagen und Cybio machen Gewinn
lid. FRANKFURT, 12. Dezember. Die Biotechnik-Industrie verspricht fuer die kommenden Jahre noch viel Potential. "Die Biotechnik befindet sich am Anfang", schreiben die Analysten der Deutschen Bank in einer Studie. Bis zum Jahr 2010 koennte nach Meinung der Analysten der Umsatz mit Biotechnik-Produkten, der im vergangenen Jahr noch bei 30 Milliarden Euro lag, auf knapp 200 Milliarden Euro wachsen. Das waere ein jaehrliches Wachstum um knapp ein Fuenftel. "Der Wandel in der Pharmaindustrie ist so grundlegend, daþ die Biotechnik fast zwangslaeufig wachsen muþ. Es gibt heute unendlich viele Krankheiten, die noch nicht beherrschbar sind. Mit der Biotechnik kann dieses Potential erschlossen werden", sagt Sven Dopke vom Bankhaus M.M. Warburg. Dass der Hoehenflug der Biotech-Werte in den vergangenen Wochen ein wenig ins Stocken geraten ist, beunruhigt ihn nicht: "Langfristig sind wir sehr positiv gestimmt", sagt er. Der deutschen Biotech-Industrie prognostiziert die Deutsche Bank ebenfalls hohe Wachstumsraten. Der Umsatz, der im vergangenen Jahr 520 Millionen Euro erreichte, koennte der Studie zufolge auf rund 3 Milliarden Euro steigen. Dabei hinkt die deutsche Biotechnik-Branche im internationalen Vergleich noch hinterher, holt aber auf. Erstmals hat Deutschland im vergangenen Jahr Grossbritannien in der Zahl der Unternehmen uebertroffen (279 im Vergleich zu 270). Gemessen an Umsatz, Marktkapitalisierung und Mitarbeiterzahl liegt Deutschland allerdings noch deutlich dahinter. Klar an der Spitze sind noch immer die Vereinigten Staaten, wo 12 der 15 groessten Biotech-Unternehmen der Welt ihren Sitz haben. Allerdings erzielten selbst dort von 317 boersennotierten Unternehmen nur zehn Gewinne. In Deutschland sind zwei der Biotechnikunternehmen im engeren Sinne (Qiagen und Cybio) in der Gewinnzone.
Einer der auffaelligsten Unterschiede der deutschen Biotechnik-Branche gerade im Vergleich zu den Vereinigten Staaten ist, dass es hierzulande vor allem Dienstleister fuer die Arzneimittelhersteller gibt, also beispielsweise Technikplattformlieferanten wie Morphosys und Evotec oder Bioinformatik-Spezialisten wie Lion Bioscience. Nur wenige Unternehmen entwickeln selbst potentielle Medikamente. In den Vereinigten Staaten haben sich beispielsweise Amgen und Biogen zu grossen Pharmaunternehmen entwickelt. In Deutschland gibt es als reinrassigen Medikamentenhersteller am Neuen Markt bislang nur das Unternehmen Medigene.
Fuer den Anleger wird nach Ansicht von Experten gerade die Entscheidung zwischen Arzneimittelproduzent und Dienstleister eine der wichtigsten sein. Produkthersteller bieten groessere Chancen, aber auch groessere Risiken. So war der Boersengang von Medigene einer der erfolgreichsten aus dem Biotechnik-Segment in diesem Jahr. Auf der anderen Seite gilt bei solchen Unternehmen das Ausfallrisiko als wesentlich hoeher, Rueckschlaege in den Entwicklungsphasen von Medikamenten koennen den Aktienkurs sofort abstuerzen lassen. Dafuer gab es in Grossbritannien und den Vereinigten Staaten schon zahlreiche Beispiele. "Der Anleger muss hier genau die Forschungsergebnisse in den verschiedenen Entwicklungsstadien beobachten", sagt Dopke.
Bequemer hat es der Anleger seiner Meinung nach bei den Dienstleistern: Das deutsche Paradebeispiel dafuer ist Qiagen, ein Biotechnik-Zulieferer, der keinerlei Ambitionen hegt, jemals selbst Medikamente zu entwickeln. "Wenn man an die Biotechnikindustrie glaubt, muss man auch an Qiagen glauben", sagt Dopke. Die Aktie hat sich von ihrem Jahreshoechststand von 61 Euro im Juli dieses Jahres weit entfernt und notiert derzeit um 43 Euro. Dopke meint, dass die Aktie in den kommenden zwoelf Monaten auf 55 Euro steigt.
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Die Welt, December 15, 2000 |
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Forscher wollen das Leben der Menschen verlaengern
Forscher wollen das Leben der Menschen verlaengern Revolution durch Gentechnik - WELT-Gespraech Berlin - Auf dem Weg zur kuenstlichen Verlaengerung des menschlichen Lebens stehen Wissenschaftler vor einem Quantensprung. Im Gespraech mit der WELT sagt der Genforscher André Rosenthal revolutionaere Entwicklungen voraus. "Mit Hilfe neuer Therapien werden wir die Lebenserwartung der Menschen in den hoch industrialisierten Laendem der westlichen Welt weiter erhoehen koennen", sagt Rosenthal. Bahnbrechende Fortschritte erwartet er durch die Gentechnik. "In zehn bis 20 Jahren wird es eine Vielzahl neuer Therapeutika gegen bisher nicht oder nur schlecht therapierbare Volkskrankheiten wie Krebs oder Herz-Kreislauf-Erkrankungen im Markt geben", so Rosenthal, der durch die Entschluesselung des menschlichen Genoms beruehmt wurde und auf diesem Gebiet neben Craig Venter zu den fuehrenden Forschem auf der Welt gehoert. Laut Rosenthal sind internationale Wissenschaftler zurzeit fieberhaft dabei, Gene zu finden, die den Alterungsprozess steuern. Er schliesst nicht aus, dass "man eines Tages durch somatische Gentherapie das physische Lebensalter des Menschen wird verdoppeln koennen". Auf der Suche nach der Pille fuer das ewige Leben sind US-Wissenschaftler jetzt einen wichtigen Schritt vorangekommen, und zwar in Experimenten mit Insekten. Die Wissenschaftler fanden eine Genveraenderung, die Fruchtfliegen doppelt so lange leben laesst wie gewoehnlich. Das gleiche Gen ist - ohne diese Mutation - auch im menschlichen Erbgut vorhanden. "Dieses Gen stimmt optimistisch, dass es in der Tat eines Tages moeglich wird, die aktive Lebensspanne zu manipulieren..." sagte der Genetiker Seymour Benzer vom Califomia Institute of Technology in Pasadena. Seine Forschungsergebnisse sind in der neusten Ausgabe des USFachmagazins "Science" veroeffentlicht.
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SDA, December 21, 2000 |
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Thérapie génique pour leurrer le virus du sida
Paris (ats/afp) Une percée dans la lutte contre le virus du sida pourrait avoir été ouverte par une équipe de chercheurs français. Pour la première fois, ils sont parvenus, par thérapie génique, à bluffer le virus pour l'empêcher de pénétrer à l'intérieur des cellules qui constituent sa cible privilégiée.
Pour le moment, ces travaux - publiés vendredi dans la revue américaine AIDS - ont seulement porté sur des souris. Mais les chercheurs comptent passer aux singes puis, très vite, aux essais sur l'homme. Et ils n'excluent pas, à terme, de pouvoir ainsi prendre la relève des multithérapies.
Sans défenses
Les souris sur lesquelles les scientifiques ont travaill avaient été modifiées génétiquement pour naître dépourvues de défenses immunitaires. Et ainsi pouvoir recevoir des cellules humaines sans les rejeter. Deux gènes produisant des protéines empêchant le virus de se fixer sur les cellules ont ensuite été injectés dans leur organisme, puis, une semaine plus tard, le virus du sida.
Attir
"Quand le virus du sida rencontre une cellule humaine, il est attiré par des récepteurs précis, les CD4, sur lesquels il se fixe pour pénétrer à l'intérieur de celle-ci", a expliqué le Dr Kamel Sanhadji. Responsable du laboratoire sur les déficits immunitaires de l'hôpital Edouard-Herriot de Lyon, il a dirigé l'équipe de chercheurs.
"Nous avons voulu imiter ce processus en fournissant ces récepteurs au virus, mais sous une forme soluble", a précisé le chercheur. Ainsi trompé, le virus se précipite sur les CD4 qui se promènent librement dans l'organisme, s'y fixe, et finit par mourir faute de pouvoir prendre le contrôle de la cellule.
IndÈtectable
"En trois semaines, la quantité de virus présente dans le sang devient indétectable, même avec les moyens les plus sophistiqués comme l'amplification génique", a souligné le Dr Sanhadji. L'évaluation de cette "charge virale" a été réalisée dans le service de virologie du Pr Christine Rouzioux, à l'hôpital Necker de Paris.
Il n'est toutefois pas exclu que le virus puisse se cacher ailleurs, dans le cerveau, la moelle épinière ou les ganglions, comme il le fait normalement chez l'homme.
Deux trois ans à venir
Mais comme les souris - même génétiquement modifiées - ne s'infectent pas, même un examen post-mortem de ces organes ne permet pas de vérifier cette hypothèse. Les chercheurs vont maintenant devoir procéder à des essais sur des animaux plus proches de l'homme, chimpanzés ou macaques.
Selon le Dr Sanhadji, dans les "deux trois ans ý venir", desessais pourraient débuter chez des malades. Notamment ceux qui se montrent résistants aux tri-thérapies et dont la proportion - actuellement de 10 à 20 % - augmente régulièrement.
(SDA - ep/fd/4/c4fra sozm for/001221 1911)
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Tagesanzeiger, December 27, 2000 |
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Gentherapeuten melden erste Erfolge
goto: http://www.tagesanzeiger.ch
Von Nicola Siegmund-Sohultze
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Source & Date |
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Gentherapeuten
melden erste Erfolge