NFP37 SOMATIC GENE THERAPY

'MEDIA and NEWS 1999'

a collection of Gene Therapy-related news

updated Feb 15, 2000


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Catalogue of Entries

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Date

Source

Contents

13 Dec 1999

Reuters, Wash.

Panel urges strict reporting of gene therapy trial complications

11 Dec 1999

Washington Post

Gene Therapy Firms Resist Publicity

12 Dec 1999

Reuters, Wash.

Patients Keep Faith Despite Gene Therapy Death

08 Dec 1999

ATS / Washington

La thérapie génique accouche de super-cochons

02 Dec 1999

Washington Post

Researchers Claim No Error in Gene Therapy Death

01 Dec 1999

Bild der Wissenschaft

Gentherapie: Silberstreif am Horizont: Erste positive Ergebnisse

01 Dec 1999

Neue Zücher Zeitung

Gentherapie-Forscher: verkannte Helden oder Roulettespieler? Missverhaeltnis von Wunsch und Wirklichkeit

26 Nov 1999

The Associated Press

Gentherapie steht noch am Anfang: ´Erwartungen zu hoch geschraubt' - Nur bescheidene Erfolge

Nov 21 1999

Washington Post

Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns

Nov 13 1999

BritMedJour

Where are we going? Gene therapy: lessons learnt from the past decade

Nov 3 1999

Washington Post

Six gene therapy deaths kept from NIH

Oct 20 1999

BBC Sci/Tech

Artificial chromosomes

Oct 15 1999

Tagesanzeiger

'GENE THERAPY STOPPED' (front page & special report including annual meeting NFP37 1999)

Oct 1999

News agencies

Successful bypass amelioration with gene therapy (reports of Dr. Victor Dzau, Boston)

Sept 29 1999

Washington Post

Report on death of teenage patient under gene therapy

Aug-Sept 1999

News agencies & Tagesanzeiger

Successful gene correction with Chimeraplasty (in animals and plants)

 

 

 

 

 

 


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TagesAnzeiger vom 15.10.99

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Gentherapie gestoppt

(FRONT PAGE TITLE ON TWO COLUMS)

Reaktion auf einen Todesfall: In den USA und der Schweiz wurden Versuche zur Gentherapie vorerst gestoppt.

Zuerich. - Die Schweizerische Kommission fuer Biologische Sicherheit (SKBS) setzt "fuer den Moment" eine laufende internationale Studie zur Gentherapie aus. Es laegen "gewisse Aehnlichkeiten" mit einer US-Studie vor, lautet die Begruendung.

Ein Gentherapieversuch an der US-Universitaet Pennsylvania hatte Mitte September den Tod eines 18-Jaehrigen zur Folge. Die amerikanische Aufsichtsbehoerde FDA stoppte daraufhin am vergangenen Freitag "vorsorglich" zwei weitere Gentherapieversuche an Krebspatienten. Nun reagiert auch die Schweiz. Sandro Rusconi, Leiter des nationalen Forschungsprogramms "Somatische Gentherapie", sieht dennoch keinen Grund, die neue Methode endgueltig zu verurteilen. Gerade jetzt stellten sich erste Erfolge ein, so Rusconi.

Noch ist nicht endgueltig geklaert, woran genau der Amerikaner starb. Sicher ist jedoch, dass die Gentherapie dafuer verantwortlich ist. Der Versuch zielte darauf ab, eine erblich bedingte Stoffwechselstoerung der Leber zu heilen. Dazu wurden dem Patienten Adenoviren injiziert, die "gesunde" Gene einschleusen sollten. "Die Virendosis war zu hoch", erklaerte Gentherapeut Inder Verma dem "Tages-Anzeiger".

Noch im Versuchsstadium

Die Gentherapie am Menschen befindet sich noch im Versuchsstadium. Seit 1990 wurden weltweit rund 3000 meist todkranke Menschen mit der neuen Methode behandelt. Geheilt wurde bisher keiner. In der Schweiz wurde 1993 ein Nationalfonds-Programm zur Foerderung der neuen Technik lanciert. Seither wurden 22 Versuche zur Gentherapie vorgenommen, vier weitere stehen kurz vor dem Start. (kess)

 

 

Bisher haben die fremden Gene nicht geheilt
(PAGE 43: TITLE OVER ENTIRE PAGE)

Die Gentherapie hat bis heute keine Heilung gebracht. Auch in der Schweiz wurden die meisten Studien erfolglos abgeschlossen.

Von This Wachter

"Weiter so!" ruft der Biochemiker Sandro Rusconi von der Universitaet Freiburg seinen Forscherkollegen zu, "auch wenn euch jemand fragt: Wo ist eigentlich das Fleisch an der Sache?" Den flammenden Appell richtete Rusconi an 200 Fachleute der Schweizer Gentherapieforschung. Diese versammelten sich kuerzlich in Freiburg zur Jahrestagung des Nationalen Forschungsprogramms "Somatische Gentherapie".
Rusconi, Leiter des Programms, zieht Bilanz ueber den jungen medizinischen Forschungszweig. Mit dem Fleisch an der Sache deutet Rusconi die Heilungschancen durch das neue Verfahren an - und die ist gering. Denn was noch zu Beginn der Neunzigerjahre als kommende Technologie gefeiert wurde, funktioniert noch nicht. Bis heute sind weltweit rund 3000 meist todkranke Menschen gentherapiert worden. Geheilt worden ist davon keiner.
Auch in der Schweiz haben die klinischen Studien noch nichts gefruchtet. 1993 hatte der Bundesrat das Nationalfonds-Programm lanciert, um die Schweizer Kliniken und Forschungsinstitute zur gentherapeutischen Weltspitze vorstossen zu lassen. Dies ist bezueglich der Anzahl der klinischen Studien zwar gelungen: In insgesamt 22 Versuchen in der Schweiz wurden bis anhin 300 Patientinnen und Patienten gentherapiert, vier Versuche stehen kurz vor dem Start. Doch bei allen bisherigen Gentherapie-Versuchen verloren die Forscher den Kampf gegen die Krankheit, und sie bliesen zum Rueckzug. Das Fazit: Weg von den Versuchen an den Menschen, zurueck in die Labors, zur Grundlagenforschung.

Viren fuer den Gentransport
Dabei scheint das Verfahren so einfach: Ein fehlerhaftes Gen in den Koerperzellen wird durch ein funktionstuechtiges ersetzt. Als Transportmittel fuer die Gene in den Koerper haben sich Viren als am hoffnungsvollsten erwiesen. Denn Viren koennen die Zellen infizieren und ihr Erbgut in das menschliche einfuegen. Die Forscher wollen dieses Phaenomen ausnuetzen. Sie veraendern das Virus-Erbgut, damit das Virus seine Gefaehrlichkeit verliert. Zudem schleusen sie das gesunde menschliche Gen in das Virus-Erbgut ein.
Noch steht die neue Technik vor sehr grossen Problemen: Wie bringt man die Transportviren in den Koerper ein, ohne eine Immunabwehr auszuloesen, die das Virus wieder vernichtet? Wie verbreitet man die eingebrachten Gene in moeglichst viele Zellen? Wie kann man Gene dazu bringen, ueber laengere Zeit in der neuen Umgebung zu funktionieren?
Solange diese Fragen nicht geklaert sind, brauchen die Forscher vor allem Glueck, um in klinischen Studien zum Erfolg zu kommen. Das verhehlt auch Sandro Rusconi nicht. Und trotzdem verstroemt er Zuversicht, betont, wie sich die Erkenntnisse ueber die Genuebertragung in letzter Zeit bedeutend vermehrt haetten. Rusconi erwartet gar, dass die Gentherapie in zehn Jahren zum Routinegeschaeft der Kliniken wird: "Ich bin stolz zu sehen, wie viele Wissenschaftler und Kliniker in unserem Land fest an diese Herausforderung glauben."

Forscher regulieren selber
Die Gentherapie in der Schweiz ist gesetzlich noch nicht geregelt: Die Schweizerische Kommission fuer Biologische Sicherheit (SKBS) und die lokale Ethik-Kommission, meist jene des entsprechenden Spitals, pruefen die Gesuche. Kommt die SKBS zu einer negativen Beurteilung, gibt der Schweizerische Nationalfonds kein Forschungsgeld.
Mit dem neuen Heilmittelgesetz wird sich das vermutlich aendern. Es kommt fruehestens in der Wintersession in die eidgenoessischen Raete und sollte naechstes Jahr in Kraft treten. Das Gesetz beinhaltet den Aufbau eines Schweizerischen Heilmittelinstituts. Ob dieses die Versuche bewilligen soll, ist noch offen. Vorlaeufig gilt ein Verfahren, das auf der wissenschaftlichen Selbstverantwortung beruht. Die Praxis habe gut funktioniert, sagt Karoline Dorsch-Haesler, Geschaeftsleiterin der SKBS, auch wenn sie gesetzliche Regelungen bevorziehe. "Wir haben uns sehr bemueht, der Gentherapie keine Steine in den Weg zu legen."

 

 

Tod durch die Viren
COMMENTARY (1 column)

Der erste Todesfall in den USA waehrend einer Gentherapie hat auch in der Schweiz Folgen.

Von Volker Stollorz

Der 18-jaehrige Jesse Gelsinger war der letzte Patient in einem gewagten Menschenversuch: Mediziner am Institute for Human Gene Therapy der US-Universitaet Pennsylvania versuchten, seine erbliche Stoffwechselstoerung der Leber mit Genen zu heilen. Um die Wirkung zu steigern, erhoehten die Aerzte die Dosis der als Transportmittel fuer das "gesunde" Gen verwendeten Adenoviren. Die Injektion dieser so genannten Genfaehre in solch hoher Dosis direkt in die Pfortader vor der Leber war zuvor nur bei einer 19-jaehrigen Frau erprobt worden und dort erfolgreich verlaufen. Anders bei Gelsinger: Er entwickelte eine Gelbsucht und starb vier Tage spaeter an akutem Leberversagen.

USA: Versuche gestoppt
Zwar steht die Todesursache noch nicht eindeutig fest. Da aber gegen 20 Prozent aller Gentherapieversuche auf dem Einsatz von Adenoviren als Transportmittel beruhen, sorgte der Unfall weltweit vor allem unter Gentherapeuten fuer Aufsehen. So verkuendete die amerikanische Food and Drug Administration (FDA) vergangenen Freitag, sie habe "vorsorglich" mindestens zwei weitere Gentherapieversuche bei Krebspatienten gestoppt. Die Versuche mit Leber- und Darmkrebs aehnelten demjenigen von Pennsylvania sehr. FDA-Direktor Philip Noguchi begruendete die Vorsicht: "Vielleicht sind einige der in Gentherapieversuchen verwendeten Mengen von Adenoviren nicht vertretbar."
Sollte der Tod Gelsingers tatsaechlich mit dem verwendeten Virus in Zusammenhang stehen, waere der Ruf der Gentherapie als ungefaehrliche Behandlungsart in Frage gestellt. Hinzu kaemen bohrende Fragen, ob nicht zu frueh mit Menschenversuchen begonnen wurde. "Die Menschen sollten daran erinnert werden, dass das Heilen mit Genen zwar Gentherapie heisst, dahinter jedoch ein noch aeusserst experimenteller Eingriff steht", kommentiert Arthur Caplan, Direktor fuer Bioethik der Pennsylvania State University. "Wie andere experimentelle Therapien birgt auch die Gentherapie derzeit das Risiko, zu sterben."

Schweiz: Studie gestoppt
Inzwischen hat auch die Schweizerische Kommission fuer biologische Sicherheit (SKBS) auf den Vorfall reagiert. Von den derzeit vier hier zu Lande laufenden Versuchen mit Adenoviren sei eine internationale Studie "fuer den Moment gestoppt, da dort gewisse Aehnlichkeiten mit der US-Studie vorliegen", sagt SKBS-Geschaeftsleiterin Karoline Dorsch-Haesler. Von den uebrigen drei Studien wuerden nur fuer eine neue Patienten rekrutiert. Auch wuerden bei dieser "bedeutend niedrigere Dosen" verwendet. Trotzdem klaere man ab, ob auch dort "Vorkehrungen getroffen werden muessen".
Sandro Rusconi von der Universitaet Freiburg haelt den Tod von Gelsinger fuer "aeusserst bedauerlich". Als Leiter des nationalen Forschungsprogramms "Somatische Gentherapie" sieht er aber keinen Grund, die neue Methode gerade in dem Moment zu verdammen, "wo erste Beispiele von Patienten bekannt werden, deren Leben durch die Therapie gerettet wird oder deren Lebensqualitaet sich zumindest verbessert".

 

"Die Patienten wurden enttaeuscht"
(BOX: INTERVIEW WITH I VERMA)

Sollen wir die Gentherapie begraben?
Nein, sagt der renommierte Gentherapeut Inder Verma. Rueckschlaege gehoerten immer zu neuen Technologien.

Mit Inder Verma sprach This Wachter

1990 ging die Meldung von den ersten Gentherapien in den USA um die Welt. Wie geht es den beiden Maedchen, die an einer Stoffwechselkrankheit litten, heute?
Inder Verma: Das Ganze war keine Erfolgsgeschichte. Bei dem einen Maedchen passierte gar nichts. Beim anderen wurde das vom eingefuehrten Gen produzierte Eiweiss tatsaechlich in den Zellen gefunden. Aber nur fuer kurze Zeit. Zudem bekam dieses Maedchen nicht nur eine Gentherapie, sondern man verabreichte auch direkt das entsprechende Eiweiss, das bei dieser Krankheit fehlt. So konnte eigentlich nie festgestellt werden, ob das Maedchen wegen der Gentherapie oder wegen der Behandlung mit dem Eiweiss gesuender wurde.

Wegen eines Gentherapie-Versuchs ist vor wenigen Tagen der erste Patient gestorben. Was sagen Sie dazu?
Es ist der erste Fall in der Geschichte der Gentherapie, bei dem der Patient nicht an seiner Krankheit, sondern an der Behandlung gestorben ist. Der 18-jaehrige Mann hatte eine Stoffwechselkrankheit in der Leber. Durch Aenderung der Essgewohnheiten kann sie allerdings in Schach gehalten werden. Der so weit gesunde und arbeitsfaehige Mann wollte aber diese spezielle Diaet nicht mitmachen und wuenschte eine Gentherapie. Die Aerzte spritzten ihm eine sehr hohe Dosis der Viren, mit denen sie das Gen einschleusten. Die Viren wirkten toxisch, und er starb daran. Ein anderer Patient hat die gleiche Dosis bekommen und ist wohlauf.
Der Vorfall ist eine deutliche Botschaft an die Forschungsgemeinde: Diese Art von Transportviren sollten nicht mehr in so hohen Dosen verabreicht werden.

Sie werten es also nicht als Zeichen, die Gentherapie als Ganzes zu ueberdenken?
Nein. Denken Sie daran: In 300 klinischen Versuchen sind 3000 Patienten gentherapiert worden. Der 18-Jaehrige war nun der erste Patient, der an der Behandlung gestorben ist. Offensichtlich sind die meisten Gentherapien sicher, aber noch wirkungslos. Bei einer jungen Technik wie der Gentherapie gehoeren Rueckschlaege dazu.

Hat man nicht zu Beginn zu stark die Werbetrommel geruehrt?
Es wurde tatsaechlich zu frueh zu viel versprochen. Man haette den Leuten sagen muessen: Es ist eine neue Technologie. Wir muessen lernen und brauchen Zeit. Gewisse Forscher aber wollten die Ersten sein und den ganzen Ruhm ernten. Dieses Denken ist sehr verbreitet, fuehrt aber nicht zum Erfolg. Das Resultat ist nun, dass die Leute enttaeuscht sind.
Nun beginnt aber eine neue Phase des Optimismus. Wir haben bessere Transportsysteme fuer die Gene, und die Oeffentlichkeit ist mehr fuer die Probleme sensibilisiert.
Die Gentherapie war noch nicht einmal bei relativ einfachen Erbkrankheiten erfolgreich, die durch ein einzelnes Gen verursacht werden. Heute stehen aber komplexe Krankheiten wie Krebs oder Aids im Zentrum der Forschung. Warum?
Der Hauptgrund ist, dass diese Krankheiten unheilbar sind. Wo eine Behandlung fehlt, wird der Ruf nach revolutionaer neuen Mitteln laut. Wenn Patienten Tumore haben, an denen sie in zwei oder sechs Monaten sterben werden, sind sie zudem viel eher bereit, bei einem Experiment mitzumachen. Hinzu kommt, dass sehr viele Menschen an Krebs und Aids leiden. Entsprechend koennte die Gentherapie solcher Erkrankungen zum Geschaeft werden. Auf der anderen Seite ist es wohl nicht sehr lukrativ, seltene Erbkrankheiten zu erforschen.

Die Gentherapie von Keimzellen kommt immer mehr ins Gespraech. Wann kommt sie?
Die groessten Anstrengungen gelten momentan der Gentherapie von Koerperzellen. Solange wir nicht wissen, wie Gene in eine undifferenzierte Keimzelle richtig einzufuehren sind, ist die Keimbahntherapie nicht zu realisieren. Ueberhaupt glaube ich nicht daran, dass sie je wirklich eingefuehrt wird. Man brauchte dafuer sehr gute Gruende.

Welche?
Etwa, wenn durch eine Erbkrankheit das Ueberleben einer ganzen menschlichen Population bedroht waere.

Sehen Sie keine Gefahren eines Missbrauchs?
Es gibt immer Menschen, die alles versuchen. Ich sah eine Leihmutter, die sich zwei Embryos von verschiedenen Paaren einpflanzen liess. So kann sie doppelt verdienen. Ich hielt so etwas nie fuer moeglich.

Kann man so etwas nicht verhindern?
Man kann Wissenschaft nie kontrollieren. Das Einzige, was uns bleibt, ist die Kraft der moralischen Ueberzeugung. Wenn in Pakistan oder Turkmenistan jemand eine Keimbahntherapie machen moechte, kann das kein Gesetz verhindern. Das ist so wie mit den Atomwaffen.

Befuerchten Sie, dass Ihre Arbeit den Boden fuer unheilvolle Taten bereiten koennte?
Ich glaube nicht, dass meine Arbeit fuer die Zukunft gefaehrlich werden koennte. Ich versuche einfach eine Frage der Grundlagenforschung zu beantworten: Wie kann man ein Gen in den kranken Menschen einfuehren, so dass es auch wirkt?
Wenn ich im Labor stehe, denke ich nicht daran, was ich fuer andere Menschen leisten koennte. Ich mache meine Experimente, und wenn diese per Zufall Menschen helfen, ist das wunderbar. Will dies jemand missbrauchen, kann er das natuerlich. Aber das ist kein Argument, den wissenschaftlichen Fortschritt zu stoppen.

 


COMMENTS

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S. Rusconi, 16.9.99, email: sandro.rusconi@unifr.ch

I was very glad to see several journalist attracted by our annual meeting and I must thank specially Mr. This Wachter, Olivier Dessibourg and Volker Stollorz, whom from different angles tried to catch some facets of the moving world of gene therapy. We must be thankful to the national press for having brought gene therapy in the front page of a major Newspaper. Unfortunately, this occurred under the influence of a very tragic event. Within the above titles and lines of the Tagesanzeiger one can identify the exactly anticipated vehemence in accusing gene therapy for being not only ineffective but also deadly. This is like pretending that a 1880 car should be able to make the stretch Rome-Paris in ten hours, and this without risking any accident. At those times, they were missing the cars as well as the roads and the services. The vehemence is certainly not wanted but is a natural consequence of the mediatic style by which a bad new has much more weight than a good new.

This is the reason why I told the attendees of the annual meeting 99 to expect and to take with ease similar emotional reactions. I also said and wrote in my message that we should not abandon our conviction right now that we are at the brink of showing the very first real successes. Of course, the journalists have the full right to amplify the death of a person while keeping silence on the good news such as the really fantastic results from Dr. Isner's Lab (see also the impressive data on cardiac angiogenetic therapy presented by Doug Losordo at our annual meeting) or the recent promising data of Victor Dzau with the reduction of restenosis. The journalist or editors will tell us that they did separately report on those good news, thus that they are finally 'objective'. They will also tell us that it is not so important that these news did not make it into the front page. This may leave us with some bitter feelings, but we must realize that it is in their full right to strongly outline this single regrettable event and to ignore the other 2999 events which had no such complications, and among those, the few dozens of GT-treated patients whose life or life-quality was saved or considerably improved. We must be ready to accept that the accidental loss of a young person is more important than few good news and some good perspectives. We have to keep cool with this attitude and wait for our turn to speak out. It is like running a restaurant: it takes years of patient work to generate a number loyal customers but you may lose all them overnight with one single mistake.

What I appreciated less from the Tagi reports was the (probably unintentional) blending of true and untrue informations, in a a way that helped blow up the case. In this specific case the media imply that the NFP37 started in 1993 while it physically started in 1996 and mix up the entire Swiss efforts in gene therapy by implying that all the 22 clinical trials are under the NFP37 while it counts only 3 running and 4 planned clinical trials. The subtitle of the front page may suggest that all the GT trials have been temporarily stopped. The substance for gene therapy in Switzerland does not change, but the image of the NFP37 and of the field of gene therapy may result distorted.

Finally I think that also the style of the titles (with its perhaps also unintentional telegraphic absolutism) has not helped to convey a correct picture. For instance when you say: 'gene therapy stopped', you may imply 'the entire gene therapy'. People usually read and remember mainly the titles: now, try to figure out the bottom-line message that they have got from our beloved and nationally read 'Tagesanzeiger':

'gene therapy stopped' (front page)
'so far, foreign genes have not healed'
'death through viruses'
'the patients have been deceived'

I don't know who has edited the titles but frankly speaking I don't think this way can bring us towards an unclouded dialogue with the public opinion. But "so is the world of media" and we learned to be patient with this conformism during the last year's referendum campaign.

At the end the truth will win, and we are on its side.
May the force be with us!

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


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BOSTON, Oct 05, 1999 (Reuters Health)

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Tuesday October 5 6:10 PM ET

New gene therapy helps bypass patients

BOSTON, Oct 05 (Reuters Health) -- Treating the vessels used to bypass clogged heart arteries in coronary bypass surgery with gene therapy helps to keep the grafts open, keeping blood flowing to the heart years after the operation, researchers report.
The finding may help reduce the risk of these grafts becoming blocked after the surgery. Experts estimate that about half of all grafted veins close within 10 years.

Leg veins are often used to make grafts across diseased parts of heart arteries. A new gene therapy in which genetic material is forced, under pressure, into a vein graft prior to the graft being used in surgery may prevent the graft from becoming blocked, according to findings discussed at a seminar for reporters sponsored by Harvard Medical School.
``Right now, three-quarters of a million patients are getting bypass as primary therapy, when all other treatments have failed,'' noted Dr. Victor Dzau, chief of medicine at Brigham and Women's Hospital and professor at Harvard Medical School. ``Ten to 30% of these will fail in one year, with a 50% failure rate in high-risk patients.''
In a preliminary study of 42 such high-risk patients, Dzau treated 17 with the new therapy. After one year, the blockage rate in the new vessel in this subgroup was around 20%, compared with about 60% for patients receiving either conventional therapy or a sham procedure. Further details of these findings will be presented at the American Heart Association meeting in November, Dzau added.
Because there are so few arteries in the body available for coronary grafts, Dzau explained that surgeons harvest veins from the patient. But veins are not designed to handle the very high blood pressure demand of arteries. The grafted veins respond by undergoing rapid thickening, which often leads to blockage.
The gene used in the technique blocks cell growth, thus stopping the chain of events that leads to the graft becoming clogged.
By using a physical pressure technique to force DNA into the vein outside of the body, Dzau has also bypassed the need to use a virus to deliver the gene. This increases the safety of the procedure because there is no chance that the virus itself could cause infection, he said.

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BOSTON, Oct 06, 1999 (Reuters )

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Wednesday October 6 12:19 AM ET

Gene Therapy May Help Heart Bypass Last Longer

By Maggie Fox, Health and Science Correspondent

BOSTON (Reuters) - New techniques that use gene therapy to make heart bypasses work better are showing promise in some of the most difficult patients, researchers said Tuesday.
They said they had found ways to make veins -- natural and artificial -- last longer when they are stitched into patients to bypass clogged arteries.
Dr. Victor Dzau of Brigham and Women's Hospital and Harvard University in Boston said the method could mean bypasses will last longer for many people who get them -- good news because many bypasses clog up after a few years.
``It is absolutely safe,'' Dzau told a seminar for science reporters sponsored by Harvard.
Dzau said about 750,000 Americans undergo heart bypass surgery every year. But anywhere between 10 percent and 50 percent of them fail, depending on whether a patient smokes or has complications such as diabetes. For most bypasses, doctors remove a vein from the patient's leg and reattach it around the clogged arteries, usually leading from the heart. However, veins are not meant to withstand the high pressures that arteries are subject to. So in an effort to protect itself, the vein builds a layer of muscle cells to make itself as thick as an artery. ``But the biology is not right,'' Dzau said, and the thickened vein is even more likely than a normal vein to get clogged by fat blood clots.

BLOCKING CELL DIVISION
Researchers have found that some cells will become stronger and more muscular when they are blocked from dividing. ``It is what I call the Schwarzenegger effect,'' Dzau said, referring to the bodybuilder-turned-actor. A gene called E2F controls cell division. Dzau's team developed a strand of DNA that can block E2F from working, stopping the cells from dividing and making them grow stronger instead. The result, when used on a vein, is a stronger healthy vein. ``You take the vein out of the body, put the DNA into the graft,'' he said. Specifically, the graft is threaded into a plastic tube, the DNA is squirted in and pressure makes the vein absorb the DNA. Dzau said the procedure takes just minutes. ``The graft is harvested from the patient while the surgeon is cracking open the chest (and) getting the patient on bypass,'' he said.
Dzau, whose team is testing the method in 2,000 patients, said the technique has shown promising results in 16 patients he has examined. These were not patients with heart bypasses, but those who had claudication -- blocked arteries in their legs that cause pain and difficulty walking. The patients had many risks. Some had diabetes or smoked, and some had already had bypasses clog up once. He said that with the exception of a few patients who got immediate blood clots, the bypasses have held for six months. In 17 patients whose veins were not treated, most bypasses have failed. ``It could be a fluke,'' said Dzau in calling for more information from larger studies.
Doctors have tried to get around the problem of veins clogging up by using an artificial blood vessel made from synthetic material. To make the grafts act more like real arteries, they have tried to grow epithelial cells -- which naturally line vessels -- on the grafts. But once installed into animals, the blood flow washed these cells away. Dzau's team is also working on a way to better install the cells in the grafts and then treat them with cell signaling chemicals that will make them grow better. They can also insert genes that should stimulate the growth of natural cells.

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BOSTON, Oct 07, 1999 (BBC Health)

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Thursday, October 7, 1999 Published at 00:15 GMT 01:15 UK
BBC Health

Genetically-modified veins could save lives

A hi-tech procedure, dubbed the 'Schwarzenegger effect' by its creator, could help extend the life of blood vessels used in heart bypass operations. Veins from elsewhere in the body are commonly used to replace clogged up or hardened arteries supplying blood to the heart. However, arteries are naturally stronger than veins, and the bypass operation often fails because the vein reacts badly to the increased blood pressure. Very often, the vein will a grow a thick layer of muscle to protect itself - and this can make it more likely to clog than the blood vessel it replaces. A patient undergoing major surgery could require more surgery - at higher risk - within five to 10 years.
Dr Victor Dzau, of Brigham and Women's Hospital in Boston, says he has found a way of making the veins develop the right sort of muscle, which should help them become stronger and last longer. The vein, removed ready for implantation, is injected with DNA which alters the genetic makeup of the muscle cells, and stops them from dividing as quickly. "It is what I call the Schwarzenegger effect," Dr Dzau said. "The graft is harvested from the patient while the surgeon is cracking open the chest and getting the patient on bypass."

Tested on legs
At the moment, his technique has not been tried on heart bypass patients, but has been tested on a condition called claudation, in which an artery in the leg becomes similarly clogged and needs replacement. With the exception of a few patients who suffered immediate blood clots, the bypasses have held beyond the six month mark. Dr Keith Channon, clinical reader in cardiovascular medicine at the University of Oxford, and a consultant cardiologist from the John Radcliffe Hospital in the city, is also developing gene therapy on veins taken for bypass. He said: "It has great potential as this is an extremely large problem in modern medicine. It could save lives and improve outcomes from surgery. "About 50% of venous bypass grafts used for coronary artery surgery will be blocked by the 10 year mark." He cautioned that other experiments hailed as breakthroughs in gene therapy, such as potential treatments for cystic fibrosis, had not yet translated into effective treatments.

Viruses used to change veins
Dr Channon's own work uses viruses - modified to make them safe - which "infect" the cells making up the veins with new genetic material. Other surgeons are overcoming the problem of clogging vein grafts by using arteries which do not have a vital role in the body. However, there is usually only enough material for one graft, and most patients need a triple, or even a quadruple heart bypass, in which three or four arteries have to be tackled.


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Washington Post, September 29, 1999

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Washington Post, Wednesday, September 29, 1999

Teen Dies Undergoing Experimental Gene Therapy

By Rick Weiss and Deborah Nelson

Washington Post Staff Writers

An 18-year-old Arizona man with a rare metabolic disease has died while participating in a controversial gene therapy experiment, marking the first death attributed by doctors to a burgeoning field of research that seeks to cure people by giving them new genes. The death is the latest in a series of setbacks for a promising approach that has so far failed to deliver its first cure and that has been criticized as moving too quickly from the laboratory bench to the bedside. Some members of a federal advisory committee that approved the study had expressed concerns about the experiment because they felt it posed unduly serious risks and included people who were already being treated successfully with conventional therapy.

Jesse Gelsinger, a high school graduate who had suffered on and off from a serious genetic disorder that often leads to coma and death in childhood, died Sept. 17 after undergoing an experimental therapy administered at the University of Pennsylvania in Philadelphia, university and federal officials said yesterday. Scientists and doctors involved in the case said Gelsinger succumbed over a four-day period after doctors infused a batch of genetically engineered viruses into his liver at the highest dose allowed under an experimental protocol approved by the Food and Drug Administration. The experiment, the first in which such a virus was shot directly into the liver's blood supply, has been halted pending an investigation, and federal officials today will send out letters to the more than 100 researchers in the country conducting human research with similar viruses, asking them to report any evidence of trouble. Seventeen other University of Pennsylvania patients who received various doses of the virus before Gelsinger had no notable problems, and a few improved. "This was a tragic unexpected event," said James M. Wilson, director of the university's Institute for Human Gene Therapy. "I hope in a month we'll have looked at every angle so we can share with whomever is interested in listening what we've learned from this." Researchers and officials familiar with the case said they had few clues about what may have triggered the death, so its impact on the field of gene therapy remained uncertain. Thousands of U.S. patients have been treated with various kinds of gene therapy, an experimental technique in which doctors use live viruses and other means to transport potentially therapeutic genes into the body. The class of virus used in the Philadelphia experiment, a modified version of a cold virus called an adenovirus, is the most common type of gene therapy virus in use today. But the study had raised several novel concerns when the researchers began their long effort to gain federal approval to conduct the work.

Typically gene therapy studies involve desperately ill patients who have failed conventional therapy. But this one included healthy people and people who were already being treated successfully with dietary and drug regimens. The method was controversial because the genetically altered virus, which often causes severe inflammation, risked exacerbating the disease in some patients when it was injected directly into their livers, while promising at best only a transient improvement.
Gelsinger suffered from ornithine transcarbamylase (OTC) deficiency, a genetic disorder that affects mostly boys. The disease blocks the body's ability to break down ammonia, a normal byproduct of metabolism, and often causes death soon after birth.
Gelsinger was born with a mild form of the disease and had it well under control during the past year with drugs and a strict non-protein diet, said his father, Paul Gelsinger, of Tucson. But he volunteered in the hope that it might lead to a cure that would benefit him and children with more deadly forms of the disease.

"I lost a hero," Paul Gelsinger said. Gelsinger said he is not angry at the researchers. "They're as hurt as I am. They've promised full disclosure." At the same time, he said, "I've got a ton of questions for them." Among them, Paul Gelsinger said, was why they accepted his son as a subject when they knew that he had a different form of the disease than most affected individuals.

Mark Batshaw, the study's principal investigator and now chairman of pediatrics at the George Washington University Medical School, yesterday confirmed that Gelsinger did not have the usual inherited form of OTC deficiency. Typically it is caused by a tiny missing piece of genetic material passed along from the mother, but Jesse Gelsinger's form was caused by a much larger deletion that occurred after he was conceived. Perhaps because of that difference, Gelsinger's liver functioned at an especially low efficiency level -- lower than anyone else in the clinical test even though he was healthier than many others with the disease. Batshaw and other doctors involved in the case said they did not know if that difference left Gelsinger more susceptible to fatal liver damage from the therapy. They said when the trial started, they had no reason to believe so, and had some reason to believe he might benefit more than most. That question will be among many it the things they will now investigate. Whatever the reason, his liver went into a steep decline the day after getting the virus infusion, which was meant to deliver a gene that would help him make the enzyme he lacked. Other organs progressively failed over the next three days, including much of his brain. "By Friday morning, studies suggested that even if -- and this was a big 'if' -- he were able to come through the multiple organ system failure, the chances that Jesse would be able to be Jesse again were essentially zero," said Steven Raper, a Penn surgeon involved in the clinical trial. The team recommended to the young man's father that they withdraw life support equipment, and he agreed.

Staff researcher Alice Crites contributed to this report.

© Copyright 1999 The Washington Post Company


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NEW YORK, Sep 10 (Reuters Health)

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Friday September 10 4:53 PM ET

Gene repair in rats raises hope for genetic diseases

By Penny Stern, MD

NEW YORK, Sep 10 (Reuters Health) -- Through the use of a novel technique termed 'chimeraplasty,' researchers have, for the first time, successfully repaired the genetic defect associated with Crigler-Najjar syndrome, a rare but devastating liver disease, in lab rats.
The finding may lead to gene therapies that cure other genetic diseases such as hemophilia and sickle cell anemia, according to the report published in the Proceedings of the National Academy of Sciences. Principal investigator Dr. Clifford Steer, of the University of Minnesota School of Medicine in Minneapolis described his team's work in an interview with Reuters Health. ``We did two things that were important: one, we developed a system whereby we could go in and literally rewrite the genetic sequence in a specific gene of interest; and two, we developed a technology that would do it in the hepatocyte, the type of liver cell that controls the major defect (of Crigler-Najjar syndrome).'' The syndrome is characterized by an inability to properly metabolize bilirubin, a byproduct of normal red blood cell degradation. The genetic disease features jaundice and destructive changes in parts of the brain.

The researchers created a molecule called a chimeraplast, which is based on the structure of the defective gene and ''targeted to that portion of the gene with the mutation,'' Steer explained. When the molecule is introduced into the cell, ``it tricks the cell into thinking that there is a defect in its DNA sequence for that particular gene and by tricking the cell, the cell basically repairs (what it perceives as) its own defect.'' What is being accomplished, in essence, is genetic repair without having to employ techniques that require ``the introduction of new genes (via genetically modified viruses) to take the place of the (original defective) genes,'' as is the case in conventional gene therapy, according to Steer. ``All we are doing is repairing the genetic defect in a gene that is already there,'' he explained. ``And when you think about it, what is really the best way to do gene therapy? It would be to go in to correct the defect so that the gene is in the right position, controlled and regulated by the (appropriate) regulatory elements that would normally control that gene.'' An important aspect of this technology is that ``once the genetic change is made, the repair is permanent,'' Steer said. And although this work was carried out in an animal model, the Gunn rat -- which has a genetic defect similar, though not identical, to that seen in human Crigler-Najjar syndrome -- Steer ``feels very confident that it's going to work in humans. It works in animal models, it works in plants, in works in bacteria, it works in any structure that has DNA in it.''

The type of mutation corrected in the study involves an omission or deletion of one ``letter'' in a specific DNA genetic sequence. DNA is composed of basic units called nucleotides, which are designated by specific letters. These combine into sequences that ``spell out'' a genetic code. Changing one ''letter'' into another is easier than replacing a missing letter, Steer said, and in the human disease, changing rather than replacement is required to correct the defect. Consequently, ``we hope that our results will be even more exciting in human beings than they were in the rodent model.'' Together with his colleagues at the Albert Einstein College of Medicine in the Bronx, New York, Steer expects to submit a clinical trial application for the technique to the Food and Drug Administration early next year. ``We're going to involve 3 to 5 pediatric patients already identified with Crigler-Najjar, who live in the Amish country in Pennsylvania,'' Steer told Reuters Health. He commented that the Amish have a very high frequency of this disorder and that these particular children all have the same genetic defect, a mutation at a single point in the genetic code.

The majority of genetic diseases in human beings are single-point mutations, Steer explained, ``so we have a technology here that can be applied to many different types of disease. The technology is here, it's here to stay, and it is very different from gene therapy.'' The investigators are already developing a number of other animal models to look at potential clinical applications in disease such as Gaucher's disease, hemophilia, thalessemia, and sickle cell anemia. Though sickle cell anemia's defect originates in the bone marrow, Steer believes that the team will be able ``to develop a delivery system for the chimeraplasts'' that will direct them to the marrow, the site of the stem cells from which the defective red blood cells in sickle disease originate. ``It's going to be more challenging than liver, only because it's bone marrow and the progenitor cells are more difficult to deal with,'' he noted.

Steer emphasized that though the results achieved thus far are ``very, very exciting,'' with potentially ``broad-based application,'' much remains to be done. Further developing and refining the technology's seemingly limitless possibilities will ``keep the medical profession busy for many, many years,'' he predicts.

SOURCE: Proceedings of the National Academy of Sciences USA 1999;96:10349-10354.

Copyright © 1996-1999 Reuters Limited

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Tages Anzeiger vom 11.08.99

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Tages Anzeiger vom 11.08.99

Eine neue Gentechnik fuer die Skeptiker

Genforscher entwickeln eine Methode, um gezielt Gen-Bausteine in Zellen auszutauschen. Erster Erfolg: Herbizid-resistente Mais- und Tabakpflanzen.

Von Tobias Frey

Seit Jahren schleusen Gentechniker artfremde Gene in das Erbgut von Pflanzen ein, um die Nutzpflanzen ertragreicher oder resistenter gegen Krankheiten zu machen - und seit Jahren protestieren Kritiker gegen dieses Tun. Ethisch verwerflich sei es, der Mensch spiele sich auf als lieber Gott, die Langzeitfolgen des Gentransfers seien zudem kaum absehbar. Nun haben amerikanische Forscher der Cornell University in Ithaca und der amerikanischen Biotechfirma Kimeragen an Pflanzen eine neue Gentech-Methode eingesetzt, die den Kritikern den Wind aus den Segeln nehmen koennte. Dabei wird kein fremdes Gen in den Organismus eingefuehrt, sondern ein bestehendes gezielt veraendert. Auf diese Weise konnten die Forscher Herbizid-resistente Tabakpflanzen erzeugen. Dies berichteten sie kuerzlich im amerikanischen Fachblatt "PNAS"*. In derselben Ausgabe der Zeitschrift verkuendeten Forscher der amerikanischen Firma Pionier-HiBred International, dass ihnen ein aehnliches Experiment auch mit Mais gelungen sei.

Mechanismus bleibt ein Raetsel
Die Wissenschaftler aus Ithaca schleusten einer isolierten Tabakpflanzenzelle ein kurzes Stueck des Gens eines zelleigenen Eiweisses ein. Es handelt sich um das Genstueck eines Enzyms, das auf Herbizide empfindlich reagiert. In dem kleinen Genstueck, dem so genannten Oligonukleotid, hatten die Forscher im Reagenzglas einen einzigen Baustein veraendert. Eine solche Veraenderung im Enzym-Gen hat zur Folge, dass die Zelle ein Enzym produziert, das unempfindlich ist gegen Herbizide. Damit ist auch die Pflanze geschuetzt gegen das Unkrautvertilgungsmittel.

Das Ueberraschende und auch Erstaunliche am Experiment der amerikanischen Forscher war: Nur dieser eine Baustein wurde in das Erbgut der Pflanzenzelle eingebaut, nicht aber das gesamte Oligonukleotid. Der Rest des Genstueck wurde, so vermuten die Wissenschaftler, von der Zelle verdaut. Das heisst, diese neuartige und gezielte "Reparatur"-Methode hinterlaesst im Erbgut offensichtlich keine unerwuenschten Nebeneffekte. Aus der genetisch veraenderten Zelle wuchs schliesslich ein Herbizid-resistentes Tabakpflaenzchen heran. Ueber den genauen Mechanismus tappen die Wissenschaftler noch im Dunkeln. Der Molekularbiologe Josef Jiricny von der Universitaet Zuerich sagt: "Es ist absolut nicht klar, was bei diesem Vorgang in der Zelle ablaeuft." Erstmals wurde die neue Methode vor fuenf Jahren der Fachwelt vorgefuehrt - doch keiner der Wissenschaftler nahm sie zur Kenntnis.

Molekularbiologe Jiricny hat die Entwicklung der Methode verfolgt: "Das ist vielfach so bei neuen Ideen. Es braucht den Glauben von einigen Forschern und die Vision, sie umzusetzen." Glaube und harte Arbeit tragen mittlerweile die ersten Fruechte. Heute sind sich die Wissenschaftler einig: In dieser Technik liegt ein enormes Potenzial - auch fuer die Medizin. Theoretisch koennten Gene mit einem einzelnen Defekt auf diese Weise korrigiert werden, ohne dass gesunde, ganze Gene in die Zellen eingeschleust werden muessten. Und das waere ein Vorteil: Bis heute koennen Gentechniker naemlich nicht vorhersagen, wo sich fremde Gene im Erbgut einnisten.

Kranke Leber geheilt

Einen bemerkenswerten Erfolg konnten im vergangenen Jahr Wissenschaftler um Cliff Steer von der University of Minnesota in Minneapolis verbuchen. Sie spritzten Ratten mit einem Gendefekt in der Leber bestimmte Oligonukleotide in die Blutbahn und konnten spaeter erkennen, dass rund ein Drittel der defekten Leberzellen geheilt wurde. Pioniere der Methode, Eric Kmiec von der Thomas Jefferson University in Philadelphia, New York, und seine Kollegen, versteigen sich in Euphorie: "Wir hoffen, noch im letzten Jahr des Millenniums an der ersten Heilung einer Erbkrankheit teilnehmen zu koennen." Ein Kandidat waere die vererbte Lungenkrankheit zystische Fibrose. Bei dieser Krankheit ist der 508. Baustein eines Gens anders als bei den Gesunden. Doch das reicht aus, dass der Austausch von Salzmolekuelen in der Lunge nicht richtig funktioniert. Die Jugendlichen leiden an zaehfluessigem Schleim in der Lunge, der von infektioesen Erregern besetzt wird. Die Lunge wird sukzessive zerstoert. Theoretisch koennten Spermien und Eizellen von Gentraegern oder dann gar ein Embryo in einem sehr fruehen Stadium mit Oligonukleotiden behandelt werden und auf diese Weise das defekte Gen "repariert" werden.

Fachwelt bleibt skeptisch

Neben ethischen und rechtlichen Fragestellungen zu solch tollkuehnen Visionen bleiben allerdings noch technische Fragen offen. So weist die Methode eine kapitale Schwaeche auf: Sie ist vorlaeufig nur begrenzt reproduzierbar. Immer wieder stellen naemlich Wissenschaftler fest, dass ein unerwuenschter Baustein ins Erbgut eingebaut wird. Zudem braucht es heute noch extrem grosse Mengen an Zellen und Oligonukleotiden, bis das Experiment glueckt. Die Pflanzengenetikerin Barbara Hohn vom Basler Friedrich-Miescher-Institut hat die neue Gentech-Methode unter die Lupe genommen. Fuer sie ist klar, dass sie in der breiten Fachwelt den Durchbruch noch nicht geschafft hat. Damit werden auch die Verbreiter von uebersteigerten Hoffnungen vorlaeufig in die Schranken verwiesen. Eines ist sich auch Barbara Hohn allerdings gewiss: "Die neue Methode ist so wichtig, dass auch ein Teilergebnis bereits ein sehr guter Erfolg ist." Bekannte Gentech-Kritiker der Schweiz wollten sich zur neuen Technik nicht aeussern: Sie war ihnen zu wenig bekannt.

* Proceedings in the National Academy of Sciences, Bd. 96, S. 8774 resp. 8768

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Washington Post 3.11.99

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Wednesday November 3, 2:39 am Eastern Time

Six gene therapy deaths kept from NIH, public-Post

WASHINGTON, Nov 3 (Reuters) - Scientists and drug companies did not notify the National Institutes of Health about six people who died during gene therapy experiments in the past 19 months, in the latest sign of a possibly finance-driven shift toward secrecy in the research area, the Washington Post reported on Wednesday.

The deaths are the first in gene therapy to come to light that were purposely withheld from the NIH, one of two federal agencies charged with overseeing the safety of the controversial field of medical research that seeks to cure diseases by giving patients new genes, the Post said. Federal regulations have long held genetic treatments to a higher level of public scrutiny than conventional new therapies because of public discomfort with the idea of manipulating people's genetic makeup, the report said. But as the field has become increasingly dominated by private industry, drug companies and scientists with a financial stake in their research are challenging the broad interpretation of that rule. They are filing reports with demands for confidentiality, the Post reported, or maintaining that they do not have to file them with the NIH at all.

Confirmation of the six deaths follows revelations last week of a death and two serious illnesses in gene therapy patients that were reported to the NIH with the unprecedented insistence that they be kept confidential, defying a long-standing agency policy of public disclosure. In the case of the six deaths, all of the people died during heart studies headed by two leading gene researchers -- Ronald Crystal of the New York Hospital-Cornell Medical Center in Manhattan and Jeffrey Isner of Tufts University in Boston, the Post said, citing interviews with researchers and scientists.

The two founded competing gene therapy companies -- Isner's Vascular Genetics of Durham, North Carolina, and Crystal's GenVec (NasdaqSC:GNVC - news) of Rockville, Maryland -- and are racing to be the first to grow new blood vessels around blocked ones as an alternative to heart bypass surgery, the report said. The Post said Crystal was the first to request confidentiality from the NIH for a patient death report in May 1998, just two weeks after his company GenVec announced its initial public offering of stock. The report reported that NIH staff said at the time Crystal cited concerns about the impact on his business if the death were made public. But Crystal has in the past week, according to the Post, said the public offering had no bearing on his confidentiality request.

Crystal and Isner told the Post they believe the fatalities in their studies were not directly caused by the gene therapy but by complications stemming from the patients' underlying illnesses. Because they decided the deaths were not caused by gene therapy, they argued, federal regulations do not require them to notify the NIH -- a new interpretation of those regulations that stands in sharp contrast to the one held by NIH officials and a decade of practice, according to the Post report. The researchers told the Post they reported the deaths to the Food and Drug Administration, which keeps such information secret.

But NIH officials in the federal office that oversees gene therapy were adamant that even deaths not initially believed to have been caused by the therapy must be reported to the NIH and made public, because often it is not clear until later whether the therapy actually caused the deaths. ``It may take five, six, seven patients ill, or 20 patients, before you find out, 'Hey, this is also happening in other people's trials,''' Amy Patterson, who heads the NIH Office of Recombinant DNA Activities, which oversees gene therapy studies, told the Post. ``And if you don't know what's going on in other people's trials, then you can't put two and two together,'' she said.

Most of the new deaths are coming to light only because federal officials put out a plea for gene researchers across the country to report any undisclosed deaths or illnesses. They issued the plea after the death of a teenage patient at the University of Pennsylvania in September. His death is thought to be the first directly caused by gene therapy, and NIH officials are looking for indications of similar problems in other studies that may not have been attributed to the treatments themselves.

Copyright © 1999 Reuters Limited


BBC Sci/Tech, October 20, 1999

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Wednesday, October 20, 1999 Published at 23:09 GMT 00:09 UK
BBC Sci/Tech

Major step forward for gene therapy

Canadian scientists have succeeded in putting an artificial, extra chromosome into mice that is passed to their offspring. The development, reported at a London conference this week, is a significant development in the on-going efforts to find more effective ways of introducing new genes into humans and animals.

Current methods of incorporating genes, such as simply injecting them into cells, is highly inefficient and risky. Introducing a whole chromosome - the structure used by cells to bundle up DNA - could be a more successful solution. And it also raises the prospect that germline gene therapy in humans - making genetic changes that are inherited by future generations - will one day be technically feasible. However, the team behind this latest development stress that they will not be using their technology, or allow anyone else to use it, for this purpose.

At the moment, geneticists wanting to make major genetic modifications to an animal - to create a transgenic animal - inject genes into newly-fertilised embryos. It is a problematic process because the genes are not always taken up by the embryo's genome. And even when they are, the genes can be spliced into chromosomes where they will have no effect or, worse still, where they can disrupt other genes. Millions of laboratory animals are "wasted" each year in this process and are destroyed. Whilst society might accept this in animals, it would be an intolerable way to introduce genetic changes into humans.

A 'first' in mammals

What Chromos Molecular Systems Inc of Burnaby, British Columbia, have done is to "build" an artificial chromosome, with the new DNA already spliced in, and introduce the whole structure into the developing embryos. By attaching a fluorescent dye to the chromosomes, they were able to confirm that the mice could subsequently pass the "gene packets" on to their offspring. "It's the first time an artificial chromosome has ever been shown to be inherited in any mammal," Eileen Utterson, vice-president of corporate development for Chromos, told New Scientist magazine. "Because the artificial chromosome is separate, it doesn't interfere with the cell's own genetic machinery." The company plans to use the technology to create herds of genetically-modified (GM) animals which will express useful drug compounds in their milk. It may also have a significant advantage over current methods used in conventional, non-germline gene therapy in humans. In these treatments, scientists try to add therapeutic genes to the cells of specific tissues in adult or child patients. The intention is to counter the genetic mutations which give rise to diseases like cause cystic fibrosis. But none of the techniques employed are very successful.

Using an artificial chromosome to ferry the DNA into a cell may prove more fruitful. It would also allow much larger quantities of genetic material to be introduced than is currently possible.


British Medical Journal, 13 November 1999

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BMJ 1999;319:1310

Where are we going? Gene therapy: lessons learnt from the past decade

British Medical Journal, 13 November 1999 BMJ 1999;319:1310

Where are we going? Gene therapy: lessons learnt from the past decade

Richard A Morgan, interim chief a, R Michael Blaese, chief scientific officer b. a Clinical Gene Therapy Branch, National Institutes of Health, Bethesda, MD 20892, USA, b Kimeragen Inc, Newtown, PA 18940, USA Correspondence to: R A Morgan rmorgan@nhgri.nih.gov

It is more than a decade since the first approved clinical trial to put genes into the cells of human beings was initiated. In that first trial, investigators at the US National Institutes of Health used a modified mouse leukaemia virus to insert a DNA marker into lymphocytes being used to treat cancer.1 A year later, a similar viral technique was used as treatment for two girls who had severe combined immunodeficiency with mutant adenosine deaminase.2 Ten years and more than 3000 patients later, it is appropriate to ask, "Where are we now?"

Where are we now?

Initial speculation that gene therapy would quickly revolutionise medicine has clearly been wrong. As is often the case when entirely new areas of work develop, there was an overoptimistic view of the pace of progress and an underestimation of the problems remaining to be overcome. In something of a knee jerk reaction, many scientific pundits declared gene therapy dead or, at best, a potentially useful research tool that was being aggressively oversold by a few biotechnology companies. In reality, the science of gene transfer was progressing quickly in a classic reiterative process, where lessons learned from the early clinical studies were redirecting the course of research. Gene therapy is now a robust scientific discipline encompassing specialties and subspecialties, and an array of new reagents are nearing availability for specific clinical applications.

Delivery

One of the challenges that was not fully appreciated was the difficulty encountered in delivering genes to the cells that need correction. Since the techniques for modifying mutant genes directly (gene correction) were far too inefficient to be useful clinically, it was necessary to treat genetic disorders by adding a normal copy of the mutant gene to the cells (addition gene therapy). Both viral and non-viral techniques for gene delivery have been tested clinically.3 Viral methods have proved to be the most efficient to date, particularly in applications that require stable integration of the delivered gene. The molecular weight of the DNA encoded by clinically relevant genes is very large and this mass becomes even larger (greater than one million) when it is packaged into a replication inactivated virus. The viral vectors used in gene therapy are inactivated to remove any chance that they might themselves cause disease. However, by crippling replication, the mechanism that ! viruses normally use to spread genes in the body is also inactivated. The laws of physics concerned with diffusion of large molecules then govern the spread of the vector. This diffusion is often further limited by the small intercellular spaces through which the viral particles must move and by the presence of viral binding ligands on the surface of the cells they are trying to move beyond. Although ex vivo gene treatment should avoid some of these delivery problems, the limited tropism and the dependence on the cell cycle of early gene transfer vectors gave disappointing results in initial efforts to target cells such as haematopoietic stem cells.4

Physiological regulation

Physiological regulation of the added genes is another major challenge. To achieve a long term effect, integration of the added gene into the chromosomal DNA of the host may be essential. Unfortunately, the most efficient integrating gene transfer systems use small viral vectors such as retroviruses that are unable to accommodate full length human genes containing all of their original regulatory sequences. In most viral vectors, genomic gene sequences are replaced by smaller cDNAs, thereby losing the regulatory information (enhancers, etc) encoded in the deleted introns. Furthermore, short viral or heterologous cellular promoters are often substituted, resulting in a gene expression pattern that may be fundamentally different from the expression of the normal endogenous gene. Random integration of gene transfer vectors at different chromosomal locations can also adversely influence gene expression. In addition, some of the early attempts to use these gene transfer systems hav! e encountered problems related to the development of immune responses directed towards the viral vectors and even against some of the transgenes expressed in the treated cells. 5 6 These technical limitations forced investigators to look for candidate disorders outside the traditional genetic diseases.

Current trials

Clinical trials are currently addressing a very broad range of potential delivery systems and disease targets (figure, tables 1 and 2, and box). Of the 313 trials listed in the public database maintained by the US National Institute of Health, 70% are involved in the treatment of cancer. The preponderance of cancer related trials (figure, table 2) may surprise readers who think of gene therapy as a treatment option for genetic diseases (table 1). However, in the broader context, gene therapy is another form of drug delivery, and this accounts for the wide variety of applications of the "technique." These applications include treatments aimed at a diverse list of disorders including arthritis, HIV infection, dozens of different types of cancers, and extremely rare genetic diseases. With a few exceptions, the number of patients enrolled in any given trial is small (generally fewer than 20). This is mainly because of the requirement for ex vivo manipulation of the individual pati! ent's cells.

Gene therapy trials in United States  Genetic disease18 trials  HIV disease21 trials  Cancer196 trials  Other3 trials Information supplied by US National Institutes of Health, Office of Recombinant DNA Activities

Direct in vivo gene transfer

Direct in vivo gene transfer (often called the holy grail of gene therapy) is being tested with increasing frequency and with some encouraging results. The types of gene transfer reagents being used in the clinic range from injections of simple DNA molecules and DNA-lipid complexes to genetically modified hybrid animal viruses. Naked DNA alone, either in the form of an oligonucleotide or as a plasmid, is the simplest form of gene transfer reagent that can be used to transfect some cell types directly. For example, direct DNA injections are being used as a new generation of vaccines where the DNA directs the expression of an antigen.7 One of the more encouraging results in recent reports comes from the use of injections of DNA encoding vascular endothelial growth factors to promote angiogenesis in tissues affected by vascular insufficiency.8

Viral vectors

The list of modified viruses that can be used in gene therapy experiments continues to increase, as does the understanding of the biology and immunology of these systems (box). Early experiments using adenovirus showed a rapid and important immune response against viral proteins and transgenes.5 Subsequently, investigators have worked to produce a new generation of adenoviral vectors without viral genesthe so called "gutted" adenovirus.9 These highly modified adenoviral vectors have shown appreciable long term persistence in a number of animal model studies. There are also exciting reports on the use of the human adeno-associated virus as a gene transfer vector.10 This ubiquitous virus is not associated with any serious human disease and has the useful property of being able to infect mature differentiated cells such as muscle or neurons. The main drawbacks to using the adeno-associated virus vector system are the limited coding capacity of the vector (about 4.0 kb) and the la! borious production systems.

Viral vectors used in gene therapy Integrating viral vectors - Retrovirus (murine leukaemia virus) - Adeno-associated virus - Lentivirus Non-integrating viral vectors - Adenovirus - Alphavirus - Herpes simplex virus - Vaccinia

Encouraging results have been reported from long term animal studies of gene transfer and expression by direct injection of vector into the brain, muscle, and liver. 11 12 These data have led to an increased interest in adeno-associated virus and expanded its use in human gene therapy trials. One of the most exciting applications is adeno-associated vector injection into muscle. A trial was recently initiated to inject factor IX expressing adeno-associated vectors into the muscles of patients with haemophilia B, and similar approaches have been proposed for retinitis pigmentosa, familial hypercholesterolaemia, and muscular dystrophy.

Nucleotide exchange

Viral mediated gene transfer methods result in new genetic material being added to the existing cells' genomethey do not correct the underlying genetic defect that causes the disease. Revolutionary changes are under way in non-viral mediated gene transfer and gene correction, which may lead to a paradigm shift in our thinking about the types of diseases that can be treated by gene therapy. A new experimental strategy to correct single nucleotide mutations in genomic DNA has recently been developed. 13 14 A chimeric oligonucleotide comprising RNA and DNA residues in a duplex conformation was used to target the desired nucleotide exchange. The approach was based on the observation that RNA-DNA hybrids were highly active in homologous pairing reactions in vitro. The duplex conformation was designed with 2'-O methylated RNA-DNA stems and poly-T hairpin loops for chemical and thermal stability as well as resistance to helicases and RNA and DNA nucleases. The RNA-DNA sequence is com! plementary to that of the target gene, except that it contains one mismatched nucleotide when aligned with the genomic DNA sequence. It seems this unpaired nucleotide is recognised by endogenous repair systems, resulting in an alteration of the DNA sequence of the targeted gene. If these methods can be developed for clinical application, they could mediate the correction of mutations that cause disease. This would be a major advance for gene therapy.

Gene therapyrelated links on world wide web

 European Society of Gene Therapy at www.cbt.ki.se/ewgt/  American Society of Gene Therapy at www.asgt.org/  US National Institutes of Health, Office of Recombinant DNA Activities (RAC), www.nih.gov/od/orda/  Clinical Gene Therapy Branch, National Institutes of Health, at www.nhgri.nih.gov/Intramural_research/Clinical_therapy/

Hopeful future

Gene therapy today is at a stage similar to that experienced in the 1980s by recombinant proteins and monoclonal antibodies in medicinethat is, much hope and speculation but very few products. Recombinant proteins such as insulin, erythropoietin, and various cytokines are now common in medical practice. The future of gene therapy is equally exciting, and the next few years should prove interesting.

Footnotes Competing interests: RMB is employed by Kimeragen, Inc and has consulted for ARIAD Pharmaceuticals, Genetic Therapy/Systemix/Novartis, and Baxter Healthcare. RMB has shares or stock options in Kimeragen, ARIAD, and Cell Genesys Inc.

References

1. Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA. , Moen R, et al. Gene transfer into humansimmunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990; 323: 570-578[Medline]

2. Blaese RM, Culver KC, Miller AD, Carter CS, Fleisher T, Sheare G, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 1995; 270: 475-480[Abstract]

3. Gewirtz AM, Sokol DL, Ratajczak MZ. Nucleic acid therapeutics: state of the art and future prospects. Blood 1998; 92: 712-736[Full Text]

4. Dunbar CE, Cottler-Fox M, O'Shaughnessy JA, Doren S, Carter C, Berenson R, et al. Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation. Blood 1995; 85: 3048-3057[Abstract]

5. Yang Y, Nunes FA, Berencsi K, Furth EE, Goenczoel E, Wilson JM

Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 1994; 91: 4407-4411[Medline]

6. Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, et al. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 1996; 2: 216-223[Medline]

7. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA. DNA vaccines. Annu Rev Immunol 1997; 15: 617-648[Abstract/Full Text]

8. Henry TD. Therapeutic angiogenesis. BMJ 1999; 319: 1536-1539

9. Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Longston C, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nature Genet 1998; 18: 180-183[Medline]

10. Muzyczka N. Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 1992; 158: 97-123[Medline]

11. Miao CH, Snyder RO, Schowalter DB, Patijn GA, Donahue B, Winther B, Kay MA. The kinetics of rAAV integration in the liver. Nature Genet 1998; 19: 13-15[Medline]

12. Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, et al

Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci USA 1998; 95: 14384-14388[Abstract/Full Text]

13. Cole-Strauss A, Yoon K, Xiang Y, Byrne BC, Rice MC, Gryn J, et al

Correction of the mutation responsible for sickle cell anemia by an RNA-DNA oligonucleotide. Science 1996; 273: 1386-1389[Abstract]

14. Kren BT, Bandyopadhyay P, Steer CJ. In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides. Nat Med 1998; 3: 285-290.


Washington Post, Sunday, November 21, 1999

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Washington Post, Sunday, November 21, 1999; Page A01

Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns

By Deborah Nelson and Rick Weiss Washington Post Staff Writers

Four days after scientists infused trillions of genetically engineered viruses into Jesse Gelsinger's liver as part of a novel gene therapy experiment, the 18-year-old lay dying in a hospital bed at the University of Pennsylvania. His liver had failed, and the teenager's blood was thickening like jelly and clogging key vessels while his kidneys, brain and other organs shut down. It was a rare and irreversible blood reaction, but it wasn't the first time the researchers had seen it. Unbeknown to Gelsinger, who had signed up for the experimental treatment for a rare and often fatal liver disorder, monkeys that the Penn team had similarly treated had succumbed in very much the same way. The team had moved forward with the human experiment despite the monkey deaths, and despite criticism from other researchers who thought it was too dangerous, because they believed that a new version of genetically altered virus they had developed was safer than the one that had killed the monkeys. "Now I have to think, 'Was I blind?' " said James Wilson, head of Penn's Institute for Human Gene Therapy and a lead scientist in the trial. "I'm asking myself that question a lot these days."

So far, the Penn team's investigation into Gelsinger's death in September--thought to be the first fatality from gene therapy--has yielded no clear indication of what triggered the fatal reaction, so it's too soon to say whether it should have been predicted and prevented. Besides, experimental therapies by definition often are dangerous, and the distinction between laudable perseverance and unjustifiable risk-taking can be blurry. Gelsinger's father remains highly supportive of the Penn team. And Gelsinger himself was eager to participate, despite the risks. But a close look at the Penn research provides a rare snapshot of that subtle scientific and ethical landscape known as the cutting edge of medicine. And it resurrects old questions about whether the Penn experiment ever should have begun.

Many experts wonder, for example, whether an impatient Penn team overlooked the study's pitfalls out of eagerness to win a nine-year-old race to produce the world's first gene-based cure. As scientists work to cure diseases by giving people new, healthy genes, some are asking whether federal regulators' enthusiasm for the hot new field--and their enchantment with Wilson's stellar reputation--may have led them to give Wilson the benefit of the doubt at too many key decision points along the way. Also anxious for success were the corporate investors who have funneled tens of millions of dollars into a gene therapy company Wilson founded and into his lab at Penn on the bet that he'd push the field forward. Wilson adamantly denies that he was influenced by financial concerns. But such tight ties between university researchers and private industry are worrisome to ethicists.

A detailed examination of research records, along with interviews with scientists and government officials, has revealed:

* The Penn experiment was the first to shoot such a heavy dose of gene-altered viruses directly into the bloodstream of patients with a genetic disease, even as researchers acknowledged that it had no chance of curing that disease and despite widespread uncertainty in the field about toxic side effects.

* Contrary to most high-risk research, the Penn study experimented with the healthiest rather than sickest segment of the patient population--people such as Gelsinger, who had the disease under control with conventional drugs and diet, or people who had no symptoms at all.

* Researchers were not deterred by early indications of toxicity as they gradually increased doses in their experiment, including an especially severe case of liver damage in one participant. And they discounted or missed evidence of serious side effects in their own and other animal and human studies.

* Volunteers were recruited in ways that federal officials had explicitly precluded as being too potentially coercive, with direct appeals on a patient advocacy Web site that heralded "promising" early results from the clinical trial and said the experiment used "very low doses" when in fact they were relatively high.

* The original consent form, reviewed publicly by the National Institutes of Health, clearly notified prospective participants that monkeys had died from a related treatment, but the final version given to patients eliminated any mention of the deaths.

* Wilson has a financial interest in a private company he founded, Genovo Inc. of Sharon Hill, Pa., which has rights to discoveries made by Wilson at his lab on the Penn campus and which has a substantial financial stake in seeing liver-directed gene therapy succeed.

Gelsinger's death may never be fully explained. But already it has revitalized longstanding criticisms that gene therapy researchers, whose treatments have disappointed more than 3,000 patients since 1990, are experimenting on too many people too soon. It may be hard to argue against rushing to test novel treatments for incurable diseases, experts said. But moving ahead too quickly could do more than just place patients at risk. It could undermine the public trust that is so crucial to gene therapy, a field long seen as controversial because of its goal of altering people's fundamental genetic makeup. "People will say they cannot cure patients and now they're killing them," said Guenter Cichon of Berlin's Humboldt University, one of several researchers who have documented the potentially deadly nature of the viruses that were given to Gelsinger in the Penn study.

Focusing on OTC Disease

Gelsinger suffered from a disease called ornithine transcarbamylase (OTC) deficiency. Victims are born with a genetic mutation that leaves their livers unable to break down ammonia, a normal byproduct of metabolism. High ammonia levels can quickly become fatal, and the disease affects newborn boys most seriously, killing about half of them soon after birth. An estimated 1 in 40,000 babies is born with a defective OTC gene, a tiny population of patients for a major scientific effort. But Wilson, one of the country's leading geneticists, saw an opportunity to tackle a horrific disease while perfecting his technique for delivering genes to the liver, which he considered the key to curing many other more common diseases that have their roots in that organ. In discussions with colleague Mark Batshaw, who pioneered a drug-and-diet regimen for OTC survivors that has saved numerous lives, Wilson became convinced that OTC deficiency was the perfect disease to prove the potential of gene therapy for the liver. Together, Wilson and Batshaw, with surgeon Steven Raper from Penn, developed a plan to use gene-altered viruses to deliver healthy copies of the OTC gene to affected newborns as soon as they were diagnosed--generally when they were on the brink of death from skyrocketing ammonia levels soon after birth.

The scientists knew the therapy was potentially dangerous, because the gene-altered virus they would use to get the new genes into the newborns' cells can trigger life-threatening reactions. They also knew the therapy would be short-lived, because the babies' immune systems would shut down the new genes within a few days or weeks. But in such a desperately ill population, for whom no effective treatment exists, the risk of the new therapy would be justified, the researchers reasoned. And once these infants made it through their first crisis, they could be placed on Batshaw's diet-and-drug regimen and perhaps live fairly normal lives. It seemed like medicine at its best: trying to save babies from an incurable disease. So the team was shocked when Penn's own ethicists rejected the proposal. Parents whose children are so close to death cannot be counted on to make rational decisions about whether to enter those children into a new, potentially dangerous and unproved experiment, they said.

Thus began a change of focus that, in many experts' eyes, triggered an unconscionable shift in the study's balance of risks and benefits: Rather than drop their focus on OTC altogether, the researchers decided to experiment on healthy or stable adult OTC patients such as Gelsinger, who had survived to adulthood because they had milder forms of the disease. If the treatment proved safe, the researchers could bolster their case for testing its usefulness in newborns. But first they would have to test its safety in adults for whom safe and conventional treatments already existed, whose livers were already stressed because of their disease, and who stood no chance of getting any lasting benefit from the experimental approach. That shift in focus stirred intense debate in 1995 when the study was reviewed by federal officials. But despite concerns that the researchers still needed to answer some basic scientific questions before moving ahead, the plan--like many other gene therapy protocols then and today--was approved by federal regulators amid a wave of optimism that scientists were on the brink of a breakthrough that would forever change the face of medicine. "We had to select one disease to move forward in for gene therapy to the liver," Wilson recalled recently. "I thought the severity of the disease would warrant and justify trying this therapy. It's such a compelling story."

In the Business of Science

Wilson also had financial incentives to stay focused on the liver, although he denies that they influenced him in any way. Since Wilson founded Genovo in 1992, the company has attracted two major corporate investors. While neither of those companies is interested in OTC specifically--it afflicts too few people to be commercially attractive--both are interested in gene delivery to the liver and both were drawn to Genovo's access to Wilson's discoveries. Biogen Inc. of Cambridge, Mass., has paid Genovo $37 million since 1995 for the right to eventually market various liver- and lung-related genetic therapies developed by Genovo. The deal, which is up for renewal next year, called for Genovo to make progress in moving gene therapy toward a marketable product, said Genovo President Eric Aguiar. Under the agreement, Genovo must share the Biogen money with Wilson's institute at Penn, which today depends on that arrangement for about 20 percent of its budget. In August, Genovo sealed an additional deal with Genzyme Corp., another biotechnology company in Cambridge, to develop liver-directed gene therapy for metabolic disorders. Genovo has a direct stake in the genetically engineered adenovirus that Wilson developed for the OTC trial, according to Wilson and Aguiar. If Wilson and his colleagues can demonstrate that the virus is a good vehicle for ferrying genes into the body, the company and Wilson could benefit financially. In a posting on the Genovo Web site, Aguiar boasts that the relationship with Wilson not only provides the company with access to Wilson's discoveries, but also minimizes business risks, because the company can wait until Wilson's lab tests new treatments on humans before deciding whether to invest in them.

Wilson said he went to great pains to ensure that his business interests would not influence his judgment during the OTC adenovirus trial. Although he was a senior scientist, for example, he gave Raper control over medical and patient care decisions. "To suggest that I acted or was influenced by money is really offensive to me," he said. "I don't think about how my doing this work is going to make me rich. It's about leadership and notoriety and accomplishment. Publishing in first-rate journals. That's what turns us on. You've got to be on the cutting edge and take risks if you're going to stay on top." Nevertheless, Wilson's own financial disclosure statement says Wilson and Genovo "have a financial interest in a successful outcome from the research involved in this study." Wilson acknowledged that the ties with Genovo are tight enough to require him to include that statement on research papers and the consent forms that patients sign when entering his clinical trials, including the OTC experiment.

Academic researchers increasingly are setting up their own companies or business deals on the side. Forty percent of the gene therapy protocols approved in the past three years have had corporate sponsors. Wilson and others argue that sponsorship provides an important source of funding for research and an eventual pipeline to get cures to the public. Yet the business-academia pipeline has been the subject of much criticism in recent years, because it may sometimes force scientists to choose between good science and good business. Aguiar said Wilson is too much a scientist to compromise. But Wilson is also very plugged in to the company, Aguiar acknowledged, and calls him on the telephone frequently during the week. One of those calls from Wilson stands out in both men's memories. It was in September, and the talk was about business. When Aguiar asked how things were going, Wilson said he was having a stressful day. Gelsinger had reacted badly to the treatment and was heading into multiple organ failure in the hospital intensive care unit. "He was really upset about it," Aguiar said.

Problematic Genetic Messenger

In their worst-case scenarios, Wilson, Batshaw and Raper thought they might see an inflamed liver in their patients. But the researchers thought they had licked earlier problems with a new, safer brew of genetically engineered adenovirus.

Adenoviruses, a class of viruses that cause the common cold and conjunctivitis, or pinkeye, are extraordinarily efficient at infecting many kinds of human cells. Because of that, they have become popular with gene therapists as a way of delivering helpful genes to sick people. But there are downsides: Adenoviruses trigger intense immune system reactions and can prompt a life-threatening inflammatory response. Because of those possible problems, many scientists have stopped using adenoviruses to treat genetic diseases and are looking for other, more promising gene delivery systems. But Wilson's team had worked feverishly during the early 1990s to develop a less inflammatory adenovirus. Over several years, the researchers methodically deleted different combinations of the virus's genes until they had one that seemed to be safe enough to use in the fairly high doses needed to be effective. The team also spliced copies of the OTC gene into the virus--the payload to be delivered to OTC-deficient patients.

While all four rhesus monkeys that had been given high doses of the first-generation virus had died in previous experiments, subsequent tests of the later viruses on monkeys and mice seemed to confirm that it was less toxic, although it still triggered liver inflammation. By cutting back the dose two hundredfold, the scientists and the FDA concluded that they could deliver it safely to humans with no or minimal side effects, especially because humans are so much bigger than monkeys. That is a presumption that federal regulators now question. But at the time, the Penn researchers were confident in their plan, which included monitoring for early signs of trouble as they gradually increased doses and treating unexpected crises with a proven backup treatment. They commenced treatments in 1997.

Some scientists today remain supportive of Wilson's decision to go forward. "I don't know anyone in gene therapy who has done more animal studies before starting in people," said A. Dusty Miller, a gene therapist at the Fred Hutchinson Cancer Research Center in Seattle. But while the new virus appeared to be safer, there remained wide disagreement over how much safer. And between the start of the clinical trial and Gelsinger's death in September, new research elsewhere in the field provided further evidence of toxicity and the need for caution in using adenoviruses in the liver. "Not many people consider it appropriate for treating genetic diseases," said NIH investigator Richard Morgan.

The NIH tested a closely related adenovirus on the livers of three macaque monkeys, which fell seriously ill with symptoms similar to those that killed Gelsinger. They recovered, but one suffered permanent liver damage. A German study involving similar adenoviruses caused acute, toxic responses in rabbits that also resembled those that killed Gelsinger. Cichon, the Berlin researcher who led that study, concluded that adenoviruses should be used only in dire circumstances, such as when the only other alternative is a liver transplant. It is a standard that other scientists say they have adopted. To give adenoviruses to patients like Gelsinger "would never be justified," Cichon said. "And I am not the only one who thinks this way. We do not understand why [researchers] are taking these risks."

Meanwhile, Schering-Plough Corp. of Madison, N.J., and the University of California at San Francisco had begun a clinical trial that infused high doses of adenovirus into the livers of dying cancer patients, a situation in which greater risks are allowed because patients have little other hope. The company lowered the dose when two early participants experienced serious drops in blood pressure. But even at that lower dose--which was lower than the total dose eventually given to Gelsinger--two patients suffered serious stroke-like attacks. Wilson said he was only vaguely aware of those studies, none of which had been published in peer-reviewed journals until after Gelsinger's death. However, the information was widely disseminated in other, less formal ways, such as postings on Web sites and presentations at scientific meetings.

Some scientists at a leading gene therapy meeting that Wilson attended in Washington in June saw disturbing similarities in the NIH and the Penn team's preliminary results, which described some drops in white blood cell counts among participants and evidence of increasing liver damage with each increase in dosage. Wilson said no one approached him at the conference with concerns. But neither did Wilson reveal in his written report at the meeting that one patient had suffered an especially serious reaction to the treatment--a reaction that threatened hopes of getting Food and Drug Administration approval to move up to the next dosage level. Ultimately, the team tested its virus on an additional monkey. "We did it and the animal got hepatitis but it lived," Wilson said. "That was reassuring." The FDA was aware of all the data, Wilson said. If the study was too risky, he asked, why didn't federal regulators stop it?

The Regulation Process

In fact, it hadn't been easy for Wilson and his team to convince federal regulators that they should be allowed to try their approach in people. In 1995, when the researchers first pitched their plan to the NIH committee of scientists and ethicists that then reviewed all gene therapy proposals in advance, several committee members expressed strong reservations. The approach looked too dangerous, they said. And because the immune system would quickly destroy the genetically repaired cells, the treatment would not have any lasting benefit. But according to several scientists and some NIH committee members, Wilson's charismatic style and his good reputation as a scientist won the day. "Wilson said that you should let people be heroes if they want to be," said Robert Erickson, a committee member at the time and a University of Arizona scientist. "In retrospect, I wish I hadn't been convinced." The committee approved the protocol but insisted on two changes. The viruses should be infused into a distant blood vessel, not directly into the liver, hopefully reducing the trauma to that already diseased organ. And the researchers should recruit their subjects only through physicians, not by making direct appeals to patients, who might be swayed too easily into participating in the potentially dangerous study. The researchers agreed, but that's not what happened. First, the FDA became convinced that direct infusion to the liver was preferable and made the team switch back. Penn is now investigating whether that direct infusion contributed to Gelsinger's reaction. The committee never had a chance to review the change because in 1996, shortly after approving the Penn trial, its powers were greatly reduced by the NIH, under pressure from biotechnology companies seeking relief from federal regulations that the industry deemed overly burdensome. The NIH committee members say they also never got word of a significant change in the consent form. Although the final form included a perfunctory clause stating that the experiment could result in injury or death, it dropped mention of the original fatal animal studies. Neither the FDA nor the Penn team can explain today why the reference to monkey deaths was dropped. The Penn team also broke its assurance to the NIH committee that it would recruit participants only through physicians.

In the summer and fall of 1997, Batshaw wrote pieces that appeared in the National Urea Cycle Disorders Foundation newsletter and on its Web site, seeking volunteers. "Obviously, the faster we can complete the Phase I study," he wrote, "the sooner we can move on to the treatment phase in children." When asked about his call for volunteers, Batshaw said: "We did recruit through the foundation newsletter. It was passive recruitment in that it just appeared there. I wouldn't want to say it was advertised." The possibility of volunteering was merely "posed," he said. As for his comments that some participants had experienced some "correction," he now concedes that might be an overstatement. "Perhaps it could have been stated better."

Volunteering 'to Help the Babies'

There's little question that Gelsinger was a willing and eager participant in the Penn experiment. He had a mild form of the disease that could be controlled through diet and drugs. He didn't always follow the grueling regimen, and a year ago nearly died from an ammonia attack. But since then, he'd felt better than ever, thanks to a new regimen developed by Batshaw. After hearing about the experiment from his doctor, he tried to volunteer at age 17--too young for the protocol--then returned as soon as he turned 18. The research team made it clear that the experiment wouldn't cure him, and the teenager also knew there was a small chance it could hurt him. But he was swayed by the scientists' dream that the treatment might someday help severely stricken newborns. "He wanted to help the babies," said his father, Paul Gelsinger, in a recent interview. "My son had the purest intent."

Paul Gelsinger also remains an outspoken fan of the researchers, whom he considers "very ethical men." "Kids are dying all the time from these orphan diseases," he said. "How long do you wait to do something?" Raper, Batshaw and Wilson are deep into their investigation of Gelsinger's death and will present their results to the NIH Dec. 8-10. "As a scientist it's very difficult to do the tests, because of what they might show," Wilson said. However, he added, "If a mistake was made, we've got to own up to it and learn from it. Ultimately, the tragedy of Jesse's death would be if we don't learn anything."

Staff researcher Alice Crites contributed to this report.

© Copyright 1999 The Washington Post Company


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The Associated Press, 26 Nov 1999

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Freitag, 26. November 1999, 15:39 Uhr

Gentherapie steht noch am Anfang

´Erwartungen zu hoch geschraubt' - Nur bescheidene Erfolge

Von AP-Mitarbeiterin Angela Stoll

Muenchen (AP) Zehn Jahre nach den ersten Experimenten mit Gentherapie ist die Euphorie verflogen. Kaum ein Forscher glaubt noch, dass die neueBehandlungsmethode bald als Wunderwaffe gegen Krebs und das HI-Viruseingesetzt werden kann. Bislang wurden weltweit 4.000 Menschen behandelt - mit eher bescheidenem Erfolg, wie Bernd Gaensbacher vom Institut fuer experimentelle Onkologie der Technischen Universitaet Muenchen einraeumte: ´Die Erwartungen waren zu hoch geschraubt.' Der Forscher eroeffnete am Freitag den dreitaegigen Kongress der Europaeischen Gesellschaft fuer Gentherapie in Muenchen, an dem rund 500 Wissenschaftler aus 24 Laendern teilnehmen.

In den vergangenen Wochen ist die Gentherapie zudem ins Zwielicht geraten. Der Fall eines 18-jaehrigen Amerikaners, der im September bei einem gentherapeutischen Experiment der Universitaet Pennsylvania starb, sorgte fuer Furore. Kritik zogen die Forscher vor allem deshalb auf sich, weil der junge Mann zwar unter einer Stoffwechselstoerung litt, aber keine Symptome hatte. ´Es handelt sich um einen tragischen Fall', sagte Gaensbacher. Trotz Fehlern muessten die Universitaeten aber weiter neue Therapiestrategien entwickeln: In den USA erkrankten jaehrlich mehr als eine Million Menschen an Krebs. Die Haelfte davon sterbe innerhalb eines Jahres. Der Biotechnologe Klaus Cichutek vom Paul-Ehrlich-Institut in Langen erklaerte, dass hier zu Lande ein Fall wie dieser nicht haette passieren koennen. ´In Deutschland werden Patienten ohne Symptome nicht behandelt.' Eine Ethikkommission pruefe jeden Fall und lasse die Behandlung nur dann zu, wenn der Nutzen groesser sei als das Risiko.

´Geben Sie dieser Therapie Zeit' - Gentherapie funktioniert nach einem einfachen Grundprinzip: Durch Uebertragung gesunder Gene sollen insbesondere Tumore und Erbkrankheitengeheilt werden. Dabei gibt es zwei Methoden: Bei der ´ex-vivo'-Behandlung werden dem Patienten Zellen entnommen, praepariert und wieder eingesetzt. Bei der ´in-vivo'-Therapie werden dem Patienten die Gene direkt verabreicht. Dazu muessen sie mit Hilfe von Vehikeln, so genannten Vektoren, in die Zellen geschmuggelt werden. Meistens werden dazu gentechnisch praeparierte Viren verwendet. Bislang seien aufwendige ´ex-vivo' Behandlungen haeufiger, erklaerte Cichuteck. Erfolg versprechender seien aber die Direkt-Therapien: ´Sie sind einfacherer und sicherer.' Die groþe Herausforderung fuer die Forscher besteht nun darin, geeignete Vektoren zu finden. Viele von ihnen haben Nebenwirkungen. So koennen Viren Immunreaktionen ausloesen, die eine wiederholte Behandlung verhindern. Auþerdem koennen zum Beispiel die haeufig eingesetzten Adenoviren in hohen Dosen toxisch sein. Mit diesen Viren, die normalerweise nur Erkaeltungen ausloesen, war der junge Amerikaner behandelt worden.

Bezueglich der Vektoren habe die Forschung in den vergangenen zehn Jahren viel erreicht, betont Gaensbacher. Derzeit erarbeiteten die Mediziner ´Genfaehrenª aus einem Mix aus Fettkuegelchen und viralen Bestandteilen. Doch Peter Hans Hofschneider vom Max-Planck-Institut fuer Biochemie in Martinsried bremste auch hier zu kuehne Erwartungen: ´Es wird nie einen Ideal-Vektor geben.' Je nach Anwendung muessten immer wieder andere Vektoren verwendet werden.

Trotz der Risiken und Fehlschlaege mahnte Gaensbacher zu Geduld: ´Es ist immer noch sehr frueh', sagte er, ´geben Sie dieser Therapie Zeit, das kann 20 bis 30 Jahre sein.'

 

Copyright 1999 The Associated Press


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Neue Zürcher Zeitung, 01.12.99

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Neue Zuercher Zeitung FORSCHUNG UND TECHNIK Mittwoch, 01.12.1999 Nr. 280 77
Der Gast aus der Wissenschaft

Gentherapie-Forscher: verkannte Helden oder Roulettespieler? Missverhaeltnis von Wunsch und Wirklichkeit

Von Sandro Rusconi

Die ersten Gentherapie-Versuche wurden erst vor knapp zehn Jahren gestartet. Heute liest man eher von Misserfolgen - in juengster Zeit gar von einem Todesfall - als von einem zu erwartenden Durchbruch. Was kann man von der Gentherapie tatsaechlich erhoffen? Wo liegen die Gefahren? Welche Erwartungen sind ueberhoeht?

In unserem Jahrhundert haben Gesellschaft und Medien immer schon regen Anteil an technischen Errungenschaften genommen. Pioniertaten und ausserordentliche Erfolge wurden euphorisch bejubelt - wie beispielsweise der Transatlantikflug von Charles Lindbergh oder die Mondlandung. Andere Fortschritte wiederum - man denke an die Antibabypille, das Internet oder das Antidepressivum Prozac - kamen eher ueberraschend, und ihre neue ethische Dimension laesst sich nur schwer abschaetzen. Der Transfer menschlicher Gene, auch unter dem vielversprechenden Namen ´Gentherapie' bekannt, ist bisher in den Medien nur am Rand aufgetaucht. Ungluecklicherweise betreffen diese mageren Berichte meist spektakulaere, allerdings vorlaeufige und nicht bestaetigte Resultate, oder aber sie prangern Fehlschlaege und Misserfolge an. Nur zu selten zeichnen diese Darstellungen ein treffendes Bild der Tatsachen und der Fortschritte auf diesem Gebiet. Wuenschbar waere aber, dass unsere Gesellschaft die Chance wahrnimmt, die potentiellen Gewinne, aber auch die Grenzen dieser neuen Technologie zu erkennen, bevor sie routinemaessig zur Anwendung kommt.

Gezielt, wirksam und dauerhaft

Dezember 1990: French W. Anderson und seine Kollegen starten mit einfachsten Mitteln und ohne grosse Erfolgschancen den ersten klinischen Gentherapie-Versuch: die ´New York Times' widmet diesem Ereignis eine halbe Spalte auf der ersten Seite. Im Sommer 1998 veroeffentlichen Iris Baumgartner und Jeff Isner vom St. Elisabeth Hospital in Boston die erste Erfolgsmeldung in der Geschichte der Gentherapie: Patienten mit von Faulbrand zerstoerten Fuessen werden dank einem gentherapeutischen Eingriff von einer Amputation verschont. Seit 1990 sind weltweit rund 3000 Patienten in verschiedene, noch experimentelle Gentherapie-Versuche eingeschlossen - keine dieser Geschichten wurde jemals auf einer Titelseite gedruckt, selbst wenn die Versuche erfolgreich waren. Im September 1999 stirbt der erste Patient an den Folgen der Gentherapie: der 18jaehrige Jesse Gelsinger aus Pennsylvania. Die Schlagzeilen flimmern ueber die Bildschirme, die ´Washington Post' meldet den Todesfall auf der ersten Seite. Ist dies ein Einzelfall? Wie laesst sich die breite Kluft zwischen erhofften und konkreten Ergebnissen in diesem juengsten medizinischen Gebiet erklaeren?

Die Gentherapie versucht, mit der Uebertragung von Genen - dem direkten Gentransfer - Krankheiten vorzubeugen, zu mildern oder zu heilen. Jede der rund 100 000 Milliarden Zellen im menschlichem Koerper besitzt eine exakte Kopie des urspruenglichen Erbmaterials. Das Genom besteht aus DNA, einem unglaublich langen Molekuel, in dem etwa drei Milliarden Grundbausteinen in einer bestimmten Folge aneinandergereiht sind: die gesamte Laenge betraegt rund zwei Meter, das Riesenmolekuel ist im Zellkern dicht verpackt. Abschnitte der DNA bilden die einzelnen Gene. Jedes Organ und jedes Gewebe exprimiert eine bestimmte Palette von Genen, die auf molekularer Ebene in Eiweisse uebersetzt werden: die sogenannte Gen-Expression. Jedes Protein hat eine bestimmte Funktion: Enzyme, gewisse Hormone und zellulaere Strukturen bestehen aus Eiweissen. Seit ungefaehr dreissig Jahren kann man einzelne DNA-Strecken, also einzelne Gene, im Labor ´zuechten' und veraendern. Vor etwa fuenfzehn Jahren hat man begonnen, bestimmte Gene in Mikroorganismen zu exprimieren - mit dem Zweck, grosse Mengen von therapeutisch wirksamen Eiweissen wie beispielsweise Wachstumshormon, Insulin und Erythropoetin zu produzieren. In den letzten zehn Jahren hat man nun versucht, diesen Gentransfer nicht nur an Mikroorganismen oder Tieren durchzufuehren, sondern mittels Gentherapie direkt in menschliche Gewebe einzugreifen, um so auf den Verlauf gewisser Krankheiten Einfluss zu nehmen. Dieses Vorgehen laesst sich am besten anhand eines Beispiels darstellen: Die Absicht sei, einen Gendefekt, der die sogenannte Mukoviszidose verursacht, zu korrigieren. Das Gen ist bereits isoliert und in grossen Mengen gezuechtet worden. Nun muss es in diejenigen Organe eingeschleust werden, die von den schaedlichen Auswirkungen des vererbten Gendefekts am meisten betroffen sind, insbesondere die Lungen. Im Idealfall sollte das korrekte Gen in jede der etwa 1000 Milliarden Lungenepithelzellen eingeschleust werden. Allerdings wuerde es genuegen, lediglich zehn Prozent dieses Epithels zu ´transformieren', um einen ausreichenden therapeutischen Effekt zu erreichen. Die Aufgabe ist trotzdem nicht einfach: 100 Milliarden Lungenzellen sollen so transformiert werden, dass das gesunde Gen auch langfristig exprimiert wird. Zudem darf diese Prozedur keine Veraenderung der Keimbahnzellen verursachen - der Gentransfer soll also auf die Koerperzellen beschraenkt bleiben und ist somit auch nicht vererbbar. Alle diese Probleme sind in den letzten zehn Jahren einzeln aufgegriffen und bis heute nur teilweise geloest worden. Um die Gene effizient in moeglichst viele Zellen zu schleusen, hat man nach geeigneten Transportsystemen Ausschau gehalten und ist dabei auf die Viren gestossen. Viren sind etwa 10 000mal kleiner als Koerperzellen und haben im Laufe ihrer Entwicklung das Problem eines effizienten Gentransfers elegant geloest. Sie besitzen aber ein fuer therapeutische Zwecke unguenstiges Merkmal: normalerweise machen Viren diejenigen Zellen, die sie befallen, krank. Also hat man die Mikroorganismen fuer den medizinischen Gentransfer modifiziert, um einerseits Raum fuer die therapeutischen Gene im Virus-Genom zu schaffen und andererseits die Gefaehrlichkeit des Virus soweit wie moeglich zu mindern. Verschiedene Viren - von den Adeno- ueber die Herpes-Viren bis hin zum Aids-Virus - hat man als Grundgeruest fuer den Gentransport verwendet. Die erste Generation solcher Viren, die Anfang der neunziger Jahre eingesetzt wurde, genuegte den geforderten Kriterien kaum. Heute versucht man bereits, eine dritte Generation zu zuechten, die hoechsten Sicherheitsanforderungen gerecht werden soll. Gleichzeitig sind viele nichtvirale Gentransfer-Methoden erprobt worden, die bis jetzt aber weniger effizient sind. Der groesste Vorteil dieser nichtviralen Methoden ist die hoehere Sicherheit und die geringere Gefahr, vom Immunsystem erkannt und abgefangen zu werden.

Klinische Versuche am Menschen koennen nicht durchgefuehrt werden, bevor nicht die Prinzipien und allfaellige Nebenwirkungen an Zellkulturen und Tiermodellen nachgewiesen worden sind. Diese ´praeklinische' Forschung nimmt aber bereits mehrere Jahre in Anspruch. Bei der anschliessenden ´Klinischen Phase I' werden 10 bis 30 Patienten oder Freiwillige mit einer Dosis, die weit unter der gefaehrlichen Grenze liegt, behandelt. Ziel dieser ersten, zwei bis drei Jahre dauernden Phase ist es, allfaellige Nebenwirkungen zu erkennen. Erst wenn dieser Studienabschnitt erfolgreich abgeschlossen ist, darf eine ´Phase II' in Angriff genommen werden. Hier werden mehrere Patienten mit verschiedenen Dosen behandelt, um erste therapeutische Effekte zu messen. Im Rahmen der ´Klinischen Phase III' werden dann einige hundert bis tausend Patienten mit dem Medikament in seiner endgueltigen Form behandelt. Erst nach abgeschlossener und erfolgreicher Phase III darf ein Medikament zur Genehmigung der Food and Drug Administration (FDA) oder einer entsprechenden Institution eingereicht werden. Bis ein Medikament tatsaechlich zugelassen ist, vergehen deshalb durchschnittlich zehn bis fuenfzehn Jahre; der finanzielle Aufwand betraegt rund hundert Millionen Dollar pro Medikament und Verfahren.

Das enorme Potential der Gentherapie hat das Interesse der Privatwirtschaft auf sich gezogen. Nicht nur die grossen Pharmakonzerne wie Novartis, Roche, Merck, Hoechst oder Schering, sondern auch mittlere und kleinere Unternehmen haben sich teilweise oder ganz dieser Technologie verschrieben. In den USA sind ueber 170 Unternehmen direkt in der Gentherapie-Forschung und -Entwicklung taetig, und fast jeden Monat wird ein neues Unternehmen gegruendet. Die Mehrheit dieser Firmen wird mit Risikokapital finanziert. Es ist schwierig, die Betraege zu beziffern; eine Uebersicht, die kuerzlich in der Zeitschrift ´Nature Biotechnology' publiziert worden ist, hat die Gesamtinvestition in Amerika fuer das Jahr 1998 auf 800 bis 900 Millionen Dollar geschaetzt. Die Werte der oeffentlichen Hand dagegen sind transparent und belaufen sich auf 15 bis 25 Millionen Dollar. In der Schweiz fliessen jaehrlich rund 4 bis 6 Millionen Franken an oeffentlichen Geldern direkt in die Gentherapie-Forschung. Weitere Beitraege werden von Stiftungen und Privatunternehmen aufgebracht, so dass insgesamt weniger als 3 Prozent der gesamten Kosten fuer die Gentherapie von oeffentlichen Mitteln finanziert werden. Die Monopolisierung der Gentherapie-Forschung durch die Privatwirtschaft foerdert den Fortschritt zwar enorm, hat aber gewichtige Nachteile: die wissenschaftliche Kommunikation wird durch Patentierungsverfahren oft verzoegert. Zudem werden vorlaeufige Resultate haeufig unkritisch den Medien weitergereicht, um so Kapital anzuziehen; und schliesslich werden viele schwere Krankheiten mit abnehmender Intensitaet erforscht, weil sie sehr selten sind und daher keinen potentiellen Markt darstellen. Diese zynischen Zustaende sind zum Teil am schlechten Ruf der Gentherapie in der Oeffentlichkeit mitschuldig.

Was wurde bis jetzt erreicht?

Seit 1995 sind in der Schweiz ueber 20 klinische Gentherapie-Anwendungen - meistens der Klasse I und hauptsaechlich im Bereich der Krebsbehandlung - durchgefuehrt worden. Eingeschlossen waren rund 290 Patienten, was einem Zehntel der weltweiten Gentherapie-Versuche entspricht. Seit 1996 ist das Nationale Forschungsprogramm 37 ´Somatische Gentherapie' im Gang, mit der Absicht, die Anstrengungen zu koordinieren. Von den weltweit ueber 200 klinischen Versuchen, die bis heute gemeldet worden sind, gehoeren 97 Prozent zur Klasse der Phase-I-Experimente, was bedeutet, dass keine ausfuehrlichen Informationen betreffend therapeutischen Wert erwartet werden koennen. Rund ein Dutzend Versuche sind jetzt in die Klinischen Phase II gelangt, erste offizielle Meldungen zu den Resultaten sollen in einigen Monaten praesentiert werden. Zusaetzlich sind grosse Fortschritte in der Entwicklung von noch sichereren und zuverlaessigeren viralen und auch nichtviralen Vektoren gemacht worden, die nun an Tiermodellen getestet werden. Hoffnungen werden auch in ´artificial viruses' oder synthetische ´Ersatzviren' gesetzt. Auch ohne diese juengsten Entwicklungen konnten mit Hilfe der Gentherapie einige erfreuliche Erfolge verbucht werden. Dem Forschungsteam um Jeff Isner in Boston gelang die Heilung mehrerer Patienten von schwerster Gangraen - dem Gewebezerfall infolge einer Durchblutungsstoerung - mittels eines einfachen und sehr wirkungsvollen Gentransfers: die Forscher transferierten ein Gen, das das Wachstum von Blutgefaessen foerdert. Kuerzlich ist es Victor Dzau aus Boston gelungen, den erneuten Verschluss von frisch implantierten Blutgefaessen zu unterdruecken, indem er ein Gen transferierte, das die Zellvermehrung hemmt. Daneben hat die Firma Onyx spezielle Viren entwickelt, die sich bevorzugt in Krebszellen vermehren und diese zerstoeren. Versuche mit diesen ´onkolytischen' Viren befinden sich bereits in Phase III.

Und was wurde noch nicht erreicht?

Die Gentherapie muss noch viele technische Huerden ueberwinden. Einerseits existiert bis heute noch keine Methode, die gewaehrleistet, dass das gesunde Gen an einer bestimmten Stelle im Genom der kranken Zelle eingesetzt wird. Zudem stellt die Immunreaktion der Patienten eine Schwierigkeit dar, vor allem wenn eine Wiederholung der Behandlung notwendig ist. Weiter gibt es keine absolute Garantie, dass kein Gentransfer in die Keimbahn des Patienten stattfindet. Diese Sicherheitsbetrachtungen sowie die noch immer erhebliche Gefaehrlichkeit der Vektoren beschraenken die Anwendung gentherapeutischer Methoden heute noch auf die Behandlung schwerer Krankheiten. Der Tod von Jesse Gelsinger sollte uns daran erinnern, dass sich diese Technologie noch in der Fruehphase ihrer Entwicklung befindet und dass noch viele Anstrengungen notwendig sind, um das erste Hippokratische Prinzip (Primum non nocere) zu garantieren. Dass die Gentherapie wegen verfruehter Versprechen und der privaten Finanzierung unter enormem Zeitdruck steht, mag fuer den allgemeinen Fortschritt eine gesunde Herausforderung sein - im medizinischen Bereich aber ist es gefaehrlich, denn der ´Experimentierstoff' ist nicht so ´neutral' wie beispielsweise bei der Astrophysik, Nanotechnologie oder der Telekommunikation. Vor allem herrscht eine enorme Divergenz zwischen der gewuenschten Beschleunigung und der vergleichsweise langen Dauer von klinischen Experimenten.

Ist die Gentherapie realistisch?

Die Behandlung erworbener oder vererbter Krankheiten mittels Gentransfer bietet eine bisher unerreichte Genauigkeit und ist daher eine der beliebtesten Visionen der modernen Medizin. Die Liste der behandelbaren Krankheiten waechst taeglich; sie umfasst die klassischen Erbkrankheiten wie die zystische Fibrose und Muskelkrankheiten ebenso wie erworbene Leiden - Infektionskrankheiten, Unfaelle und chronische Erkrankungen. Die neuen Gentransfermethoden moegen fuer die menschliche Anwendung noch zuwenig ausgereift sein - sie haben sich aber zu wertvollen Werkzeugen fuer die Grundlagenforschung entwickelt und dienen beispielsweise immer haeufiger als Alternative zu transgenen Tieren. Die Risiken einer solchen Therapie sind in den Anfaengen der klinischen Anwendung noch immer ziemlich hoch. Trotzdem wurden bis jetzt nur sehr wenige Zwischenfaelle gemeldet. Der ´Fall Gelsinger' hat sich offenbar wegen einer Haeufung verschiedener Fehler ereignen koennen. Jesse Gelsinger litt an einer Erbkrankheit (dem sogenannten Ornithin-Transcarboxylase-Mangel oder OTC), wobei sich dieser Gendefekt teilweise mit Medikamenten und Diaet kompensieren laesst. Die Krankheit ist also nicht unmittelbar lebensbedrohlich. Um den genetischen Defekt zu kompensieren, ´infizierte' man die Leber von insgesamt 15 Patienten der Jesse-Gelsinger-Gruppe mit rekombinanten Adenoviren. Diese Viren sind genetisch so manipuliert, dass sie sich nicht mehr vermehren koennen, und tragen in ihrem Genom das gesunde OTC-Gen. Vierzehn Patienten zeigten keinerlei Nebenwirkungen der Behandlung. Bei Jesse Gelsinger hingegen scheint sich eine schwere Leberentzuendung entwickelt zu haben, wie die spaerlichen Informationen vermuten lassen, so dass er innerhalb weniger Stunden starb. Es ist moeglich, dass der verstorbene Patient auf den Adenovirus-Vektor speziell empfindlich war und entsprechend massiv reagiert hat. Es fragt sich, ob und wieviel die ´Branche' Gentherapie daraus lernen wird. Groessere Vorsicht? Bescheidenere Versprechen? Realistischere Protokolle? Keine voreilige Anwendung? Alles dies ist wuenschbar, und viele Kontrollinstanzen (in den USA beispielsweise die FDA, in der Schweiz die Eidgenoessische Fachkommission fuer biologische Sicherheit sowie die Leitung des NFP 37) haben unmittelbare Massnahmen ergriffen. Vielleicht hat dieser Fall tatsaechlich die notwendigen Bremsen aktiviert. Es waere aber aeusserst unguenstig, wenn der ´Fall Gelsinger' instrumentalisiert wuerde und es damit zu einer ´Tschernobylisierung' kaeme.

Ist Gentherapie ´notwendig'?

Nein. Genau wie Viagra, Mobiltelefone, portable Computer oder das Internet gehoert die Gentherapie zu den rasanten Entwicklungen dieses Jahrhunderts. Keine davon ist wirklich notwendig. Man kann ohne diese Errungenschaften gut leben - gewisse Leute meinen sogar: besser leben. Die Frage liegt im Gleichgewicht zwischen ´use and abuse'. Gentherapie ist nicht noetig, sie ist Wirklichkeit, die zu uns kommt wie etwa Gen-Food oder Virtual reality. Gentherapie stellt wahrscheinlich nicht die endgueltige Therapieform dar, aber mit ihrer Hilfe koennten sich viele uralte medizinische Probleme sehr wirkungsvoll und elegant loesen lassen. Und im Gegensatz zu Gen-Food hat die Oeffentlichkeit bei der Gentherapie die Moeglichkeit, Vor- und Nachteile der Methode ausgiebig zu diskutieren, lange bevor sie tatsaechlich zu einer breiten Anwendung kommt.

Nationales Forschungsprogramm 37 ´Somatische Gentherapie' (NFP 37): www.unifr.ch/nfp37


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Bild der Wissenschaft, 1.12.99

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bild der wissenschaft on-line vom 1.12.1999

Gentherapie: Silberstreif am Horizont: Erste positive Ergebnisse

Einen durchschlagenden Erfolg konnte bis heute noch kein Gentherapeut vorweisen. Noch immer steckt diese vor zehn Jahren als Revolution gehandelte Therapieform in den Kinderschuhen. Doch bei einigen Projekten zeigt sich ein Silberstreif am Horizont, wie Forscher auf dem 7. Treffen der Europaeischen Gesellschaft fuer Gentherapie in Muenchen berichteten.

So konnte Alain Fischer vom Krankenhaus Necker in Paris seine Patienten nach Hause schicken. Zwar waren die vier von ihm behandelten Patienten nicht geheilt. Doch das konnte man auch nicht erwarten, da sie an einer schweren Immunschwaeche, der severe combined immunodeficiency (SCID), leiden. Patienten mit dieser Kranheit besitzen einen Defekt in einem Gen, das die Bauanleitung fuer die Gamma-Untereinheit der sogenannten Interleukin-Rezeptoren ist. Ohne diese Rezeptoren koennen Lymphozyten ihre Funktion bei der Abwehr von Infektionserregern nicht wahrnehmen. Deshalb muessen SCID-Patienten quasi keimfrei leben. Fischer und seine Kollegen bauten in koerpereigene Immunzellen der Patienten eine intakte Version des Rezeptorgens ein. Da diese Art der Gentherapie praktisch im Labor und nicht im Koerper durchgefuehrt wird, spricht man auch von einer ex-vivo Therapie. Wieder im Koerper der Patienten funktionierten die so veraenderten Zellen einwandfrei - die Rezeptor-Untereinheiten wurden hergestellt und damit auch die Funktion des Immunsystems der Patienten, die heute wieder zu Hause leben koennen. Die Patienten muessen allerdings staendig kontrolliert werden, da nicht klar sei, wie lange die Gene aktiv bleiben, so Fischer.

Noch nicht so weit ausgereift sind die Anti-Krebs-Therapien der Arbeitsgruppen von Thomas Kipps von der University of California, San Diego, und von David Kirn von der Firma Onyx Pharmaceuticals im kalifornischen Richmond. Kipps arbeitet an einer Therapie der chronischen lymphatischen Leukaemie (CLL), die haeufigste Leukaemie-Form bei Erwachsenen. Die entarteten Lymphozyten vermehren sich dabei unkontrolliert, weil sie vom koerpereigenen Immunsystem nicht als krank erkannt und daher nicht zerstoert werden. Kipps' Arbeitsgruppe versah solche Krebszellen mit einem "Erkennungsmolekuel", dem CD145, und injezierte diese modifizierten Zellen den Patienten. Durch die Markierung wurde das Immunsystem der Patienten aktiviert und die Anzahl der Lymphozyten sank innerhalb von nur 24 Stunden nach der Injektion auf ein normales Mass. Da die Patienten jedoch alle Krebs im Endstadium hatten, konnte niemand mehr geheilt werden.

Die Arbeitsgruppe von David Kirn versucht, Hals-Gesichts-Tumore zu therapieren, indem sie die Tumorzellen gezielt in den Selbstmord treiben. Erste klinische Versuche der Gentherapie in Verbindung mit einer Chemotherapie an einzelnen Tumorherden waren erfolgversprechend. Manche der Patienten, die bereits viele Metastasen hatten, "leben auch heute noch, 18 Monate nach der Gentherapie", so Kirn. Dies sei deshalb ein Erfolg, weil Patienten mit solch einem schweren Krankheitsbild in der Regel nur noch drei Monate zu leben haetten. Allerdings, so Kirn, haetten sie die Krankheit nicht heilen koennen, sondern nur die Lebenserwartung verbessert.

Die Forscher dokumentierten, dass Gentherapien "im Prinzip" funktionieren. Doch bedarf es noch viel Grundlagenforschung, bis effiziente Therapien entwickelt seien, so das Fazit der Forscher.

[Quelle: Dr. Karin Hollricher] © 1996-98 bild der wissenschaft


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Washington Post, 2 Dec 1999

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Washington Post, Thursday, December 2, 1999; Page A06

Researchers Claim No Error in Gene Therapy Death

By Deborah Nelson and Rick Weiss, Washington Post Staff Writers

A teenager's death during a gene therapy experiment at the University of Pennsylvania was caused by the treatment but not by any errors by the research team, according to the preliminary findings of a two-month internal investigation.

The death is the first attributed to gene therapy, a nine-year-old field of research that is trying to find a way to use genes to overcome inherited diseases, cancer and other problems.

The findings were disclosed in a brief summary report released yesterday by the researchers who conducted the experiment. The researchers declined to provide the supporting documentation until next week, when they make a public presentation before a federal oversight board looking into the death.

The experiment had been controversial even before the death of Jesse Gelsinger, an 18-year-old Tucson resident, because it tested unusually large doses of a gene-altered virus on relatively healthy volunteers with a rare liver disorder.

"The findings suggest that the experimental drug used in the trial--a modified cold virus, or vector, incorporating a potentially corrective gene for Mr. Gelsinger's genetic disease--initiated an unusual and deadly immune-system response that led to multiple organ failure and death," the report states.

However, the researchers say they still don't know why the virus, known as an adenovirus, triggered a lethal reaction in Gelsinger. Gelsinger received a significantly larger dose of vector than all but one of the other participants. But there were no early warnings of trouble in the other volunteer who received the high dose or in 16 earlier volunteers who received smaller doses, the report states.

The report acknowledges that some participants suffered temporary liver damage but says a review of patient data and of animal studies performed before the clinical trial "revealed no information that would have predicted the events that led to Mr. Gelsinger's death."

"There was no evidence of human error in his clinical management," the report says. The Washington Post reported last week that monkeys given a high dose of a genetically engineered virus by the Penn team a few years ago had died in a manner similar to Gelsinger. Penn researchers subsequently developed what they considered to be a safer version of the virus for the experiment.

However, some scientists, citing a growing body of evidence that adenovirus in any form causes serious side effects, have questioned the wisdom of using it to treat genetic diseases. The risk might be warranted if the participants were dying and had exhausted conventional treatments, they said. But the Penn team chose to experiment on adults with a mild form of a liver disorder--ornithine transcarbamylase deficiency--who either suffered no symptoms or had them under control with drugs and diet.

The report states that the researchers were mindful of the potential side effects and "carefully monitored all patients for liver inflammation and/or injury using liver-function tests and liver biopsies. While there was evidence of liver inflammation in some patients, all such episodes proved transitory in nature," and their livers returned to normal within two weeks. Gelsinger died within four days of receiving the infusion on Sept. 13. His decline began within a day, as he developed a systemic blood clotting disorder followed by respiratory distress and then liver and kidney failure on Sept. 17.

In the investigation that ensued, Penn researchers checked the vector for abnormalities but found none, according to their summary. All laboratory data that they reviewed pointed to an unusually severe reaction to the genetically altered virus, the report says.

"In the context of this unexpected tragedy, the researchers--Dr. James Wilson, Dr. Steve Raper, and Dr. Mark Batshaw--remain committed to fully evaluating all potential leads," the report states. "The purpose of these efforts is to understand the precise nature of Mr. Gelsinger's unfortunate death, and to share the knowledge gained with the research community and the public in order to prevent another such occurrence."

Gelsinger's death prompted the Office of Biotechnology Activities at the National Institutes of Health to call on all researchers using adenoviruses to report any ill effects that might shed light on his death or prevent future injuries.

The results of that solicitation and of the Penn investigation will be presented next week in Bethesda to a special NIH advisory committee that monitors gene therapy experimentation.

© Copyright 1999 The Washington Post Company


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ATS Washington Dec 8, 1999

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La thérapie génique accouche de super-cochons

Washington (ats/afp) Des chercheurs américains ont créé des cochons 22 % plus gros que des bêtes non traitées grâce à une nouvelle thérapie génique. Celle-ci favorise la production d'hormone de croissance directement dans le corps des animaux.

Cette découverte, présentée mardi dans la revue "Nature Biotechnology", pourrait avoir d'importantes applications pour l'élevage agricole. Elle permettrait également le traitement chez l'homme du nanisme ou de l'ostéoporose, selon les auteurs de l'étude.

Jusqu'à présent, les hormones de croissance devaient être injectées périodiquement, car elle étaient rapidement détruites dans l'organisme sous l'effet de protéases. Cez enzymes dégradent en effet les protéines. De plus, l'utilisation de ces hormones s'accompagnaient parfois de malformations osseuses ou d'anomalies organiques.

Sous la direction du professeur Robert Schwartz, des chercheurs du Baylor College of Medicine, à Houston, ont eu l'idée de faire fabriquer l'hormone de croissance directement par le cochon lui-même. Ils ont injecté dans ces animaux de l'ADN contenant le code génétique nécessaire à la production d'une hormone de croissance résistante aux protéases (GHRH).

Après 65 jours, les cochons ainsi traités étaient 22 % plus gros que les autres. Cette approche nécessite de faibles doses et semble dénuée d'effets secondaires, indiquent les auteurs de l'étude.


Reuters, Dec 12, 1999

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Patients Keep Faith Despite Gene Therapy Death

By Maggie Fox, Health and Science Correspondent

 

BETHESDA, Md. (Reuters) - When a sleepy Brett Rosen kissed his mother goodbye as she left for a National Institutes of Health hearing Thursday morning, he asked her to tell scientists there to press ahead with gene therapy trials, despite the death of another teenager.

``He said, 'Mom, please tell them I want to have gene therapy,'' Mindy Rosen, of Cherry Hill, New Jersey, told the hearing. ``'I hate being sick. I just want to be normal'.'' While scientists investigating the first-ever gene therapy death tossed about terms such as ``patient cohorts'' and ''adverse events'', patients, and parents of patients provided reminders about why desperate patients would join in an experiment unlikely to directly help them.

Jesse Gelsinger, 18, died last September after he became the 18th patient in a trial meant to test the safety of a potential gene therapy treatment for a genetic liver disorder known as ornithine transcarbamylase deficiency (OTC), a genetic defect that causes ammonia to build up in the body.

The disorder affects between 1 in 40,000 and 1 in 80,000 babies, about half of whom die soon after birth because they go into a coma before doctors even know what is wrong with them. But several hundred children survive with the defect, managing with a strict low-protein diet and drugs to clear excess ammonia from their bodies. Liver transplants can also help but there is no cure. Patients and their families, including Gelsinger's father, Paul, strongly support the gene therapy research. ``It was a beautiful thing he did. You don't get any purer than that,'' he told the hearing. ``Gene therapy is our only hope,'' Rosen said.

Cindy Le Mons, co-president of the National Urea Cycle Disorders Foundation, told the hearing that the condition leaves a patient vulnerable to any infection. ``One day your child is laughing, playing; and the next day your child is gone. Every day is a gift. Every virus that goes around strikes fear in your heart. Your child's life depends on your vigilance and knowledge.'' Le Mons said Gelsinger's death had not hurt her faith in gene therapy. ``This was a safety study. We knew the risk. Three participants told me 'I'd do it again in a heartbeat'.''

Patricia Simon, herself an OTC patient, took part in the same trial as Gelsinger. She had hoped her son, who had more severe OTC, could take part, but he was too young to join the trial and he died in 1996 at the age of 14. She said she did not regret joining the trial. ``Sadly, patients die in the name of medical science and we all know that,'' she said. ``Hopefully, the benefits will outweigh the risks.'' Managing the condition is difficult and unpleasant, she said, describing holding a whimpering child through countless blood draws, skin biopsies and intravenous infusions of drugs. ``You must constantly control your child's diet,'' she said. ''You must ... administer medicine that is at best distasteful. It is so difficult to take that it is often given and then vomited right back up.''

Keeping a child on a strict diet is not any fun, either. ''There's no ice cream, pizza or hamburgers for these kids,'' she said. ``Most of the foods of childhood are denied them.'' Dr. Arthur Beaudet of the Baylor College of Medicine in Houston said researchers should keep such desperation in mind when signing patients up for clinical trials. ``Patients are so enthused about gene therapy that they may be willing to take risks that are difficult to understand,'' he told the hearing.

Copyright © 1996-1999 Reuters Limited


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Washington Post, Dec 11, 1999

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Gene Therapy Firms Resist Publicity: U.S. Regulators, Researchers Are Divided on Releasing Information About Adverse Effects

By Rick Weiss

Washington Post Staff Writer

Federal officials overseeing the field of gene therapy searched in vain yesterday for common ground between drug companies that want to keep details of their experiments secret and advocates who favor a more open airing of the field's recently revealed problems. On the final day of an emotionally exhausting gene therapy conference at the National Institutes of Health in Bethesda, federal officials wrangled over the difference between "serious" and "severe" side effects, biotechnology company officials pushed for less burdensome regulations, and parents of sick children pleaded for more help from both the regulators and those who hope to profit from gene therapy.

The three-day meeting was prompted by the awkward confluence of two events: the September death of a teenager in a University of Pennsylvania gene therapy experiment, and recent efforts by some gene therapy companies to scale back the amount of information about side-effects they must submit to the NIH. Researchers and companies testing genetic therapies on people are required by the NIH to release to the public more details of their work than are researchers who test conventional drugs. Those rules were devised to ensure that subtle side-effect trends are noticed more quickly, and to foster public confidence in the novel field that seeks to cure diseases by giving people new genes.

Gene therapy has yet to cure anyone. But as the field has grown from one dominated by academic researchers to one driven by companies with millions of dollars at stake, pressure has built to trim the NIH public disclosure rules and have research results reviewed mostly by the Food and Drug Administration, which keeps such information confidential. "Virtually every detail about the design, size or status of a clinical trial is of potential competitive value," according to a statement by the Biotechnology Industry Organization (BIO) for the NIH Recombinant DNA Advisory Committee (RAC) yesterday. That includes details of "adverse events," the industry group said, which "are, by definition, trade secrets and confidential commercial information."

BIO board member H. Stewart Parker told officials that biotechnology companies were willing to submit to the NIH some details of the most serious and unexpected adverse events as they occurred but only if the companies and the agency could first agree on how much of that information would be made public. NIH now makes all such information available to the public. Less serious adverse events should not have to be reported to the NIH at all except in annual summary reports, Parker and other industry representatives said, because those details are too easily misconstrued negatively by the public. "Immediate disclosure of adverse events is bad science," said an official from Schering-Plough Corp. of Kenilworth, N.J., a company whose recent effort to declare its NIH adverse-events reports "confidential" helped prompt yesterday's reassessment of reporting rules. Others at the meeting objected to that view, saying so much is still unknown about gene therapy that open sharing of results may help prevent tragedies like the one that befell Jesse Gelsinger, the Arizona teenager who died in September. Even if gene therapy is not more dangerous than other experimental approaches, some said, it is scary enough to the public to warrant extra openness.

"My feeling is it's still a unique field," said W. French Anderson, the University of Southern California researcher who conducted the nation's first gene therapy test in 1990. "Standard medical research doesn't strike the same nerve as changing genes and changing the core of what we are as human beings. It's not a safety issue. It's a public confidence issue. And that will remain until people are really starting to see some cures," perhaps in three to five years, Anderson predicted. Some RAC members questioned whether the NIH had the right to demand so much data if it didn't have the resources to make sense of it. The agency is years behind in its effort to create an online database of gene therapy trials and adverse events.

Others expressed concern that public reporting could run afoul of new patient privacy regulations under construction. Even a few details in an adverse-event report could inadvertently and illegally give away the identity of a clinical test volunteer with a rare disease. If that's the case, some said, it may be that gene therapy volunteers should be asked to sign a special consent form, which states that they accept the possibility that their identities may become public.

Asked if that extra level of public exposure was appropriate to ask of volunteers, Paul Gelsinger, Jesse's father, acknowledged that some might not be as willing as he and his son were to step into the limelight. "That's a tough one. It's a personal choice," he said. "But I'd advise people to be willing to be public, because it's so important that all the information get out."

RAC officials said they would continue the discussion at future meetings, and would welcome public comments on the issue.

© Copyright 1999 The Washington Post Company


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Reuters, Washington, 13.12.99

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Panel urges strict reporting of gene therapy trial complications

 

WASHINGTON, Dec 13 (Reuters Health) -- In order to increase patient safety in gene therapy trials, the National Institute of Health's Recombinant DNA Advisory Committee (RAC) has proposed more strict reporting requirements when serious adverse effects occur. On Friday, members of RAC's public oversight committee presented a draft of the new reporting requirements during proceedings that investigated the events leading to the death in September of teenage patient Jesse Gelsinger during a gene therapy trial being conducted at the University of Pennsylvania. A lapse in the reporting of a number of adverse effects came to light during the proceedings. Committee members discussed whether keeping both the Food and Drug Administration (FDA) and RAC better informed might have halted the trial before the 18-year-old received the highest dose yet administered of an adenovirus gene vector.

RAC is requesting immediate reporting of all adverse events, defining ``immediate'' as no later than 15 calendar days after such an event has occurred. A serious adverse event could be either ``expected or unexpected, and either related or unrelated to the treatment, at any dose that resulted in death, a life-threatening event, in-patient hospitalization or prolongation of existing hospitalization, a persistent disability/incapacity, or a congenital anomaly/birth defect.'' Also included in mandatory reporting would be other situations that require medical or surgical intervention to prevent one of these outcomes.

Bioethicist Ruth Macklin of New York's Albert Einstein College of Medicine observed that these points are clarifications of existing RAC policy, rather than substantive changes. Researchers at the University of Pennsylvania, as well as those from a number of companies conducting gene therapy trials, have breached reporting protocols, according to both the FDA and RAC.

Also coming to light during the proceedings, Drs. Jeffrey Isner of Tufts University in Boston and Ronald Crystal of Cornell University did not report a total of six deaths in their cardiovascular gene therapy trials because they believed the deaths were not related to the therapy, but rather to the underlying disease and therefore rendering it unnecessary to report the events to the RAC. The first proposed amendment clarifies that in an ill population, it may not be clear whether a patient sickens due to the disease or the treatment. In either case, reporting will be mandatory.

On behalf of the Biotechnology Industry Organization, H. Stewart Parker, CEO of Seattle's Targeted Genetics, told RAC committee members that his and other biotech companies are not in favor of expanded reporting on trials because ``virtually every detail about the design, size, or status of a clinical trial is of potential competitive value.'' Reports of adverse events ``are, by definition, trade secrets and confidential commercial information,'' Parker asserted.

``We are changing the language to reflect that adverse events do not fall into the category of 'confidential,''' said RAC chairperson Dr. Claudia Mickelson, biosafety officer at the Massachusetts Institute of Technology. The RAC published its proposed changes in the November 22nd issue of the Federal Register, asking for public comment.

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