In the Issue of Science
of June 28 2002 (vol 296, page 2410 and following) the
team of Claudio Bordignon officially publishes the results
obtained with two patients suffering from
Adenosine-Desaminase-deficiency. This disease causes a
severe immunodeficiency that if not cured results in the
death by infection few months after birth. In the reports
cited below you can get some details in various languages.
continuation of this
commentary
Sandro Rusconi, July 2002
Prof Shimon Slavon (Hadassah Hebrew Medical center) holds
one of the two young reported patients, Salsabil (22 months
old at time of picture).
No satisfactory treatment:
The available cures for ADA before the gene therapy era were either a
bone marrorw transplantation (with the associated risks and the
difficulties in getting an appropriate donor) or the detoxification
of the immune cells by systemic injection of bovine Adenosine
Deaminase in a special formulation (PEG-ADA). This latter treatment
is available since about 12 years but is extremely expensive and it
is out of reach in many countries.
The long history of ADA gene therapy:
Back in 1990, French Anderson and colleagues started the very first
gene therapy clinical trial for the treatment of a hereditary
disorder indeed with an ADA patient (Ashanti De Silva). their form of
treatment involved the isolation of peripheral lymphocytes and the
transfer of the functiuonal gene with a retroviral vector. their
results were however masked by the effect of the concomitant
PEG-ADAtherapy. After the follow-up, the general impression in the
field was that the gene transfer was successful but could not lead to
a therapeutic success due to the progressive disappearance of the
treated cells and the silencing of the transferred gene in the
surviving cells. In fact it was the ethically acceptable principle of
not abandoning an established medication that in this case was
obscuring the correct interprestation of the clinical data.
The success of these days:
In this more recent work, Claudio Bordignon shows that when the
patient is subjected to a mild conditioning that removes part of the
immune cells and is then engrafted his own bone marrow cells that
have been tranferred with the functional gene, the treated cells
efficiently repopulate the immune compartment and give a very stable
correction of the diseas. Now these two kinds can conduct a normal
life. C. Bordignon already mentioned the preliminary results at the
ESGT meeting 2000 in Stockholm. It is a pride for us to announce this
also because Claudio has been acting in the Expert's board of the NFP
for several years.
Good news among bad news
It is somewhat refreshing to learn that one of the treated patients
comes from an area of the world which is tortured by a long standing
war that from our distance is essentially incomprehensible. May this
demonstrate that positive thinking can blossom also in spite of the
nasty winds of war that continue to sweep our planet.
The second undisputable success:
The observation of the Milanese team is in line with the breakthrough
experiments of Alain Fischer (also published in Science, in 2000) who
could permanently cure four young patients from a similar
immunodeficiency (yet caused by another defect).
An NFP37 team along the same strategy:
It is with particular pleasure that I also take the occasion to
announce that one of our NFP37 teams (R. Seger and HP Hossle from
Zuerich, in Collaboration with M. Grez, Frankfurt) are just starting
these weeks the first treatments for chronic granulomatosis under
similar experimental conditions. Good luck to all of you!
The lessons that we draw from these events are the following:
a) the principle of curing by gene transfer is feasible and
can indeed save lives
b) in some treatments it may be crucial to be able to confer a
selective advantage to the gene-modified cells
c) several disorders of the blood and immune system
(hematopoietic disorders) could be treated with analogous
protocols.
d) sometimes, good-aimed action (see ethical dilemma of
PEG--ADA) can turn into disadvantage
All this encourages us go go on with
the idea that Gene Therapy has a great
and promising future !
Neue Gene fuer Kinder ohne Immunschutz - Kleinkinder mit
angeborener Immunschwaeche wurden erfolgreich gentherapiert ,
Sonntags Zeitung, 30.06.2002
VON MICMAEL HAGMANN
Von all den Hightech-Medizinern, die der Menschheit seit laengerem
eine krankheitsfreie Zukunft versprechen, mussten die Gentherapeuten
in den letzten Jahren wohl am meisten Pruegel einstecken. Am 17.
September 1999 starb der 18-jaehrige Jesse Gelsinger, der an einer
erblichen Leberkrankheit litt, im Verlauf eines Gentherapie-Versuches
in den USA. Nicht nur Gentech-Kritiker stimmten daraufhin den
Abgesang auf das offenbar allzu riskante Herumbasteln am menschlichen
Erbgut an. Doch Totgesagte leben laenger: Mit kaum mehr fuer moeglich
gehaltenen Erfolgsmeldungen bei verschiedenen angeborenen
Immunschwaechen ist die Gentherapie gerade dabei, ihr arg
ramponiertes Image kraeftig aufzupolieren.
Die neueste Frohbotschaft kommt aus Italien. Die Gruppe um Claudio
Bordignon vom Mailaender San Raffaele Telethon Institut fuer
Gentherapie hat mit einer Gentherapie zwei Kinder, die an der
Immunschwaeche ADA-SCID (Severe Combined Immune Deficiency) litten,
zumindest vorerst geheilt.
Doch damit nicht genug: Alain Fischer vom Pariser Hôpital
Necker hatte im Maerz 1999 das defekte Gen von zwei Kleinkindern, die
an einer anderen Immunschwaeche, SCID XI, litten, mittels Gentherapie
repariert - mit zunaechst durchschlagendem Erfolg. Die «bubble
kids", die, ohne funktionierende Immunabwehr, in sterilen Zelten ihr
Dasein fristeten und meist trotzdem bereits im Saeuglingsalter ihrer
Krankheit erlagen, konnten innert kuerzester Zeit nach Hause
entlassen werden.
Diesen April hat Fischers Team nachgedoppelt; die Forscher konnten
zeigen, dass es sich bei ihrem Erfolg keineswegs nur um ein
Strohfeuer handelte. Nach dreijaehriger Beobachtung seiner
mittlerweile fuenf kleinen Patienten ertreuen sich vier nach wie vor
bester Gesundheit - ohne jegliche Zusatzbehandlung. Und erst letzte
Woche wurde in Frankfurt, in Zusammenarbeit mit Zuercher Forschern,
ein Patient mit septischer Granulomatose - ebenfalls eine
Abwehrschwaeche - auf aehnliche Weise wie in Mailand behandelt.
Es herrscht derzeit also Freude bei den Gentherapeuten. «Seit
Jahren hat man immer nur das eine gehoert: "Gentherapie, das
funktioniert nie. > Jetzt sehen wir, dass das nicht stimmt»,
sagt Sandro Rusconi von der Universitaet Fribourg, der das von 1996
bis 2001 laufende nationale Forschungsprogramm «Somatische
Gentherapie" leitete. «Ich glaube, wir werden in den naechsten
Jahren einige gute, vielleicht sogar spektakulaere Resultate im
Bereich Gentherapie sehen." Die ersten Therapie-Versuche zeigten noch
keine Wirkung Zeit wirds. Denn die Gentherapie hat schon ein Dutzend
Jahre auf dem Buckel. 1990 wagte der Amerikaner French Anderson
erstmals eine Gentherapie an einer vierjaehrigen ADA-SCID-Patientin.
Ihr fehlte, wie allen ADA-SCID-Patienten, auf Grund eines genetischen
Defekts das Enzym Adenosindesaminase. Dadurch haeuft sich in den
Koerperzellen ein giftiges Stoffwechselprodukt an. Unreife
Abwehrzellen reagieren darauf besonders empfindlich, sterben ab - und
ueberlassen die Patienten schutzlos dem Angriff von Viren, Bakterien
und Pilzen. Bis zu Andersons «pioniertat" hatten Aerzte
lediglich zwei Optionen: Entweder spritzten sie ihren
ADA-SCID-Patienten regelmaessig das fehlende Enzym, ein «enorm
teures Unterfangen", wie Reinhard Seger, Leiter der Immunologie und
Haematologie am Kinderspital Zuerich, sagt. Oder aber es brauchte
eine vollstaendige Knochenmarktransplantation. Fuer rund ein Drittel
der Patienten gibt es indes keinen geeigneten Spender. Da war
Andersons Idee schon viel versprechender. Er wollte den Blutzellen
der Patienten ein intaktes ADA-Gen verabreichen.
Die gute Nachricht; Die zwei damals behandelten Kinder sind am
Leben und wohlauf. Doch diesen Umstand verdanken sie keineswegs
Andersons Gentherapie: Die Kinder bekamen weiterhin regelmaessig das
ADA-Enzym injiziert. «Als man das Enzym absetzte, sah man, dass
die Gentherapie allein nicht ausreichte, um die toxischen
Stoffwechselprodukte zu entgiften», erklaert Seger. «Das
Einzige, was Anderson zeigen konnte, war, dass die Gentherapie keine
unerwuenschten Nebenwirkungen hat.,> Auch in der Schweiz will man
Kinder bald so behandeln Zwoelf Jahre spaeter hat Claudio Bordignon
nun Andersons Experiment abgeschlossen. Sein Trick:Vor der
Stammzelltransfusion behandelte er die kleinen Patienten mit einer
milden Chemotherapie, um einen Teil der defekten Stammzellen
abzutoeten und so "Platz zu machen, damit sich das reparierte
Knochenmark einnisten und vermehren kanna. Der Trick hat
funktioniert: Mehr als ein Jahr nach der Prozedur fuehren beide
Patienten ein normales Leben, ohne von ernsten Infektionen geplagt zu
werden.
Schweizer Gentherapie-Experten zeigen sich ob solcher Meldungen
begeistert. «Bahnbrechend>, findet das etwa Sandro Rusconi,
und von einem «Traumergebnis» spricht Reinhard Seger.
Allein, wie lange der Therapieerfolg andaure, warnen die Experten,
stehe in den Sternen. Seger: «Die meisten von uns denken, dass
die Therapie vielleicht fuenf, maximal zehn Jahre anhaelt. Doch
selbst wenn man die Therapie alle zehn Jahre wiederholen muesste,
waere das immer noch ein Riesentortschritt gegenueber den bisherigen
Behandlungsmethoden.»
Seger will nun den gleichen Weg wie Bordignon einschlagen und so
die septische Granulomatose besiegen. Bei dieser Immunschwaeche sind
die Fresszellen des Immunsystems, die so genannten Phagozyten, nicht
in der Lage, Bakterien oder Pilze abzutoeten. Folge: Regelmaessig
wiederkehrende, lebensgefaehrliche Infektionen und eine mittlere
Lebenserwartung von 20 Jahren. Geht bei der Therapie des ersten
erwachsenen Patienten alles glatt, plant Seger, im naechsten
Fruehjahr die ersten Kinder zu behandeln.
Blut- und Knochenmarkerkrankungen sind also in Reichweite der
Gentherapie gerueckt. «Insgesamt kennen wir rund 100 angeborene
Immunschwaechen, und hier hat die Gentherapie sicher ihren
Platz», sagt Reinhard Seger. Diese sind zwar alle recht selten,
nicht aber Blutkrankheiten wie Haemophilie (Bluterkrankheit),
Sichelzellanaemie oder Thalassaemie, fuer die bereits viel
versprechende Tierversuchsergebnisse vorliegen.
Die Zukunft der Gentherapie, so scheints, bricht also - endlich -
an.
Zwei Kinder, die ohne innere Abwehrkraefte auf die Welt gekommen
sind, brauchen jetzt nicht mehr ihr Leben in der sterilen Isolation
eines Plastikzelts zu verbringen. Einem italienisch- israelischen
Forscherteam ist es mit einer bereits erprobten Gentherapie gelungen,
die Immunschwaeche-Krankheit zu heilen. Die Mediziner haben den
Kindern gentechnisch gezuechtete Abwehrzellen eingepflanzt. Um den
neuen, verbesserten Blutzellen einen Startvorteil zu verschaffen,
behandelte man die Babys vor Gabe der neuen Zellen mit der milden
Dosis eines Transplantationsmittels. Innerhalb weniger Wochen haben
sich die angereicherten Blutzellen im Knochenmark angesiedelt und
dort Immunzellen gebildet. Nur einen Monat nach der Behandlung
konnten die Kinder die Klinik verlassen. dpa Schnelltest erkennt
Herzinfarkt Einen Test, der bereits erste Anzeichen von einem
Herzinfarkt aufdeckt, hat jetzt die Schweizer Vitatest GmbH auf den
Markt gebracht. Dazu wird Blut des Patienten aus der Fingerkuppe
analysiert. Der Schnelltest weist drei Proteine nach, die nach einem
Herzinfarkt ausgeschiedenen werden. Nach Angaben des Herstellers
koennten so selbst kleinste Herzinfarkte nachgewiesen werden, die nur
eine Stunde vorueber seien. hsn Haemoglobin heilt chronische Wunden
Eine Methode, mit der auch chronische Wunden geheilt werden koennen,
hat die SanguiBioTech AG aus Witten entwickelt. Das Problem bei
schwer heilbaren Wunden ist, dass die inneren Zellen nicht mehr mit
genug Sauer stoff versorgt werden. Die Wittener haben nun einen Weg
gefunden, wie der Sauerstoff mit Hilfe von Haemoglobin an die
Wundzellen gebracht werden kann. Erste Patienten haben von der
Behandlung profitiert und sind vollstaendig geheilt worden, pew
Gene therapy can chalk up its second success. Two children with a
defective immune system and metabolic problems have been cured by
replacing their defective gene with a healthy one. The results, which
appear in the 28 June issue of, Science, suggest gene therapy
techniques that can be applied to other blood diseases as well.
Severe combined immunodeficiency, or SCID, is a rare group of
conditions in which a person's immune system doesn't develop properly
and common infections, such as chicken pox, can prove fatal. In the
first successful genetic modification of an inherited disease, French
doctors repaired the immune systems of two babies with SCID-X1 in
2000 (ScienceNOW, 28 April). Seven other afflicted children have been
cured since then.
The newly treated patients have a more severe form, ADA-SCID,
which makes up 15% to 30% of SCID cases. These children can't make
the enzyme adenine deaminase (ADA), a lack that wipes out more of the
immune system than in SCID-X1 and causes a host of metabolic
problems, such as enlarged livers anddiarrhea. Previous attempts at
gene therapy replaced the damaged ADA gene in
some circulating immune cells, but the cells didn't make enough
enzyme.
In the current study, the researchers removed stem cells, the
progenitors of many blood cell types, from the bone marrow of a
7-month old and a toddler in Israel. The team inserted the corrected
ADA gene in culture and injected the modified stem cells 4 days
later. But first, the team had partially obliterated the children's
marrow with chemotherapy. The bone marrow responds by cranking up its
stem cell production, and the genetically modified cells receive the
same push, says gene therapist Claudio Bordignon, lead researcher for
the team at the San Raffaele Telethon Institute for Gene Therapy in
Milan, Italy.
Several months later, both patients had high levels of healthy
immune and other blood cells. The children made normal amounts of
ADA, which reduced toxic metabolites in their bloodstreams, and when
they were vaccinated against tetanus, they made antibodies to the
injected toxin, indicating that the treatment had fully repaired the
immune system.
According to pediatrician Donald Kohn of Children's Hospital in
Los Angeles, the results are very encouraging for gene therapy. The
technique's success with SCID is "almost to the point where we can
talk to insurance companies about making it a reimbursable
procedure," he says. More important, though, he says the addition of
the chemotherapeutic step suggests the method can help a variety of
blood diseases, such as anemias
Gene therapy may offer release from sterile isolation for patients
lacking immune systems
EUREKAlert (AAAs press release Public release date:
27-Jun-2002
Science authors report new success with improved technique
This news release is also available in French and Italian
A new gene therapy method has turned the bone marrow of two young
children from an "immune cell desert" into a healthy breeding ground
for a variety of infection-fighting agents.
The children have a form of severe combined immunodeficiency
disorder (SCID) that typically requires patients to stay in sterile
environments. They are now living and developing normally, Italian
and Israeli researchers report in the journal Science, published by
the American Association for the Advancement of Science.
Specifically, the two children have a form of the disease called
ADA-SCID, in which they do not produce the ADA enzyme necessary for
making immune cells. The disease can be controlled to a certain
degree by regular injections of the bovine form of ADA, an expensive
proposition in many countries.
Approximately 30-50 infants with ADA-SCID are born each year, but
only a small portion of them are diagnosed, according to study
co-author Claudio Bordignon of the San Raffaele Telethon Institute
for Gene Therapy and Università Vita-Salute San Raffaele, in
Milan.
Bone marrow transplants have also been successful in some cases,
but they pose serious risks of their own. There was no available
donor for the two children in the study, who were seven months old,
and two years and six months old.
"With gene therapy you can treat every patient, and the toxicity
is enormously lower than for bone marrow transplants. We propose, at
this stage, that every patient lacking a donor with an identical
tissue type should be directed to gene therapy," said Bordignon.
Bordignon's team must test their therapy on more volunteers before
it will be approved for researchers to use in Italy or abroad. They
will start with patients without a matched donor for a bone marrow
transplant, and may then include patients for whom a donor is
available. Because ADA SCID is a relatively rare disorder, these
studies would function as phase I and II clinical trials, meaning
they aim to demonstrate that the procedure is both safe and
effective, Bordignon said.
In order to extend this method to a larger population of Italian
patients, the group is seeking the approval of Italy's Istituto
Superiore de Sanità. A similar application process will be
necessary for performing the therapy elsewhere in Europe, and in the
United States. Because the therapy could considered under the "orphan
drug" category, meaning a treatment for a rare disease, the approval
process in Europe should likely be relatively fast, lasting a few
months, according to Bordignon.
Bordignon and his colleagues removed some of the bone marrow from
the pelvises of the two patients in the study. Next, they isolated
the blood stem cells, which have the potential to develop into the
body's various red and white blood cells. When researchers exposed
the stem cells to an engineered virus carrying a healthy version of
the ADA gene, the virus inserted the gene into the stem cells'
genome.
Before injecting the engineered stem cells into the patients, the
Science authors performed an additional step, which they believe will
make their efforts more successful than previous efforts to treat
SCID with gene therapy. Until now, Bordignon says, these efforts have
not established enough healthy stem cells in the body for the results
to last. This time around, a process called "non-myeloblative
conditioning" may make the difference, according to the
researchers.
"Non-myeloblative condition means you don't really wipe out the
bone marrow, you just give one of the drugs used for a transplant, at
a much lower dose, to make 'space' for engineered marrow to seize,
expand, and grow better," Bordignon explained.
Within weeks after being injected into the patient, the engineered
stem cells migrated to the bone marrow and began spawning key types
of immune cells, such as B cells, T cells, and NK cells. Within
months, antibodies appeared, and the patients responded normally to
small amounts of certain pathogens, such as the tetanus vaccine. One
year later, one of the patients no longer had the respiratory
infections, chronic diarrhea or scabies that were common before the
therapy.
Because the ADA enzyme is used for a variety of metabolic
processes in the body, it's a more complex disease than other SCIDs.
In previous studies, Bordignon said, researchers had to continue
giving patients enzyme replacement therapy for the metabolic
problems, even when gene therapy had the immune component of the
disorder under control.
The two patients in the Science study never received enzyme
replacement therapy, which is not an option for them in their home
countries. Bordignon's group observed the buildup of minimal amounts
of toxic metabolites, indicating that the gene therapy was
controlling the metabolic side of the disorder as well.
Eventually, Bordignon plans to try using the gene therapy method
for treating other diseases, including AIDS.
This study follows earlier research by Marina Cavazzana-Calvo and
colleagues, published in the 28 April, 2000 issue of Science. The
French research team used blood stem cells in gene therapy to treat
two infants with SCID X1, a variation of the disease caused by a
mutation on the X chromosome.
###
The other members of the research team are Alessandro Aiuti,
Francesca Ficara, Sara Deola, Alessandra Mortellaro,
Grazia Andolfi, Federica Cattaneo, Sergio Vai, and Maria Grazia
Roncarolo, of the San Raffaele Telethon Institute for
Gene Therapy, in Milan, Italy; Shimon Slavin, Memet Aker, and
Shoshana Morecki, of Hadassah University Hospital,
in Jerusalem, Israel; Antonella Tabucchi, Filippo Carlucci, and
Enrico Marinello, at the University of Siena, in Siena,
Italy; Paolo Servida, of Scientific Institute H.S. Raffaele, and
Roberto Miniero, at the University of Turin, in Turin.
Maria Grazia Roncarolo is also at Università Vita-Salute San
Raffaele, in Milan, Italy. The study was funded by the
Italian Telethon Foundation.
La thérapie génique peut libérer les patients
souffrant d'immunodéficience de l'isolement stérile
auquel ils sont contraints
EUREKAlert (AAAs press release Public release date:
27-Jun-2002
Une étude publiée dans la revue Science signale le
nouveau succès remporté grâce une technique
améliorée
Une nouvelle méthode de thérapie génique a
transformé la moelle osseuse de deux jeunes enfants d'un "
désert immunitaire " en un terrain fertile où abondent
une variété d'agents anti-infectieux.
Ces enfants souffraient d'une forme de déficit immunitaire
combiné sévère (SCID, severe combined
immunodeficiency disorder), qui exige en général que
les patients soient placés dans un environnement
stérile. À présent, ces enfants vivent et se
développent normalement, annoncent les chercheurs italiens et
israéliens dans leur rapport de la revue Science,
publiée par l'American Association for the Advancement of
Science.
Plus spécifiquement, les deux enfants souffrent d'une forme
de la maladie appelée ADA-SCID, un déficit de l'enzyme
ADA nécessaire à la production de cellules
immunitaires. Il est possible, dans une certaine mesure, de
contrôler la maladie à l'aide d'une forme bovine de
l'ADA, une solution très coûteuse dans de nombreux
pays.
Selon l'un des auteurs de l'étude, Claudio Bordignon de
l'Institut San Raffaele Telethon de thérapie génique et
l'Universitá Vita-Salute San Raffaele, à Milan, il
naît approximativement 30 à 50 enfants souffrant
d'ADA-SCID chaque année, mais seule une faible proportion
d'entre eux sont diagnostiqués.
Les greffes de moelle osseuse ont également donné de
bons résultats dans certains cas mais elles présentent
elles-mêmes des risques importants. Et aucun donneur
n'était disponible pour les deux enfants de l'étude,
âgés l'un de sept mois et l'autre de deux ans et six
mois.
"Avec la thérapie génique, il est possible de
traiter tous les patients et la toxicité est infiniment moins
importante qu'avec les greffes de moelle osseuse. Nous proposons,
à ce stade, que soit dirigé vers la thérapie
génique tout patient possédant un type de tissu
identique et pour lequel aucun donneur n'est disponible ", recommande
Bordignon.
L'équipe de Bordignon doit faire l'essai de sa
thérapie sur un plus grand nombre de volontaires avant que son
utilisation ne soit autorisée pour les chercheurs, en Italie
ou ailleurs. Elle commencera par les patients ne
bénéficiant pas d'un donneur compatible pour une greffe
de moelle osseuse et pourra par la suite également inclure
ceux pour lesquels un donneur est disponible. L'ADA SCID étant
une maladie relativement rare, ces études tiendront lieu
d'essais cliniques de phase I et II, ce qui signifie qu'elles
viseront à démontrer que la procédure est
à la fois efficace et sans danger, selon Bordignon.
Afin de mettre sa méthode à la portée d'un
plus grand nombre de patients italiens, le groupe de chercheurs a
fait une demande d'approbation auprès de l'Istituto Superiore
de Sanità en Italie. Un processus de demande similaire sera
nécessaire pour étendre la thérapie à
d'autres pays d'Europe et aux États-Unis. La thérapie
pouvant être classée dans la catégorie "
médicament orphelin ", c'est-à-dire comme traitement
d'une maladie rare, le processus d'approbation pour l'Europe devrait,
d'après Bordignon, être relativement court, quelques
mois au plus.
Bordignon et ses collègues ont fait un
prélèvement de moelle osseuse au niveau du pelvis des
deux patients de l'étude, dont ils ont ensuite isolé
des cellules souches sanguines, qui ont le potentiel de se
développer en érythrocytes et en leucocytes
variés. Lorsque les chercheurs ont exposé les cellules
souches à un virus génétiquement modifié
porteur d'une version saine du gène de l'ADA, le virus a
inséré ce gène dans le génome des
cellules souches.
Avant de réinjecter les cellules ainsi modifiées,
les auteurs de l'article de Science ont introduit une étape
supplémentaire dont ils pensent qu'elle augmentera leurs
chances de succès dans le traitement génique du SCID
par rapport aux tentatives précédentes. Jusqu'à
présent, souligne Bordignon, la thérapie
expérimentée n'établissait pas suffisamment de
cellules souches saines dans l'organisme pour que les
résultats perdurent. Cette fois-ci, un processus appelé
conditionnement non myéloblatif pourrait faire toute la
différence, pensent les chercheurs.
"Le conditionnement non myéloblatif signifie que la moelle
osseuse n'est pas détruite mais que le patient reçoit
un seul des médicaments utilisés lors de greffes,
à dose beaucoup plus faible, afin de " faire de la place "
pour la moelle modifiée et lui permettre de mieux s'implanter
et de se développer ", explique Bordignon.
Quelques semaines après l'injection, les cellules souches
modifiées avaient migré vers la moelle osseuse et
commencé à produire des types clés de cellules
immunitaires, telles que des lymphocytes B, T et NK. Au bout de
quelques mois, des anticorps sont apparus et les patients ont
réagi normalement à de petites doses de certains
pathogènes, tels que le vaccin antitétanique. Un an
plus tard, l'un des patients ne souffrait plus d'infections des voies
respiratoires, de diarrhée chronique ou de gale, des
problèmes communs avant la thérapie.
L'ADA étant une enzyme utilisée dans une
variété de mécanismes métaboliques,
l'ADA-SCID est une maladie plus complexe que les autres
déficits immunitaires combinés sévères.
Lors d'études précédentes, note Bordignon, les
chercheurs ont dû continuer l'enzymothérapie de
remplacement pour les problèmes métaboliques, alors
même que la thérapie génique contrôlait le
composant immunitaire de la maladie.
Les deux patients de l'étude décrite dans Science
n'ont jamais reçu d'enzymothérapie de remplacement car
cette option ne leur était pas offerte dans leur pays. Le
groupe de Bordignon a observé le cumul de quantités
minimes de métabolites toxiques, indiquant que la
thérapie génique contrôlait également
l'aspect métabolique de la maladie.
A long terme, Bordignon compte essayer d'utiliser la
thérapie génique pour traiter d'autres maladies,
notamment le SIDA.
Cette étude fait suite a des recherches
réalisées par Marina Cavazzana-Calvo et ses
collègues, parue dans le numéro du 28 avril 2000 de
Science. L'équipe de chercheurs français avait
utilisé une thérapie génique par cellules
souches sanguines pour traiter deux nouveau-nés souffrant de
SCID X1, une variante de la maladie due à une mutation du
chomosome X.
###
Les autres membres de l'équipe de recherche sont Alessandro
Aiuti, Francesca Ficara, Sara Deola, Alessandra Mortellaro,
Grazia Andolfi, Federica Cattaneo, Sergio Vai et Maria Grazia
Roncarolo, de l'Institut San Raffaele Telethon de thérapie
génique, à Milan, en Italie, Shimon Slavin, Memet Aker
et Shoshana Morecki, du Centre hospitalier universitaire de
Jérusalem, en Israël, Antonella Tabucchi, Filippo
Carlucci et Enrico Marinello, de l'Université de Sienne, en
Italie, Paolo
Servida, de l'Institut scientifique H.S. Raffaele, et Roberto
Miniero, de l'Université de Turin, en Italie. Maria Grazia
Roncarolo est également à l'Università
Vita-Salute San Raffaele, à Milan, en Italie. L'étude a
été financée par la Fondation
Telethon italienne.
La terapia genetica libera dall'isolamento sterile i pazienti che
mancano di sistema immunitario
Degli autori scientifici riportano nuovi successi con migliori
tecniche
EUREKAlert (AAAs press release Public release date:
27-Jun-2002
Un nuovo metodo di terapia genetica ha trasformato il midollo
osseo di due bambini da "un deserto di cellule immunitarie" in un
sano terreno fertile per molti diversi agenti che combattono le
infezioni.
I bambini soffrono di un forma grave di deficienza immunitaria
combinata (SCID) che di norma richiede che il paziente viva in
ambienti sterili. Ora essi vivono e si sviluppano normalmente,
secondo quanto riportano ricercatori italiani e israeliti nel rivista
Science, pubblicata dalla American Association for the Advancement of
Science (Associazione americana per il progresso della scienza).
Specificamente, i due bambini hanno un tipo della malattia
chiamato ADA-SCID, per cui non producono l'enzima ADA necessario per
produrre le cellule immunitarie. La malattia può essere
controllata fino a un certo punto da regolari iniezioni del tipo
bovino di ADA, una terapia costosa in molti paesi.
Ogni anno nascono circa 30-50 neonati con ADA-SCID, ma solo per
una piccola parte di essi viene fatta tale diagnosi, secondo il
coautore dello studio Claudio Bordignon dell'Istituto San Raffaele
Telethon per la Terapia Genetica e dell'Università Vita-Salute
San Raffaele, a Milano.
In alcuni casi hanno successo anche trapianti di midollo osseo, ma
questi presentano gravi rischi di per sé. Per i due bambini
dello studio che avevano rispettivamente sette mesi e due anni e sei
mesi, non vi erano donatori disponibili.
"Si possono trattare tutti i pazienti con la terapia genetica, e
la tossicità è enormemente inferiore al trapianto del
midollo osseo. Proponiamo a questo stadio che ogni paziente per il
quale non vi sia un donatore con il tipo identico di tessuto sia
sottoposto alla terapia genetica," ha detto Bordignon.
Il team di Bordignon deve provare tale terapia su un numero
maggiore di volontari prima che ne sia approvato l'uso da parte dei
ricercatori in Italia o all'estero. Essi inizieranno dai pazienti
senza un donatore corrispondente per il trapianto di midollo osseo, e
poi potranno includere anche i pazienti per i quali sia disponibile
un donatore. Dato che lo ADA-SCID è una malattia relativamente
rara, questi studi fungeranno da prove cliniche di fase I e II,
cioè dirette a dimostrare che la procedura è sicura ed
efficace, ha detto Bordignon.
Al fine di estendere questo metodo a un popolazione più
grande di pazienti italiani, il gruppo sta richiedendo l'approvazione
dell'Istituto Superiore di Sanità italiano. Sarà
necessario un procedimento simile di richiesta per eseguire la
terapia altrove in Europa e negli Stati Uniti. Dato che la terapia
può essere inclusa nella categoria dei "farmaci orfani",
cioè un trattamento per una malattia rara, il processo di
approvazione in Europa dovrebbe essere relativamente veloce, della
durata di alcuni mesi, secondo Bordignon.
Bordignon e i suoi colleghi hanno rimosso una parte del midollo
osseo dalle anche dei due pazienti durante questo studio. Poi hanno
isolato le cellule staminali del sangue, che hanno il potenziale di
svilupparsi in globuli bianchi e globuli rossi del sangue. Quando i
ricercatori hanno esposto le cellule staminali a un virus
geneticamente modificato in modo da portare la versione sana del gene
ADA, il virus ha inserito il gene nel genoma delle cellule.
Prima di iniettare nel paziente le cellule staminali geneticamente
modificate, gli autori di Science hanno eseguito una fase ulteriore,
che secondo loro farà riuscire la procedura meglio di quelle
eseguite in precedenza per trattare lo SCID mediante la terapia
genetica. Fino ad ora, questa procedura non aveva stabilito nel corpo
cellule staminali sufficienti affinché i risultati durassero
nel tempo. Ma questa volta, un processo chiamato "condizionamento non
mieloblativo" può far riuscire la procedura, secondo i
ricercatori.
"La condizione non mieloblativa significa che non si elimina il
midollo osseo, ma che basta somministrare uno dei farmaci usati per
un trapianto, in dose molto inferiore, per dare spazio al midollo
modificato geneticamente di insediarsi, espandersi e crescere
meglio," ha spiegato Bordignon.
Entro alcune settimane dopo essere stato iniettato nel paziente,
le cellule staminali modificate geneticamente erano migrate nel
midollo osseo e avevano incominciato a produrre tipi cruciali di
cellule immunitarie, come le cellule B, le cellule T e le cellule NK.
Entro alcuni mesi, sono comparsi gli anticorpi e i pazienti hanno
risposto in modo normale a piccoli quantitativi di determinati
patogeni, come il vaccino del tetano. Un anno più tardi, uno
dei pazienti non aveva più le infezioni respiratorie, la
diarrea cronica o la scabbia che erano comuni prima della
terapia.
Dato che l'enzima ADA viene usato in molti diversi processi
metabolici nel corpo, è una malattia più complessa di
altre forme di SCID. Negli studi precedenti, ha detto Bordignon, i
ricercatori sono stati obbligati a continuare a trattare i pazienti
con la terapia di sostituzione dell'enzima per i problemi metabolici,
persino quando la terapia genetica aveva il componente immunitario
della malattia sotto controllo.
I due pazienti dello studio in Science non avevano mai ricevuto la
terapia di sostituzione dell'enzima non avendo tale opzione nei loro
paesi. Il gruppo di Bordignon ha osservato che l'accumulo di
quantità minime di metaboliti tossici, indicante che la
terapia genetica stava controllando anche il lato metabolico della
malattia.
Eventualmente, Bordignon ha in programma di provare a usare il
metodo della terapia genetica per trattare altre malattie, tra cui il
SIDA (AIDS).
Questo studio segue ricerche precedenti di Marina Cavazzana-Calvo
e colleghi, pubblicate nel numero del 28 aprile 2000 di Science. Il
team di ricerca francese ha usato cellule staminali del sangue nella
terapia genetica per trattare due neonati con SCID X1, una variazione
della malattia causata da una mutazione del cromosoma X.
###
Gli altri componenti del gruppo di ricerca sono Alessandro Aiuti,
Francesca Ficara, Sara Deola, Alessandra Mortellaro,
Grazia Andolfi, Federica Cattaneo, Sergio Vai e Maria Grazia
Roncarolo, dell'Istituto San Raffaele Telethon per la Terapia
Genetica, a Milano, Italia; Shimon Slavin, Memet Aker e Shoshana
Morecki, della Hadassah University Hospital, a
Gerusalemme, Israele; Antonella Tabucchi, Filippo Carlucci ed Enrico
Marinello, dell'Università di Siena, a Siena, Italia;
Paolo Servida, dell'Istituto Scientifico H.S. Raffaele, e Roberto
Miniero, dell'Università di Torino, a Torino. Maria Grazia
Roncarolo appartiene anche all'Università Vita-Salute San
Raffaele, a Milano, Italia. Lo studio è stato finanziato
dalla
Fondazione italiana Telethon.
An international scientific team yesterday announced that two
toddlers with so-called ''bubble boy'' syndrome were cured using gene
therapy, the most effective reported application of the promising but
controversy-plagued treatment to date.
BOSTON GLOBE, By Raja Mishra, Globe Staff, 6/28/2002
A one-time infusion with DNA to fix a genetic defect revitalized
the children's almost nonexistent immune systems, allowing them to
emerge from their clinicall Ysterilized homes - their bubbles - to
crawl, walk, and interact freely with the world around them, the
researchers reported. Two years later, both remain healthy.
The groundbreaking work unfolded in Jerusalem, when a Jewish
doctor risked his career to attempt the highly experimental procedure
on the first patient, an Arab infant, even as political turmoil raged
around him.
''This is a complete cure. The child is completely cured,'' said
Dr. Shimon Slavin, chairman of the bone marrow transplantation
department at Hadassah-Hebrew University Medical Center in Jerusalem,
and an author of the paper describing the success, which appears in
this week's edition of the journal Science.
Gene therapy, the surgical insertion of genes that essentially
reprogram the body to eliminate disease, was born amid much fanfare a
decade ago. But, despite the investment of hundreds of millions of
dollars, the field has thus far produced no clinically widespread
treatments. The field suffered a serious blow in 1999, when a
teenaged patient died during a gene therapy clinical trial at the
University of Pennsylvania, prompting a wave of federal government
investigations and the suspension of several research programs.
But in recent months, gene therapy researchers say the field has
turned a corner from those dark days, with several labs, including
one at St. Elizabeth's Medical Center in Boston, reporting progress
in the use of genes to treat disease. The challenge of gene therapy
is to get the right genes to the right place in the body in the right
amounts. Hundreds of experiments, involving more than 2,000 patients
in the United States alone, are underway to figure out this equation
for a variety of diseases, though most of the experiments remain in
preliminary stages.
So far, researchers have been most successful in treating the rare
''bubble boy'' syndrome, also called severe combined immunodeficiency
or SCID, which renders children extremely vulnerable to infection.
The affliction gained attention after media coverage of David, a
12-year-old Texas boy who died in 1984 after spending his life in a
sterile tent.
Worldwide, only a few hundred people have some form of SCID. But
gene therapy researchers consider the disease a good experimental
target for their work because the insertion of a single gene, in
small amounts, appears sufficient to cure it.
Last April, a French team announced that gene therapy allowed four
SCID children to live normal lives two years after treatment.
Technically, scientists cannot pronounce a patient cured until
they've lived a full life free of disease. But the French researchers
found their inserted gene had significantly revitalized the
childrens' immune systems, which gene therapy researchers saw as
proof enough.
The new study, an Italian-Israeli joint venture, involved a more
complex form of the immune disorder, called ADA-SCID. The researchers
employed a new twist on the gene therapy method used by the French
team, which beat them to publication by just two months, though both
teams completed their work at roughly the same time. First, they
removed bone marrow from the patients' pelvises. Bone marrow is
filled with blood stem cells that eventually proliferate to support
the immune system. These stem cells were removed from the marrow,
then infected with a harmless virus that researchers equipped with
healthy copies of a crucial immune system gene called ADA. The two
children had inherited defective ADA.
Then came an innovation: the toddlers were given a mild dose of a
chemotherapy drug that suppressed their natural bone marrow
production. As a result, when the gene therapy-treated stem cells
were injected, they faced no competition for space from the toddlers'
natural marrow. They proliferated, spreading the healing gene.
According to the paper, a wide variety of properly functioning
immune cells resulted. The first patient is now 2 years old, living
in Israel. ''She's a normal child,'' said Slavin. ''Just like other
children.''
The experiment was replicated in Italy, and the two teams
collaborated on yesterday's paper. The name of the child treated by
the Italian team was not released. The researchers said gene therapy
should now automatically be considered instead of a bone marrow
transplant, the standard treatment, if doctors cannot find a
genetically matched marrow donor. They also said the approach could
be attempted on other afflictions.
Dr. Claudio Bordignon, with the Universita Vita-Salute San
Raffaele in Milan, leader of the Italian team, said Italian
authorities already have approved the use of gene therapy for some
AIDS patients. The trial is expected to start soon.
Local gene therapy expert Dr. David A. Roth, director of
hemophilia research at Beth Israel Deaconess Medical Center, said of
the new successes, ''It's fantastic to hear reports of promising
early clinical results that validate the general strategy of using
gene transfer.''
The first surgery in yesterday's report took place in Jerusalem on
Sept. 6, 2000, even as Israelis and Palestinians were at the United
Nations attempting to hammer out a peace plan. Under heated dispute
was East Jerusalem, claimed by both sides.
But Israeli doctors picked up 7-month-old infant Salsabil,
daughter of an Arab-Israeli cake maker, from her East Jerusalem
house. Her last name has been withheld for reasons of privacy. The
review board at Hadassah-Hebrew Medical Center was wary; they made
Slavin sign a form requiring him to personall Ypay for Salsabil's
lifetime treatments if the gene therapy failed. The bill would be a
bankruptcy-causing high six figures, said Slavin. Some Israeli
doctors have said that Jewish patients come first for treatment with
transplants and rare diseases where organs and medicines are
scarce.
''That was not an issue at all,'' said Slavin. ''If two patients
come, the one that is more urgent will be treated first, even if they
were a Palestinian bomber who came to kill you. They are humans
first.''
Slavin still visits the family in East Jerusalem, dispite the
violence in the region, drawing hope from his star patient.
''The Middle East could be a Garden of Eden if we could set aside
this stupid killing,'' he said.
HERALD TRIBUNE, Rick Weiss, The Washington Post Saturday, June 29,
2002 WASHINGTON
Two children born with a life-threatening immune system
disorder appear to have been cured after being given new genes,
marking the second
pair of successes in two years for the long-beleaguered field of gene
therapy.
One of the cured babies was born to a family of Muslims living in
an Arab
neighborhood of Jerusalem and was treated by a Jewish Israeli doctor.
Some are
referring to the treatment as a symbolic monument to the goal of
Middle East peace.
The apparent cures will require years of follow-up to ensure they
are lasting.
The disease that was treated - a form of severe combined
immunodeficienc
Ydisorder, or SCID - is regarded by experts as more amenable to
genetic correction
than most other ailments.
Nonetheless, the positive results offer a significant measure of
vindication for an
experimental approach that was plagued with failure for a decade.
"I'm relieved," said W. French Anderson, a University of Southern
California
scientist who led the first U.S. gene therapy trial in 1990 but was
not involved in the
latest work. "We've known it ought to work, and fortunately it did.
This tells us that
if you can get a high enough percentage of cells fixed, gene therapy
will cure you."
The children were treated by a team of Italian and Israeli
researchers about 15
months ago when the Jerusalem baby was 7 months old and the other
child, from
Colombia, was 2 years old. Both were born with a form of SCID caused
by a
defective version of the ADA gene, which is crucial to the proper
functioning of
immune system cells.
Their disease left them constantly at risk of death from otherwise
benign infections.
It can be treated by transplanting bone marrow from a healthy
relative or with regular
injections of a drug that costs thousands of dollars a year. Lacking
access to either of
those, the parents enrolled their children in an experiment in which
scientists tried to
repopulate the children's immune systems with cells that had been
geneticall
Yengineered to contain normal ADA genes.
Tests indicate that those cells have taken up permanent residence
in the children's
bone marrow, where they are doing the work the children's own cells
could not do.
After years of frequent illness, both patients are healthy, the
researchers report in the
current issue of the journal Science.
"Their problem has been clinically solved," said Claudio
Bordignon, who led the
Italian team at the San Raffaele Telethon Institute for Gene Therapy
in Milan. "The
Yare living normal lives." The results resemble those reported two
years ago b
Yresearchers in France, who used a similar approach to treat two
children with
SCID-X1. That is the form of SCID that affected David, the so-called
"Bubble
Boy," who died in 1984 after having lived virtually all of his 12
years in a sterile tent
in a Texas hospital.
Alain Fischer, who led the French effort, said that those two
children were still in
good health, with no evidence that their new genes were in any way
failing. Seven
of 8 other patients with the same disease whom he has treated since
have similarl
Ybenefited, he said, adding credence to the idea that the gene
approach is safe and
effective for this class of disease.
The field hit its nadir in 1999, when an 18-year-old patient died
in a University of
Pennsylvania gene therapy experiment. The Food and Drug
Administration later said
it had violated many federal safety rules.
Using an experimental technique that altered genes in bone marrow
stem cells, doctors cured two children who were born with the "bubble
boy" disease that leaves patients defenceless against infection. The
children were born with a form of severe combined immunodeficiency
disorder caused by a gene flaw that blocks production of an enzyme
called ADA, which is essential to make disease-fighting immune cells.
Doctors in Italy and Israel cured the children with injections of
bone marrow stem cells that had been altered to contain the missing
enzyme gene. In a matter of months, the researchers report in this
week's edition of the journal Science, both children had healthy
immune systems. Dr. W. French Anderson, a University of Southern
California researcher and a pioneer in the field, said the research
is an important advance for the entire concept of gene therapy. "This
gives a boost to the whole field because it proves our basic premise
that if you can get enough gene-engineered cells into the patient it
will cure the disease,'' Anderson said in a telephone interview
Wednesday. "That is very important and therefore this is a very
exciting paper." Anderson was the first to try genetic engineering to
cure the ADA, or adenosine deaminase, form of severe combined
immunodeficiency disorder, or SCID. His technique changed the gene in
blood cells instead of the bone marrow. Two of Anderson's early
patients have led normal lives since the 1990 procedure, but they
require periodic shots of ADA enzyme to assure healthy immune
systems. The technique used by the Italian and Israeli researchers,
Anderson, appears to be a cure that will require no further shots.
"That means that these patients have normal functioning immune
system,'' he said. Technically, Anderson added, the cure cannot be
considered complete for many decades while doctors monitor the
patients, but for all intents and purposes it is a cure. SCID is
rare, striking only about 50 children a year. In the past, the
disorder was always fatal, with the children usually dying in infancy
of uncontrollable infections. Starting in the 1960s, doctors treated
SCID patients by isolating them in sterile environments. One of the
most famous such patients was a Houston bo Ywho spent all 12 years of
his life in a plastic bubble filled with filtered air. He became
known as "David the bubble boy." He died in 1984 when, at his
insistence, doctors tried a bone marrow transplant. Since then, a
number of researchers have tried to cure some forms of SCID with gene
therapy. At least a handful of patients appear to have developed
healthy immune systems after gene therapy for one type of SCID,
called gamma C. But the new study is the first to report a cure for
ADA-SCIDS, the most complex form of the immune system disorder,
Anderson said. In the new study, the Italian and Israeli researchers
treated two children, a seven-month-old and 2*-year-old, who were
born without functioning normal ADA enzyme genes. The researchers
corrected the inherited flaw by changing the genes in the stem cells
of the bone marrow that make blood cells. To do this, the doctors
removed stem cells from the bone marrow of each patient and then used
a virus to insert into these cells the normal gene for ADA. The stem
cells where then re-injected and naturally migrated to the bone
marrow. The researchers report in the journal Science that shortly
after the procedure, the bone marrow in both children began producing
normal disease-fighting blood cells. Within months, their immune
systems were able to overcome some common childhood infections that
previously had not responded to treatment. They were even able to be
successfully immunized against tetanus. The key to their success,
said Anderson, may have been a novel use of a chemotherapy drug by
the researchers. They injected both patients with the drug which
partially killed the youngsters' bone marrow. When the new stem cells
were injected, the bone marrow was primed to use those cells to make
new blood cells. This allowed the injected stem cells to rapidly
proliferate and become the dominant blood-making cells in the
patients' body, Anderson said. Claudio Bordignon of the San Raffaele
Telethon Institute for Gene Therapy in Milan, Italy, was the senior
author of the study. The senior Israeli researcher was Prof. Shimon
Slavin of the Hadassah University Medical Center in Jerusalem.
Amelia, la prima bimba curata con terapia genica in Europa
Giuseppe Del Bello, KATAWEB Salute
È stata lei,
una bambina di dodici anni, la testimonial di Telethon a Napoli
intervenuta, insieme alla presidente della Fondazione Susanna
Agnelli, alla
manifestazione che si è svolta il 27 marzo nell'Istituto di
Genetica e
Medicina diretto da Andrea Ballabio. Sono trascorsi sei mesi
dall'inizio
dell'attività scientifica nella città partenopea e
l'ospite d'eccezione si chiama
Amelia: adesso sta bene, ma era venuta al mondo con una
gravissima
malattia genetica.
La sua storia clinica inizia dalla nascita, il 6 marzo dell'89,
quando i medici
fanno diagnosi di diabete. Non è tutto. A distanza di qualche
mese la
mamma si accorge che la piccola ha unghie e labbra nere, e soffre
pure di
una strana forma di prurito. Interpella vari specialisti e, dopo
diciotto mesi,
il verdetto: ADA SCID, che significa immunodeficienza combinata
grave,
dovuta alla mancanza di un enzima chiamato ADA (Adenosin
deaminasi).
La bimba in pratica è priva di difese immunitarie: qualsiasi
infezione,
anche un semplice raffreddore, le può essere fatale. Nel '92
la svolta.
Amelia viene trattata, per la prima volta, con terapia genica presso
l'Istituto
Telethon di Milano all'epoca diretto da Claudio Bordignon e adesso
da
Maria Grazia Roncarolo. Qui è tornata due volte l'anno per
proseguire lo
schema di cura.
Adesso frequenta la seconda media e, dicono i medici, attualmente
è in
ottima salute: non deve più vivere sotto una campana di vetro,
mentre
potrà condurre un'esistenza normale,
come i suoi coetanei.
Ma a Napoli non c'è solo Amelia: all'Istituto è
presente anche Danilo che
di anni ne ha quasi 6 e che una diagnosi prenatale ha rivelato essere
affetto
da Scid. Anche lui a rischio infezioni per una grave forma di
immunodeficienza. Scatta anche in questo caso l'allarme. Con il
consenso
dei genitori, Danilo viene "curato" dall'équipe diretta a
Brescia dal
professor Alberto Ugazio, quando è ancora nell'utero della
madre. La
terapia è d'avanguardia: il primo trapianto - per curare la
Scid - di cellule
staminali prelevate dal padre e impiantate nel feto.
Researchers Use Engineered Gene To Cure "Bubble Boy" Disease In
Two Children
INTELIHELP (assoc press text) June 27, 2002, WASHINGTON (AP)
Using an experimental technique that altered genes in bone
marrow stem cells, doctors cured two children who were born with the
"bubble boy"
disease that leaves patients defenseless against infection.
The children were born with a form of severe combined
immunodeficiency disorder
caused by a gene flaw that blocks production of an enzyme called ADA,
which is
essential to make disease-fighting immune cells.
Doctors in Italy and Israel cured the children with injections of
bone marrow stem
cells that had been altered to contain the missing enzyme gene. In a
matter of months,
the researchers report in this week's edition of the journal Science,
both children had
healthy immune systems.
Dr. W. French Anderson, a University of Southern California
researcher and a
pioneer in the field, said the research is an important advance for
the entire concept of
gene therapy.
"This gives a boost to the whole field because it proves our basic
premise that if you
can get enough gene-engineered cells into the patient it will cure
the disease,"
Anderson said in a telephone interview Wednesday. "That is very
important and
therefore this is a very exciting paper."
Anderson was the first to try genetic engineering to cure the ADA,
or adenosine
deaminase, form of severe combined immunodeficiency disorder, or
SCID. His
technique changed the gene in blood cells instead of the bone marrow.
Two of
Anderson's early patients have led normal lives since the 1990
procedure, but the
Yrequire periodic shots of ADA enzyme to assure healthy immune
systems.
The technique used by the Italian and Israeli researchers,
Anderson, appears to be a
cure that will require no further shots.
"That means that these patients have normal functioning immune
system," he said.
Technically, Anderson added, the cure cannot be considered complete
for man
Ydecades while doctors monitor the patients, but for all intents and
purposes it is a
cure.
SCID is rare, striking only about 50 children a year. In the past,
the disorder was
always fatal, with the children usually dying in infancy of
uncontrollable infections.
Starting in the 1960s, doctors treated SCID patients by isolating
them in sterile
environments. One of the most famous such patients was a Houston boy
who spent
all 12 years of his life in a plastic bubble filled with filtered
air. He became known as
"David the bubble boy." He died in 1984 when, at his insistence,
doctors tried a
bone marrow transplant.
Since then, a number of researchers have tried to cure some forms
of SCID with
gene therapy. At least a handful of patients appear to have developed
healthy immune
systems after gene therapy for one type of SCID, called gamma C.
But the new study is the first to report a cure for ADA-SCIDS, the
most complex
form of the immune system disorder, Anderson said.
In the new study, the Italian and Israeli researchers treated two
children, a
seven-month-old and 2{-year-old, who were born without functioning
normal ADA
enzyme genes.
The researchers corrected the inherited flaw by changing the genes
in the stem cells
of the bone marrow that make blood cells.
To do this, the doctors removed stem cells from the bone marrow of
each patient and
then used a virus to insert into these cells the normal gene for ADA.
The stem cells
where then re-injected and naturally migrated to the bone marrow.
The researchers report in the journal Science that shortly after
the procedure, the bone
marrow in both children began producing normal disease-fighting blood
cells. Within
months, their immune systems were able to overcome some common
childhood
infections that previously had not responded to treatment. They were
even able to be
successfully immunized against tetanus.
The key to their success, said Anderson, may have been a novel use
of a
chemotherapy drug by the researchers. They injected both patients
with the drug
which partially killed the youngsters bone marrow. When the new stem
cells were
injected, the bone marrow was primed to use those cells to make new
blood cells.
This allowed the injected stem cells to rapidly proliferate and
become the dominant
blood-making cells in the patients' body, Anderson said.
Claudio Bordignon of the San Raffaele Telethon Institute for Gene
Therapy in Milan,
Italy, was the senior author of the study. The senior Israeli
researcher was Prof.
Shimon Slavin of the Hadassah University Medical Center in
Jerusalem.
Copyright 2002 The Associated Press. All rights reserved.
Two 'bubble boy' patients recover with gene therapy
ASCO WEB site ('people living with cancer association), Last
Updated: 2002-06-27 16:04:37 -0400 (Reuters Health)
By Rossella Lorenzi
MILAN (Reuters Health) - Italian researchers have used a new gene
therapy method to restore
the immune systems of two children with adenosine deaminase (ADA)
gene deficiency, which
causes severe combined immunodeficiency disorder (SCID).
Two years after undergoing the procedure the children are both
well, Dr. Claudio Bordignon of
the San Raffaele Institute in Milan and colleagues report in the June
28th issue of the journal
Science.
They say the breakthrough might open new avenues for the treatment
of other blood diseases,
including AIDS.
A relatively rare disorder, ADA-SCID is caused by a defect in the
gene encoding adenosine
deaminase, an enzyme the immune system's T cells need to function
properly. The disorder is
commonly known as "boy in the bubble" syndrome, since without
treatment, affected
children must live in a sterile environment.
The disease can be controlled to a certain degree by regular,
expensive injections of ADA
from cows, formulated with polyethylene glycol. Bone marrow
transplants have also been
successful in some cases, but finding a compatible donor is often an
obstacle.
This was the case for the two children in the study, a girl from
Israel and a girl from
Colombia. They were 7 months old and 2-1/2 years old, respectively,
when they had the
procedure.
Bordignon's team initially used a technique similar to that
reported by other groups.
They first removed some of the bone marrow from the patients'
pelvises and isolated certain
stem cells capable of developing into red and white blood cells. They
then exposed the stem
cells to an engineered virus, which inserted a healthy ADA gene into
the stem cells' genome.
Other researchers have corrected the gene flaw in immature cells
and then reintroduced them,
but according to Bordignon these efforts have not established enough
healthy stem cells in the
body for the results to last.
"It is a scientific success, but a partial clinical failure,"
Bordignon said at a press conference
in Milan on Thursday.
The additional step that the Italian group used is a process
called "non-myeloblative
conditioning," which allowed them to fully exploit "the selective
advantage of geneticall
Ycorrected cells," the authors report.
"You don't really wipe out the bone marrow, you just give one of
the drugs used for a
transplant, at a much lower dose, to make space for engineered marrow
to expand and grow
better," Bordignon said.
Within weeks after the treatment, the engineered stem cells began
producing key types of
immune cells, such as B cells, T cells, and NK cells; antibodies
appeared within month, and
the patients responded normally to small amounts of certain
pathogens, such as the tetanus
vaccine.
After 2 years, the children are clinically well, living a normal
life in their native countries.
Their full recovery is proven by the fact that they remain off enzyme
replacement therapy.
Bordignon's team has filed an application for clinical trials to
the National Health Institute,
which is necessary before the new gene therapy is approved for use in
Italy or abroad.
Being a treatment for a rare disease, the approval process in
Europe is likely to last only a
few months, according to Bordignon.
Next month he will also begin to study applications of the new
gene therapy method for
treating other diseases, including AIDS.
Gene therapy procedure used successfully in kids' disorder
THE DAYLY CAMERA.COM, By Scripps Howard News Service; June 28,
2002
A new gene therapy technique has turned the bone marrow of two
young children from
being virtually void of immune cells into a healthy breeding ground
for
infection-fighting cells, researchers from Israel and Italy say.
The children, born with a form of severe combined immunodeficiency
disorder that
leaves them unable to produce immune cells, are the first of those
patients sometimes
called "bubble babies" to be cured using genetically-altered stem
cells.
Victims of the disorder are typically forced to stay in sterile
environments because the
Yhave no natural way to fight off disease.
Bone marrow transplants from closely matched donors have been
successful in some
cases but also pose risks of rejection and other complications.
"With gene therapy, you can treat every patient and the toxicity
is enormously lower
than for bone marrow transplants. We propose, at this stage, that
every patient lacking a
donor with an identical tissue type should be directed to gene
therapy," said Claudio
Bordignon of the San Raffaele Institute for Gene Therapy in Milan and
co-author of a
report on the treatments published today in the journal Science.
According to Shimon Slavin, head of bone marrow transplantation at
Hadassah Medical
Center in Jerusalem, the new therapy holds promise not just for those
affected b
Yimmune deficiency disorders but for many similar genetic
diseases.
Bordignon said the method might also prove useful for treating
AIDS.
