Fwd: Gene Therapy Falters

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Gene therapy falters

 

http://www.biomedcentral.com/news/20021008/04/

 

October 8, 2002

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Gene therapy faltersPossibility of leukemia-like side-effect halts trials | By

Brendan A Maher

 

 

Health officials and clinicians have suspended gene therapy trials for Severe

Combined Immune Deficiency (SCID) in the United States, France, and Germany

following observation of a leukemia-like disorder in one patient who underwent

the treatment. Recently hailed as gene therapy's first real success, the therapy

had restored immune function to at least 14 children with X-linked SCID, the

so-called " bubble boy " disease.

 

Alain Fischer at Necker Children's Hospital in Paris observed elevated

T-lymphocyte levels initially thought to be associated with a chicken pox

infection. The levels continued to rise after the infection subsided, and in

September, Fischer contacted colleagues and health officials.

 

Christof von Kalle and colleagues at Cincinnati Children's Hospital are now

trying to determine whether the condition, which Fischer calls

lympho-proliferation, is caused solely by the insertion of the " therapeutic "

gene into an inappropriate place in the genome. Cancer-causing insertions have

long been a concern of those pursuing gene therapy. " This is a theoretical

possibility that was known for some time, " said Savio Woo, past president of the

American Society for Gene Therapy, but such complications have never been seen

before in human or animal studies.

 

Fischer's ex vivo technique uses a retroviral vector to transduce pluripotent

stem cells from a sample of the patient's bone marrow, with a normal copy of the

gamma c gene. The cells are returned to the patient and can begin producing

immune cells that express the gamma c polypeptide. In the case of this boy,

T-lymphocyte production has gone out of control, and he must now undergo

chemotherapy.

 

Christof von Kalle has been working with Fischer for more than two years to

determine which of the patients' cells have been transduced with gamma c. Using

a PCR-based technique, he can also assess the exact insertion point. Preliminary

results with this patient show that a therapeutic gene has been inserted

adjacent to LMO2, an oncogene frequently activated in T-lymphocytic leukemias.

But the unfortunate insertion point does not necessarily tell the whole story

said von Kalle. " There is a hint of another genetic event in that cell clone

because usually the activation of that oncogene alone is not sufficient, " he

told The Scientist. Other factors could include a viral infection or a genetic

predisposition for cancer.

 

Though most agree that halting trials is the correct action, some also believe

that the benefits of gene therapy may still outweigh the risks. Clinical trials

are set to continue without changes in the United Kingdom said Adrian Thrasher,

a pediatric immunologist at Great Ormond Street Hospital where four infants have

been successfully treated. The alternative to gene therapy, allogeneic bone

marrow transplant, has proven effective yet, in half-matched transplants, the

mortality rate is 20% in the first year. According to Thrasher, patients'

families are counseled about risks and the technique has proven beneficial so

far.

 

The US Food and Drug Administration's Center for Biologics Evaluation and

Research (CBER) has organized an emergency session for October 10, where safety

issues and the current clinical hold on three SCID gene therapy trials in the US

will be discussed. The side-effects pose a new challenge for the field, said

Woo. " It's not a matter of 'does [gene therapy] work or not,' it's a matter of

how do we make it work better. "

 

Thrasher offered perspective, " We're at the beginning of a steep learning curve.

For any radical change in medicine — from organ transplant to bone marrow

transplantation — to start with, the results weren't as good as they are now. "

Links for this article

B. Maher: " The Bubble Bursts, " The Scientist, September 30, 2002

http://www.the-scientist.com/yr2002/sep/hot_020930.html

 

Necker Children's Hospital

http://www.necker.fr/

 

Cincinnati Children's Hospital

http://www.cincinnatichildrens.org

 

American Society for Gene Therapy

http://www.asgt.org/

 

Great Ormond Street Hospital

http://www.ich.ucl.ac.uk/

 

H. Gavaghan: " Gene therapy rebuilds immunity and its image, " The Scientist,

April 5, 2002.

http://www.biomedcentral.com/news/20020405/04/

 

U.S. Food and Drug Administration, Center for Biologics Evaluation and Research

http://www.fda.gov/cber/

 

 

 

 

 

 

 

 

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