Gene Therapy Cancers Prompt Design of

Safer Virus

The announcement last month that a fifth child who received gene therapy for an immune
system disease has developed leukemia was the latest blow to the field of gene therapy. But
there's new hope: The U.K. team running the trial reports this week that a safer formulation of
the treatment can cure the disease in mice and should also work in people.

Gene therapy's clearest success to date has been restoring the health of about 40 children with
severe combined immunodeficiency (SCID), also known as "bubble boy" disease because
patients cannot fight off infections and are often isolated to protect them from germs. The
treatment had a down side, however: Since 2002, four of 10 children in a French trial for a
form of SCID involving a defect on the X chromosome (X-SCID) have developed leukemia,
apparently because the retrovirus used to insert a curative gene into patients' blood stem cells
turned on a cancer gene (ScienceNOW, 7 March 2005). Researchers at the Institute of Child
Health at Great Ormond Street Hospital in London were conducting a nearly identical X-
SCID study without serious side effects, and some researchers suspected that their technique
was somehow safer. But in mid-December, one of their patients also developed leukemia.

Now the U.K. team says it has found a better approach. The problem with the virus used in
the U.K. and French studies seemed to be its powerful promoter, a stretch of DNA that
regulates expression of the inserted gene, IL2RG. This promoter also apparently turned on a
nearby cancer gene. To eliminate this problem, U.K. study leader Adrian Thrasher and
colleagues replaced the promoter with one less likely to turn on other genes. This "self-
inactivating" retrovirus also cannot make more copies of itself once it has stitched itself into
the host genome. In vitro studies on self-inactivating vectors, including a recent paper by this
group comparing the growth of cells treated with their new vector and the old one, are
boosting confidence. "It's very reasonable to think the [self-inactivating] vectors are going to
be safer," says Cynthia Dunbar of the U.S. National Heart, Lung, and Blood Institute in
Bethesda, Maryland.

Although the new vector is less potent, it should be more than adequate, Thrasher notes. In a
paper published online this week in the journal Molecular Therapy, Thrasher's team and
collaborators in Germany and the United States report that the new vector restored immune
system function in a mouse model of X-SCID. "It's probably going to work" in humans, says
molecular virologist Frederic Bushman of the University of Pennsylvania School of Medicine
in Philadelphia.

Thrasher's group and collaborators now hope to start multisite trials in Europe and the United
States with the new vector later this year. Donald Kohn of Children's Hospital in Los Angeles,
California, who is thinking about participating, says he's optimistic that the safety issues will
be solved and that gene therapy will eventually become the standard of care. If X-SCID can
be cured with no serious side effects, that will ease concerns about the risks of using similar
vectors to treat other blood diseases such as sickle cell disease, notes Dunbar.