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.