To all outward appearances, Ashanthi ("Ashi") DeSilva is a normal, healthy 12-year-old who loves sports and would rather play basketball than do her seventh-grade homework. But Ashi holds a unique place in medical history: she is the first recipient of successful gene therapy.
Ashi was born with a rare, inherited disorder called ADA deficiency, the disease that claimed the life of the famed "bubble boy" in 1984. Because of a faulty gene, the T cells of her immune system were unable to produce an enzyme, ADA, necessary for their survival. As they died off, Ashi's immune system virtually shut down, leaving her vulnerable to a host of common childhood diseases, some of which could have killed her.
In 1988, when she was two years old, Ashi began taking PEG-ADA, a newly developed drug that consists of the missing enzyme protected by a chemical sheath that enables it to function in the bloodstream for days. While the drug requires weekly injections for life at an annual cost of more than $60,000, it has enabled most of the handful of ADA-deficient children to survive. However, it provided only marginal help for Ashi, and she began to fail.
Ashi's deteriorating condition made her eligible for a landmark experiment proposed by researchers at the National Institutes of Health. In September 1990 a team led by Drs. W. French Anderson and R. Michael Blaese extracted T cells from Ashi and exposed them to mouse leukemia viruses into which human ADA genes had been spliced. The viruses, which the researchers had rendered harmless by removing all their genes, invaded the T cells and burrowed into their DNA, carrying the ADA gene with them. Finally, a billion or so of Ashi's T cells, many of them now outfitted with a functioning ADA gene, were dripped back into her veins. Four months later, the NIH team performed the same therapy on another ADA-deficient girl, Cindy Cutshall, 9, from Canton, Ohio.
Over the next two years this procedure was repeated a dozen or so times on the little patients. For Ashi it went on until the level of ADA in her bloodstream was 25% of normal, more than enough to protect her. As a precaution mandated by the FDA, she continued to receive weekly doses of PEG-ADA during her gene treatments.
In the past six years, neither girl has had a further infusion of her own altered T cells. Both are taking reduced doses of PEG-ADA, and periodic tests confirm that their re-engineered cells are surviving and producing the ADA enzyme.
Anderson concedes that the historic gene therapy practiced on Ashi did not produce a cure, because the T cells made by her bone marrow still lack their own functional ADA gene. "Nevertheless," he insists, "Ashi does provide the proof of principle that if you put a correct gene into enough cells in a patient, you will correct the disease."
--By Leon Jaroff