ST. LOUIS, MISSOURI--Gene therapy has apparently restored the immune systems of two patients with a rare inherited disorder called chronic granulomatous disease (CGD). The two men, who previously could not fight off fungal or bacterial infections, have been healthy for a year or more, according to several reports last week here at the annual meeting of the American Society of Gene Therapy. If the patients remain well, the experiment will mark the third clinical success for gene therapy.
The good news comes at a difficult time for the field. In the past 6 years, gene therapy has cured at least 17 children with two types of severe combined immunodeficiency disease (SCID). But three patients in a French trial developed leukemia; in at least two of these cases, the retrovirus that carried the corrective gene had disrupted a cancer suppressor gene (ScienceNOW, 7 March).
People born with CGD lack an enzyme called phagocyte NADPH oxidase, which white blood cells use to make the hydrogen peroxide needed to kill microbial invaders. Sufferers usually die from infections by age 30. In an attempt to correct the defect, molecular virologist Manuel Grez of the Georg-Speyer-Haus Institute for Biomedical Research in Frankfurt and collaborators in Germany and Switzerland focused on two male CGD patients in their mid-20s. The researchers extracted stem cells from the bone marrow of these patients and inserted a good copy of the NADPH oxidase gene, before reinfusing the cells.
Unlike in previous CGD trials, the cells not only kept growing but also went through an "unexpected expansion" of numbers, Grez reported. More than 20% of stem cells circulating in the patients' blood contained the new gene after 3 weeks--an unusually high fraction--and both men began producing functional NADPH oxidase. A lung lesion in one patient has healed, and two liver abscesses have disappeared in the other. One of the men has even been able to stop taking prophylatic antibiotics.
"It could well be" the next gene therapy success, says Donald Kohn of Children's Hospital in Los Angeles. Researchers add a note of caution, however. The cells, or clones, that multiplied in these CGD patients had gene insertions in three locations near genes involved in cell proliferation. While that could help explain why the treatment worked so well, it also raises the risk of leukemias like those seen in the three SCID patients. Grez thinks that's unlikely because the growth of the clones eventually leveled off. Still, says Kohn, "it needs to be watched."