Success story. Gene therapy restored the immune system of Christopher Reid, a patient in an X-SCID trial at Great Ormond Street Hospital for Children in London.

Committee Wants Tighter Controls on Gene Therapy

Rockville, Maryland--A U.S advisory committee last week urged tighter controls on certain gene therapy trials. The recommendation comes in response to the third case of leukemia that has cropped up in a French study of X-linked severe combined immunodeficiency (X-SCID) disease.

Trials for SCID have been gene therapy's only success; since 1999 gene therapy has restored the immune systems of at least seventeen children with two forms of the disorder. But excitement turned to worry in late 2002 when two children developed T- cell leukemia in a trial of X-SCID led by Marina Cavazzana-Calvo and Alain Fischer at the Necker Hospital in Paris (ScienceNOW, 14 January, 2003). A third child developed leukemia in January, rekindling concerns that the therapy's risks may outweigh its benefits (Science, 18 February, p. 1028).

This latest leukemia case appears to be different from the previous two. Those occurred after a retrovirus carrying a gene called gamma-c inserted into the cancer gene LMO2 in bone marrow cells, noted FDA official Carolyn Wilson at a meeting of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee on 4 March. According to data provided by Fischer and French authorities, the third child does not appear to have an LMO2 insertion.

The panel also heard about other new data, which offered a mixed message. Last September, a monkey involved in a National Institutes of Health (NIH) gene insertion study in 1999 died from a leukemia-like cancer. On the other hand, NIH's Utpal Dave described a report last year in Science on a retrovirus-induced mouse leukemia that contained mutations in both LMO2 and gamma c, the gene corrected by the X-SCID therapy (Science, 16 January 2004, p. 333). The two genes seem to "cooperate" in causing cancer, Dave said, suggesting gene therapy for diseases not involving gamma c--which itself may be oncogenic when inserted with a retrovirus--may be safer.

Indeed, panelists noted, no leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma-c gene. Nor have leukemias appeared in an X-SCID trial in Britain that has treated 7 patients. However, most of those children are not yet 33 months old, which was roughly the age the French leukemias appeared.

In the end, the panel concluded that if two X-SCID trials now on hold in the United States resume, they should enroll only children who have failed to improve after a bone marrow transplant. But the panel suggested FDA could lift its hold on a U.S. trial for ADA-SCID. And researchers will be watching expectantly for whether any leukemia cases turn up in the British trial.

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Background on gene therapy