Adenosine deaminase deficiency

Gene therapists told to do more homework

In their initial request to a National Institutes of Health subcommittee last week, federal researchers failed to win permission to perform the first U.S. gene therapy experiments in humans.

Few scientists expected instant approval of the proposal, which calls for injecting therapeutic, gene-altered cells into children with a life-threatening immune deficiency. But the degree of skepticism expressed by members of the Human Gene Therapy Subcommittee suggests the experiments may not occur anytime soon.

At the same meeting, however, some of the same researchers proposing the gene therapy work received permission to infuse cells bearing nontherapeutic genetic alterations into an expanded number of patients with malignant melanoma. Those experiments, already performed on seven patients, are designed to help reveal how the body normally defends itself against cancer (SN: 9/23/89, p. 197). With the added information from an expanded study group, the scientists may be ready this summer to adapt the procedure to include a cancer-fighting substance called tumor necrosis factor, says NIH researcher W. French Anderson. Anderson developed the melanoma protocol with NIH colleagues Steven Rosenberg and R. Michael Blaese.

Such a step would represent the first U.S.-approved administration of genetically engineered cells to treat a human disease. But Blaese and Anderson have long had their sights on another disease as the first they'd like to cure using gene therapy techniques. After years of preparation, the two researchers last week submitted to the NIH subcommittee a several-hundred-page document outlining their plan to treat an extremely rare, inherited immune disorder called adenosine deaminase (ADA) deficiency.

The disease, incurable until recently, results from a diminished supply of a critical blood enzyme, ADA. The researchers propose to inject engineered, ADA-secreting cells into affected children.

Many subcommittee members, however, said they remain unconvinced of the novel procedure's readiness for human testing. They noted that the proposal fails to answer some questions regarding the treatment's anticipated efficacy. Some expressed concern that technical problems have precluded tests of the procedure in mice -- a common prerequisite to human trials.

Matters were complicated by the FDA's licensing last month of the first drug treatment for ADA deficiency. Subcommittee members said they were unable to judge whether gene therapy held any potential advantages over the new drug, called PEG-ADA, which provides ADA through weekly injections. Michael Hershfield of the Duke University Medical Center in Durham, N.C., who coordinated the trials leading to the drug's approval, noted that many of the 13 children treated so far have now survived chicken pox and other common infections that frequently kill ADA-deficient kids before age 2.

Anderson told subcommittee members he would update the research proposal for their next meeting, now planned for June or July.

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