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Cure or Catastrophe?

By mid-summer, High’s trial and the Chiron trial should be complete. (TKT plans to finish by the end of the year.) Results are keenly awaited. As Jim Wilson told hemophilia researchers at the June American Society for Gene Therapy meeting: “The world is watching what you guys are doing, and what’s happening in the clinical trials.”

A cure for hemophilia could galvanize gene therapy. “It would be a tremendous boost to the field, particularly in view of the negative events that have happened recently,” says University of Michigan researcher Jeff Chamberlain, who’s working on Duchenne muscular dystrophy. Not only would the achievement bolster morale, Chamberlain says, it could also attract bright researchers to the field and help promote the technology across the whole spectrum of diseases. Industry analysts agree. “This would be one of the first steps towards validating gene therapy as a treatment protocol,” says Anthony Shimkin of Wedbush Morgan Securities in Los Angeles. But the flip side of the scenario is that failure in hemophilia-given all the disease’s advantages-could shake confidence in gene therapy even further. “It would be a huge problem,” says biotech analyst Al Rauch of First Union Securities in Chicago, “because you can’t really think of a good reason it wouldn’t work.” Disappointment in hemophilia, Rauch says, “would indicate people have very little understanding of how [gene therapy] works.”

Might that stall the entire field? “I think it’s a possibility,” says Shimkin. But he’s quick to stress that gene therapy will survive regardless of the outcome of the hemophilia trials: “It won’t be so much a case of, ‘gene therapy’s not here to stay,’ as ‘let’s go back to the drawing board.’”

Gene therapy’s success or failure in hemophilia could be known in a few months, but some questions won’t be answered for years. Will the new gene, randomly lodged in a cell’s chromosome, trigger cancer? Will it make its way into germ cells (sperm, in this case) and get passed on to children? That could be catastrophic, since every cell in the body would inherit the foreign gene. Normally, cells selectively repress the expression of many genes, keeping them dormant, but the new gene, because of the way it’s engineered, would be turned on everywhere. Such hyperactivity could be “devastating” to a developing fetus, says gene-therapy researcher Jon Gordon of Mt. Sinai Medical Center.

Most researchers working with viral vectors consider these risks minimal. (High’s lab found that Avigen’s vector makes it into the testes of rabbits, but not their sperm.) Still, Jesse Gelsinger’s shocking death showed how a vector commonly considered safe could deliver an ugly surprise. “We are not very sophisticated, yet, in really controlling what we’re doing when we give these vectors,” says Gordon. “Their biological distribution, their fate, and how they behave in vivo-we have a lot of knowledge that’s yet to be acquired there.”

By the end of the year, when the last of these trials should wrap up, over 30 hemophilic patients will have exposed themselves to largely unknown risks. “They’re really pretty brave,” says Kathy High. Safety aside, will gene therapy work? High is confident hers will, especially at the higher doses planned for the end of the trial. But what if inhibitors develop-or worse? “If there was a death in a hemophiliac, that would set the field back a decade,” says University of North Carolina hematologist Gilbert White.

High, as always, remains alert for any sign of trouble-even in the fortune cookies that come with the Chinese dinners she likes to order. A recent one seemed ominous: “When things are going well is the time to prepare for danger.”

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