HAS GENE THERAPY STALLED?

By Christine Gorman

Like every medical revolution before it, the field of gene therapy began with the vision of a brighter future. Researchers promised to cure such hereditary disorders as cystic fibrosis, muscular dystrophy and sickle-cell anemia, not with conventional medicine but with the magic of genetic engineering, supplanting defective genes with their normal counterparts. Patients dreamed of a life free of the diseases they had inherited. Venture capitalists dreamed of untold riches and backed the leading researchers in the field with millions of dollars of seed money.

But turning visions into reality has always been the trickiest step in conducting a successful revolution. Five years after the first approved experiments on humans in the U.S., there are now 600 Americans enrolled in 100 clinical trials. Yet after all the tests and all the hype, there is still no unambiguous proof that gene therapy has cured--or even helped--a single patient.

No one denies that gene therapy holds extraordinary promise or that it will eventually yield results. But critics have grown increasingly concerned that the initial excitement led to a premature rush to get unproved gene therapies out of the laboratory and into human patients. Researchers are still not sure which are the best methods to transport genes into affected cells. Nor have they figured out how to stop people's own immune systems from rejecting what are, in effect, microscopic transplants of foreign material.

Even more troubling are signs that financial considerations may have replaced scientific rigor in determining how and when to use gene therapy. Nearly every investigator currently running a clinical trial has a relationship of one sort or another with a biotechnology firm. Some critics charge that businessmen are pushing researchers too hard in order to get a quick return on their investment, and that some doctors have been too hasty, launching clinical trials early in hopes of "cashing out" when a large drug company buys their firm.

Now comes word of major technical snags in two areas of gene therapy that had been regarded as among the farthest along. Reporting in separate articles in the New England Journal of Medicine last week, researchers concluded that the most commonly used genetic treatments for cystic fibrosis and muscular dystrophy had run into a dead end. In both cases, scientists inserting normal genes into patients with defective ones were not able to elicit corrective changes in their patients' bodies.

Quick to put the best face on the discouraging results, investigators pointed out that they have other research paths to pursue. "You don't usually hit a home run the first time," says Dr. Michael Knowles, the University of North Carolina researcher who led the cystic fibrosis trial. "You usually make incremental steps forward, and that's what this study did."

Other genetics experts argue that the time has come to re-evaluate the approach taken by most gene therapists, and perhaps even to redirect their efforts. Last spring Dr. Harold Varmus, head of the National Institutes of Health, appointed an independent committee of scientists to look into how the NIH spends its gene-therapy research dollars (some $200 million a year) and whether the government is getting its money's worth. "I've been a bit concerned that we weren't fulfilling the promise of gene therapy in any obvious way at this point," Varmus explains. "My intuition tells me that we need to emphasize more basic aspects of gene-therapy research."

Scientists are, after all, working counter to millions of years of evolution. The basic goal of gene therapy is to take bits of DNA that did not originate in patients' bodies, insert them into the patients' tissue and somehow get them to turn on or, in the jargon of the field, "express" themselves. Yet this is precisely the sort of biological action that the body's immune system interprets as a threat and is primed to fight.

Furthermore, it is not just the immune system that scientists must outwit. They also have to get the cells that are targeted for treatment to open their molecular locks and allow the foreign genes inside. As Dr. James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania, points out, "The basic principles necessary to make gene therapy successful are only beginning to be defined."

If real clinical benefits have been slow to materialize, however, that has not stopped large pharmaceutical firms from buying up the gene-therapy concerns that seem to show the most promise. "Many, many companies have scrambled to get into the race," notes Ed Hurwitz, an analyst for Robertson, Stephens & Co. The list of recent mergers, as Hurwitz ticks them off, reads like a Who's Who of biotechnology: "Sandoz buys Genetics Institute. Chiron buys Viagene. Bristol Myers makes a big investment in Somatix. Merck makes a big investment in Vical. Rhone-Poulenc invests in Applied Immune Sciences and several other gene-therapy companies."

Some of this is unavoidable. Even the NIH's Varmus acknowledges the legitimate role commercial investment plays in moving gene therapy forward. The danger is that overreliance on commercial investors could change the kind of science that gets done. "The involvement of privately funded companies is already moving the focus away from rare genetic disorders," says Doris Zallen, a member of the NIH advisory panel that reviews gene-therapy trials for safety. Private investors tend to be more interested in diseases that affect large numbers of potential customers.

Commercial pressure has also pushed scientists to test gene treatments on human subjects as early as possible. No matter how promising a laboratory result is, clinical trials with real patients are more likely to pique Wall Street's interest. The risk is that expectations will be raised so high that the public--and investors--will lose faith in the technology when reversals occur. Flossie Wong-Staal, a molecular biologist at the University of California at San Diego, says that because "clinical trials, so far, have very little promise of curing patients," she prefers to think of her attempts to use gene therapy to boost the immune systems of AIDS patients as experiments rather than full-fledged clinical trials. Even if they do not lead to a marketable therapy, she notes, they are still valuable tools for guiding future investigations.

Nor are basic research and clinical trials mutually exclusive goals. "Humans are not big mice," says Dr. Ronald Crystal, who is working on gene therapy for cystic fibrosis at New York Hospital-Cornell Medical Center. "Unless we do clinical trials, we're never going to learn. You have to test it in the lab on animals, try it in humans and then go back to the lab. It's a cyclic process."

That process could still pay off. This week researchers led by Dr. Donald Kohn at Children's Hospital in Los Angeles will publish a report in Nature Medicine showing progress in using gene therapy to treat babies born with a disorder called adenosine deaminase deficiency. Three infants whose hereditary disorder leaves them defenseless against microbial attacks were given healthy genes using blood from their umbilical cords. Because the doctors were able to insert the good genes into the babies before their other immune defenses had fully formed, their bodies did not reject the material as foreign. Doctors do not claim to have cured the children, but, they note, the genes are "expressing."

It may turn out that a good strong dose of reality is just what gene therapy needed right now. The headiness of the early days has passed. And like cancer and aids researchers before them, gene therapists must learn to make medical progress the old-fashioned way--in fits and starts, with plenty of setbacks.

--Reported by David Bjerklie and Alice Park/New York

With reporting by DAVID BJERKLIE AND ALICE PARK/NEW YORK