Human Gene Therapy

by Food and Drug Administration (FDA)

A 4-year-old girl named Ashanthi DeSilva from the suburbs of Cleveland lay on crisp white hospital sheets with a needle stuck in a vein. She didn't mind; this happened all the time in her chronically sick childhood. At the other end of the intravenous hookup hung a clear plastic bag of very special cells: her own white blood cells, genetically altered to fix a defect she inherited at birth.

A strikingly thin middle-aged doctor stared anxiously at the tiny figure. W. French Anderson, M.D., and his colleagues R. Michael Blaese, M.D., and Kenneth Culver, M.D., all then working at the National Institutes of Health, crossed a symbolic threshold with Ashanthi DeSilva that day, becoming the first group to begin a clinical trial in the new frontier of medical treatment: human gene therapy.

The reason for the excitement was simple: Most diseases have a genetic component and gene therapy holds the hope of curing, not merely treating, a broad range of ailments, including inherited diseases like cystic fibrosis and even chronic conditions like cancer and infectious diseases like AIDS.

At least, that's the theory.

In the 10 years since that first genetic treatment on Sept. 14, 1990, the hyperbole has exceeded the results. Worldwide, researchers launched more than 400 clinical trials to test gene therapy against a wide array of illnesses. Surprisingly, cancer has dominated the research. Even more surprising, little has worked.

"There was initially a great burst of enthusiasm that lasted three, four years where a couple of hundred trials got started all over the world," says Anderson, now at the University of Southern California in Los Angeles. "Then we came to realize that nothing was really working at the clinical level."

Abbey S. Meyers, president of the National Organization for Rare Disorders Inc., an umbrella organization of patients' groups, is much more blunt. "We haven't even taken one baby step beyond that first clinical experiment," Meyers says. "It has hardly gotten anywhere. Over the last 10 years, I have been very disappointed."

And then things got worse.

In September 1999, a patient died from a reaction to a gene therapy treatment at the University of Pennsylvania's Institute of Human Gene Therapy in Philadelphia. Jesse Gelsinger, an exuberant 18-year-old from Tucson, Arizona, suffered from a broken gene that causes one of those puzzling metabolic diseases of genetic medicine. An optimistic, altruistic Gelsinger went to Philadelphia to help advance the science that might eventually cure his type of illness. Instead, the experiment killed him.

In the aftermath of his death, there has been a flurry of activity to minimize the chance of future accidental deaths. The Food and Drug Administration, along with the National Institutes of Health, launched several investigations of the University of Pennsylvania studies and others. The inquiries provided disappointing news: Gene therapy researchers were not following all of the federal rules requiring them to report unexpected adverse events associated with the gene therapy trials; worse, some scientists were asking that problems not be made public. And then came the allegations that there were other unreported deaths attributed to genetic treatments, at least six in all.

"Probably the clearest evidence of the system [to protect research subjects] not working is that only 35 to 37 of 970 serious adverse events from [a common type of gene therapy trial] were reported to the NIH" as required, says LeRoy Walters, the recently retired head of the Kennedy Institute of Ethics at Georgetown University and former chairman of NIH's Recombinant DNA Advisory Committee. "That is fewer than 5 percent of the serious adverse events."

The news hit the clinical trial community like a thunderclap. The consequences have been immediate and wide-ranging, and may threaten future research.

"Participation in gene therapy trials is way down because the public is not sure what to make of this," says Philip Noguchi, M.D., director of the Cellular and Genetic Therapy Division in FDA's Center for Biologic Evaluation and Research (CBER). "They want to know what the government is doing to help restore the confidence in this field."

Responding to the Crisis

The federal government moved quickly to do just that. FDA immediately shut down the trial in which Gelsinger had volunteered, and all clinical gene transfer trials at the University of Pennsylvania in January. The university went on to severely restrict the research of its once-high-flying gene therapy institute director James Wilson, M.D., announcing in May that all his work would be confined to animal and laboratory experiments and that he would be barred from conducting studies in people.

FDA also suspended gene therapy trials at St. Elizabeth's Medical Center in Boston, a major teaching affiliate of Tufts University School of Medicine, which sought to use gene therapy to reverse heart disease, because scientists there failed to follow protocols and may have contributed to at least one patient death. FDA also temporarily suspended two liver cancer studies sponsored by the Schering-Plough Corporation because of technical similarities to the University of Pennsylvania study.

Moreover, as nervousness spread through the field in the months after revelations about Gelsinger's death, some research groups voluntarily suspended gene therapy studies, including two experiments sponsored by the Cystic Fibrosis Foundation and studies at Beth Israel Deaconess Medical Center in Boston aimed at hemophilia. The scientists paused to review their studies and make sure they learned from the mistakes made at the University of Pennsylvania.

In March, the Department of Health and Human Services announced two initiatives by FDA and NIH. The Gene Therapy Clinical Trial Monitoring Plan is designed to ratchet up the level of scrutiny with additional reporting requirements for study sponsors. A series of Gene Transfer Safety Symposia was designed to get researchers to talk to each other, to share their results about unexpected problems and to make sure that everyone knows the rules.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.