Human Gene Therapy : Special Concern

by Food and Drug Administration (FDA)

(Page 2 of 3)

In addition, FDA launched random inspections of 70 clinical trials in more than two dozen gene therapy programs nationwide and instituted new reporting requirements. "We see the need to get the concept across that this is for keeps," says FDA's Noguchi. "You can be sloppy when you are dealing with a scientific paper, but you can't be sloppy when you are dealing with a human. Everything matters."

So far, the inspections only suggest that one other program appears to be in trouble, he says, but by the fall, "We should be able to say accurately [what is] the state of the art of gene therapy and where it needs to improve."

Meanwhile, President Clinton announced more "new actions designed to ensure that individuals are adequately informed about the potential risks and benefits of participating in research ... and steps designed to address the potential financial conflicts of interest faced by researchers." In addition, the President said in May, "We are also sending the Congress a new legislative proposal to authorize civil monetary penalties for researchers and institutions found to be in violation of regulations governing human clinical trials." If the legislation passes, FDA will, for the first time for drugs and biologics, have the power to essentially fine researchers and their institutions, up to $250,000 and $1 million respectively.

"This is a clear message," HHS Secretary Donna E. Shalala, Ph.D., said in May, "that we intend to get serious."

A History of Special Concern

Genetic engineering has always worried the general public.

When scientists first learned to clone genes in the mid-1970s, public reaction ranged from antipathy to hostility. Opponents, fearing that genetically engineered bacteria might escape from a laboratory, shut down the research at Harvard University and the Massachusetts Institute of Technology for months. Twenty-five years ago, in response to public concern, American scientists organized a voluntary moratorium on certain types of gene engineering experiments until safety questions could be resolved.

To help assuage public concern, NIH created its Recombinant DNA Advisory Committee, the RAC — which most simply call the "rack" — to provide a forum for genetic engineering debates to take place in public. As a result, the general opposition subsided.

But the RAC could do little if scientists didn't follow the rules. The promise of gene therapy, the glory of being the first to cure human ills, led at least one very smart scientist to make a very questionable decision. In 1980, an ambitious hematologist at the University of California at Los Angeles tested his gene therapy ideas on patients in Israel and Italy after being denied permission to perform the tests in Los Angeles. The experiments, conducted by Martin Cline, M.D., failed to help his subjects, and they violated federal rules designed to protect research subjects, leading to severe censure of the California scientist.

Ethical issues aside, the bigger problem for gene therapy has been basic biology. It's difficult to get new genes into billions of target cells within the body. Once inserted, the new genes need to function. Frequently, the body suppresses gene expression, essentially turning the new genes off, or destroys the transplanted genes. Although techniques have improved, today's scientists still face these challenges. To solve the problems, independent researchers have sometimes devised their own remedies of unknown safety. FDA began paying careful attention to these laboratory constructs when researchers began to request permission to test them in people under Investigational New Drug applications.

"Early investigators were more mom and pop operations," Noguchi says. "They were individual investigators making their own products ... Almost all of them went on clinical hold because there was a lack of product information." Before FDA could allow them to proceed, technical questions about safety had to be answered, and that took time.

Typically, scientific questions are answered in laboratory and animal studies, but, with gene therapy, clinicians have been anxious to test their ideas in people. Once the NIH physicians treated their tiny patient in 1990, researchers rushed to get into the game with human trials. At the halfway point in the decade, the field was not progressing well. Then-NIH Director Harold Varmus, M.D., himself critical of the gene therapy trials in people, created a committee to review NIH's investment in the field. Varmus wanted to know whether NIH should continue to invest so heavily in the new technology.

The committee's conclusions were bleak:

"While the expectations and the promise of gene therapy are great, clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol, despite anecdotal claims of successful therapy and the initiation of more than 100 ... approved protocols," concluded the ad hoc committee co-chairmen Stuart H. Orkin, M.D., of Harvard Medical School and Arno G. Motulsky, M.D., of the University of Washington in Seattle in December 1995. While they saw promise, they also saw challenges. "Significant problems remain in all basic aspects of gene therapy. Major difficulties at the basic level include shortcomings in all current gene transfer vectors and an inadequate understanding of the biological interaction of these vectors with the host."

To transfer a repair gene into a patient, the researchers must go through several steps. First, they must isolate the disease-related gene. Then it must be packaged in a vector, usually a disabled virus that cannot reproduce and cause disease, but that can act like a delivery truck to transport the gene inside the patient's cells. Once inside the body's cells, the new gene can begin to function and restore health.

But building an effective delivery truck hasn't been easy. Scientists started by using a type of mouse virus as a vector, engineered so that it cannot replicate itself, that easily infects human cells and integrates the new genes into the cell's chromosomes (structures in the cell that hold the genes). These mouse vectors, however, only infect dividing cells, so researchers switched to adenovirus, a type of human virus that causes the common cold. Because the adenovirus's own genes to reproduce itself have been removed, the remaining viral container is unable to cause an illness.

At least, that's the idea.

About the Author

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