U.S. Panel Recommends Limiting Gene Therapy Trial

Halted U.S. experiments should resume for children with no other option, FDA advisers say, experts still see hope for emerging field despite setbacks.

By Amanda Gardner
HealthDay Reporter

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SATURDAY, March 5 (HealthDay News) — Federal health advisers recommended late Friday that two U.S. gene therapy trials for children with a severe immune deficiency resume but on a very limited basis.
A Food and Drug Administration advisory panel said the two experiments should be allowed to continue only if the patients have exhausted other “reasonable alternatives,” including bone marrow transplants.
Otherwise, the panel suggested the trials — at the National Institutes of Health and the University of Southern California — remain suspended, the Baltimore Sun reported. Those trials, and another at USC, had been halted after a third child developed leukemia in a similar French study.
French authorities reported the most recent cancer case Jan. 24, prompting the FDA suspension of the three U.S. trials and the convening of the advisory committee.
“The additional data hasn’t suggested that there’s a heightened risk, but we have to be careful,” said Dr. Mahendra Rao, chairman of the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee, according to the Sun report.
The developments are the latest in a string of problems for gene therapy research, which once held the promise of revolutionizing medicine in its attempt to substitute healthy genes for defective ones.
There have been thousands of attempts to use gene therapy, but only about 10 patients have been cured, all of them children in Europe who were born with the severe immune system disorder called X-linked severe combined immunodeficiency, or X-SCID.
The doctors and scientists on the FDA panel said Friday that they didn’t want to hold up the therapy for children who have already failed to respond to bone marrow transplants, an alternative treatment for X-SCID. But they noted that the number of such children is very small, the Associated Press reported.
“What is happening here today — the big picture — is that it shows the difficulty in developing any new class of therapy,” said panel member Dr. Daniel Salomon, a professor in the Scripps Research Institute.
“There was a period of time that there was a tendency to say gene therapy … had been safe. What’s clear now is that (problems can develop in) some gene therapy for some diseases,” Salomon said.
But even as the panel was meeting, other scientists said they still believe the emerging field has a future in medicine, despite the high-profile setbacks.
“Gene therapy’s future, in my opinion, is still bright,” said Richard Heller, a professor of microbiology and immunology at the University of South Florida College of Medicine in Tampa. “It’s still a fairly young field, and genetic manipulation is not easy.”
Dr. Theodore Friedmann, director of the Program in Human Gene Therapy at the University of California, San Diego, added, “These are normal problems with a difficult new therapy. The field has obviously been hampered and complicated by some missteps, reversals and, in fact, disasters. But that also comes on the background of hype and exaggeration and failure to deliver very quickly on clinical promises.”
While acknowledging there have been tragedies, experts in the field also note that one must weigh the risks with the benefits.
“These kids with SCID don’t have much of a chance,” said Fred Modell, co-founder of the Jeffrey Modell Foundation, which represents thousands of patients with immune disorders. “These are children who would not have survived.”
Modell’s son, Jeffrey, died of an immune system disorder in 1986, when he was 15.
Added Friedmann: “At least a handful of participants [in the French trials] with SCID are leading normal lives. These are kids who have an alternative fate and that fate is dying of infection, being isolated and not leading any kind of normal childhood life.”
“What this study [the French research] shows in principle is that one can correct terrible disease in humans with this sort of approach,” he continued. “It also tells us that we’re very immature in our technology, that we don’t know nearly enough to be pleased with the technology as it is.”
Friedmann pointed to past successes that started out with mixed results: chemotherapy, organ transplantation, bone marrow transplants.
Dr. Mark Tuszynski, a professor of neurosciences at the University of California, San Diego, who is researching gene therapy in Alzheimer’s disease, said, “Whenever one’s developing a new technology in medicine, it takes time to work through things. It’s naive to think that there would not be wrinkles along the path. But the potential of gene therapy to radically alter how we treat diseases is profound, and I think there remains great enthusiasm in the field in working with gene therapy.”
Regarding the children in France, he said, “Those children had no realistic alternative. If this had been a field other than gene therapy this would have been treated as a great success. There’s something unfortunate about the perception in gene therapy that should be realistically reassessed so we can recognize that the potential is indeed being realized.”
One aspect of gene therapy under scrutiny is the “delivery systems” used to get a gene into the human body. The French researchers injected patients with inactivated retroviruses — viruses that are unable to replicate — sort of like a missile delivering a payload (the gene).
Retroviruses integrate into the genetic structure of cells, which is really what you need when trying to correct a genetic defect, Heller explained.
“The vector specifically is one that sits down in the genome of the host cell and doesn’t have a specific targeted site that it goes to,” Friedmann explained.
This can have unintended consequences, such as the development of cancer down the line, Friedmann said.
Many researchers are now looking into techniques that would better direct where the integration happens.
Heller, for instance, is using a nonviral approach, plasmid DNA, as a potential treatment for advanced melanoma. The plasmid DNA, which encodes a gene that stimulates the immune system, is injected directly into the tumor site. An electric field is then applied to help the tumor cells take up the plasmid. Eighty percent of mice with advanced melanoma were cured by this therapy. A trial in humans is under way at the University of South Florida’s Moffitt Center, he said.
“Right now, the focus is on one vector system, and there are lots of different viruses, as well as nonviral systems, which are showing success,” Heller said.
More information
The Human Genome Project (www.ornl.gov ) has more on gene therapy.