The FDA's "clinical hold" placed Tuesday on all gene therapy trials that use retroviral vectors to insert genes into blood stem cells is shaking up that sector of biotechnology research. Again.
And again the trouble comes from France, where a gene therapy experiment has led to a leukemia-like condition in a second child. The first surfaced in a 3-year-old boy last year, and both patients were among those who had been successfully treated for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble boy syndrome." (See BioWorld Today, May 1, 2000.)
James Merritt, chief medical officer for Introgen Inc., of Austin, Texas, said the news from France is being received with "genuine surprise and horror. Unfortunately, what's happened is a demonstration in humans of what has been previously produced scientifically in cell cultures."
He said the "great shock here is that, when it occurred the first time you just know it can happen. But when it happens the second time, you begin to see what its frequency might be." The trial is being held at the pediatric Hospital Necker Enfants Malade in Paris
Introgen, which does not work with retroviruses and is not affected by the FDA's clinical hold, has a gene therapy product, Advexin - an adenoviral vector containing the p53 tumor-suppressor gene, which is "only transiently in the body," Merritt said - in Phase III trials for head and neck cancer.
"Most observers have their eye on Introgen as being in the lead [in gene therapy]," he said. "We also have the broadest program, in terms of number of patients treated and trials around the globe."
Retroviral research, on the other hand, is "the minority, no question, of what's going on in gene therapy," Merritt told BioWorld Today. "Retroviral ex vivo studies are predominantly, if not exclusively, academic in nature. So one could optimistically say [the problems cited by the FDA have] no effect, but this is a new area and none of us should be advocating an incautious, pedal-to-the-metal approach," he said.
The federal agency said it has no reason to believe similar research in the U.S. is placing patients in danger but, after learning of the first case last year, stopped patient enrollment in three gene therapy studies here that most closely resembled the trial in France, and now has stopped 27 more.
Thirty retroviral gene therapy trials make up a small set of the estimated 200 gene therapy trials under way, but the move has cast a pall over the sector, especially in the general public's eye, as did the 1999 death of Jesse Gelsinger, an 18-year-old patient participating in a gene therapy study using an adenoviral vector at the University of Pennsylvania.
Michael Werner, vice president of bioethics for the Biotechnology Industry Organization in Washington, told BioWorld Today that "the FDA is being appropriately cautious, but this seems to be an instance of a very specific application - the retrovirus in stem cells in SCID [patients]."
Fast-multiplying stem cells, as compared to ordinary cells, entail more risk in gene therapy experiments, particularly for leukemia, which like other cancers is characterized by proliferating cells. And the promise of retrovirus work has been that the genes stay as part of the target cell's DNA, as a more permanent solution.
The promise has turned out to be the difficulty, too. In the first French case, the inserted retrovirus apparently turned on a cancer gene, and the second case is under investigation. Similar experiments have been done in the U.S., but nothing like this has been reported.
"We all know, as virologists and scientists, that retroviruses have this propensity of inserting into areas of the genome and turning on unwanted genes," Merritt said. The name for it is insertional mutagenesis.
"We've presented data that our product does not insert into cellular DNA," he added. "It wouldn't be expected to, but we've done the research to demonstrate it." Even after the Gelsinger death, he said, Introgen's adenovirus trials were not put on hold, thanks to the company's safety data.
Retrovirus researchers have not been so lucky. In late February, an FDA advisory committee will meet to discuss what further action might be taken. Meanwhile, advocates of gene therapy note that, in the French experiments, nine of 11 boys treated had improved to the point where they could leave the hospital and lead normal lives. It was working.
"Nobody disputes that [the French trials have] a very favorable risk-benefit ratio," Merritt said. "They're trying to cure kids who are going to die."
Babies with SCID are born without immune cells, and the "bubble boy" description came about with much media publicity for a youngster in Houston who lived in a sealed environment to avoid infection until he died in 1984 at age 12.
Companies working in gene therapy were either lying low this week or pointing out the differences in their methods as compared to the French studies.
Joseph Glorioso, president of the American Society of Gene Therapy and chairman of molecular genetics and biochemistry at the University of Pittsburgh, said he believes "something very specific about this [French] trial" led to the problems - not deficiencies in the trial, necessarily, but the specifics of its design and its aims.
"I don't think this is serious for gene therapy," Glorioso told BioWorld Today. "I'm not even sure it's serious for retroviruses yet." He said the good news is that the treatment cures the disease, and - using data from the French study - the search is on for a way to do that without side effects.
"I think it's going to be possible," he said.