Role of Gene Therapy In Death Called Unclear
Tuesday, September 18, 2007
Postmortem tests on an Illinois woman who died mysteriously in July after getting an experimental gene treatment show no evidence that she was killed directly by the genetically altered viruses she was given, a committee of experts was told yesterday.
But many questions remain, and further tests will have to be done to see if the treatment somehow contributed to her death, perhaps by leaving her vulnerable to a runaway fungal infection, the National Institutes of Health panel concluded.
"This is clearly a complex case," said Howard J. Federoff, executive dean of Georgetown Medical Center and chairman of the NIH Recombinant DNA Advisory Committee, which is investigating in concert with outside experts.
By December, he said, he hopes to be able to say "what role, if any" was played by the trillions of viruses that were injected into the woman, Jolee Mohr, 36, as part of an experiment being run by Targeted Genetics, a Seattle biotechnology company. But it is possible, Federoff and others said, that the question will never be answered.
The Food and Drug Administration has placed the experiment on hold, and the case is being watched closely by leaders of other gene therapy experiments, dozens of which are using similar viruses.
Autopsy results and tests on blood and tissue specimens indicate that Mohr died in large part from a massive infection caused by Histoplasma capsulatum, a fungus common in the Mississippi and Ohio River valleys. She also had extensive bleeding in her abdomen, perhaps caused by that infection. An enormous clot accumulated there and caused organ damage that contributed to her death.
Mohr's symptoms began the day her right knee was injected with the viruses, which were engineered to suppress the immune system reaction that causes rheumatoid arthritis, a disease that had dogged her for many years. Three weeks later, she died, leaving behind a 5-year-old daughter.
A spokeswoman for Targeted Genetics said the company was gratified by several of the test results. Perhaps most important, the viruses -- which were gene-altered so as not to multiply -- appear not to have replicated or spread in large numbers through Mohr's body.
Still unknown is whether they produced larger-than-intended doses of their immune-suppressing product, or whether the treatment in some other way affected Mohr's ability to fight the infection.
Mohr's husband, Robb, told the panel that his wife was only mildly affected by her arthritis and was not properly warned of the experiment's risks. "How she ever got signed up is still beyond my belief," he said.
If not for the experimental therapy, he said, "I think she'd still be here."
Members of the NIH panel and other experts at the meeting said that Mohr may be right but that, for now, the scientific evidence falls short of that assertion.
In one telltale sign that immune suppression played a role, the fungal cells in her tissues were not walled off by granulomas, as they typically are in patients with normal immune systems. But panelists noted that the immune-suppressing protein made by the gene-altered viruses is virtually identical to one in an FDA-approved arthritis medicine that Mohr was also taking -- which is known to increase the risk of fungal and other infections.
Some panelists echoed Robb Mohr's concerns about the way his wife was signed up for the study. They noted that, although no regulation prohibits the practice, it can be ethically problematic when a patient's personal physician recruits the patient, as was the case with Mohr. Patients routinely overestimate the chances that an experimental treatment will help them, and this "therapeutic misconception" is even more likely when the recruiter is the patient's personal doctor, studies show.
Mohr's physician also signed her up immediately, rather than having her take the materials home to consider -- also less than ideal, experts said. And there was no mention in the informed consent document that her doctor was being paid by Targeted Genetics for every patient he enlisted.
Panelists said it is still a matter of debate within the bioethics community whether physicians ought to tell patients when they have a financial stake in a medical experiment they are recruiting for.