Fungus Infected Woman Who Died After Gene Therapy

By Rick Weiss
Washington Post Staff Writer
Friday, August 17, 2007

The 36-year-old Illinois woman who died last month after being treated with an experimental gene therapy was infected with a fungus that usually causes only a mild illness. But the infection spun out of control and ravaged her organs, suggesting that her immune system was seriously impaired, said a doctor who is part of the medical investigation.

The woman's body was also teeming with a cold-sore virus that the body normally keeps in check, another indication of a faltering immune system. And because of a tear inside her abdomen -- perhaps caused by infection, perhaps by injury -- she had an internal blood clot the size of a watermelon.

No formal cause of death has been declared for Jolee Mohr, who died July 24. Mohr had been generally healthy until July 2, when trillions of genetically engineered viruses were injected into her right knee in an experimental treatment for her rheumatoid arthritis.

The injected viruses were genetically modified so they would suppress the immune system -- which is responsible for the inflammation of rheumatoid arthritis -- only in her knee. Doctors hope that tests on tissue specimens and blood samples will tell whether the treatment's effects somehow spread from the joint to other parts of Mohr's body.

The picture will be complicated, however, because Mohr was also taking conventional immune-suppressing drugs for her arthritis. One of those in particular, adalimumab, whose brand name is Humira, is known to make patients susceptible to histoplasmosis, the kind of fungal infection that Mohr had. Inexplicably, Mohr suddenly became ill in July even though she had been taking that drug for years and the fungus that causes histoplasmosis is ubiquitous in the area where she lived.

"It's a major mystery," said Kyle Hogarth, who heads the intensive care unit at the University of Chicago Medical Center, where Mohr was transferred days before she died.

The company behind the medical experiment, Targeted Genetics of Seattle, has said that the treatment has an excellent safety record and that none of the more than 100 other volunteers who got the injections suffered anything more than short-lived side effects.

Hogarth and about 20 other doctors and scientists are investigating the death with help from experts in an immune system factor called tumor necrosis factor-alpha, or TNF-alpha, which is suppressed by the experimental genetic treatment and by Humira.

The autopsy was done with particular care, using sterile techniques more commonly associated with surgery on the living because of the importance of getting good clinical evidence, Hogarth said.

"Think 'CSI,' without the criminal implications," he said, adding that he suspects it will take one to two months to complete the tests.

The fungus found throughout Mohr's body is Histoplasma capsulatum. It is common in airborne dust and bird droppings in the Mississippi and Ohio river valleys and generally causes a mild respiratory illness when inhaled. But in people whose immune systems are compromised -- because of AIDS or cancer chemotherapy, for example -- the fungal cells can spread to other organs and blossom quickly into fatal infections.

"It was in her liver. In the blood. It was essentially everywhere," Hogarth said.

It is not known whether Mohr's infection was recently acquired or was old and recently reactivated. In healthy people, the immune system walls off the fungal cells in structures called granulomas, whose integrity is maintained by TNF-alpha. When TNF-alpha is suppressed, the granulomas can dissolve and release the still-living fungi.

Experts in gene therapy are eagerly awaiting the test results. A link to the death would be a painful setback for the research field, which attempts to treat diseases by giving people new genes.

"Gene therapy holds a great deal of potential," said Arthur Nienhuis of St. Jude Children's Research Hospital in Memphis, who is president of the American Society of Gene Therapy. He noted that after more than a decade of failures and a handful of instances in which gene-based treatments caused leukemia in volunteers, the approach has recently produced what appear to be its first cures. More than a dozen children born with genetically defective immune systems are now living normal lives because of injections of new genes.

A Targeted Genetics spokeswoman declined to comment on the autopsy findings, saying the company will make a full presentation at a National Institutes of Health meeting on Sept. 17.

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