http://www.the-scientist.com/news/home/53593/

The cause of death of a patient in a July gene therapy trial was a massive fungal infection, according to an initial autopsy report presented at the NIH Recombinant DNA Advisory Committee meeting today (September 17). Preliminary evidence suggests that adeno-associated virus (AAV), the vector which delivered the therpay, was not to blame, experts said.

The subject, Jolee Mohr, 36, died from widespread histoplasmosis accompanied by a hematoma that ruptured her organs, according John Hart, a pathologist at the University of Chicago who presented the autopsy results. At the time of her death, she had disseminated histoplasmosis in several organs of her body.

Although it is highly unlikely that AAV was responsible for the infection, further tests looking for presence of the expressed protein are needed to conclusively rule out the possibility, according to speakers at the panel.

"It seems that systemic histoplasmosis was a major contributing event that led to a lot of things that went downhill," Mark Kay, at the Stanford University School of Medicine, told The Scientist. "I don't know how people will spin it, but sounds to me like this was bad result of a medical therapy that probably was unrelated to gene therapy."

Mohr was part of Targeted Genetics' phase I/II clinical trial of tgAAC94, an adeno-associated virus (AAV) vector to treat inflammatory arthritis by inhibiting tumor necrosis factor at joints. Beginning July 2, she reported a fever, nausea and vomiting and was admitted to the hospital seven days later. She was transferred to the University of Chicago Medical Center several days later. A CAT scan revealed a massive retroperitoneal hemorrhage which eventually punctured the lungs and displaced the organs in the abdominal cavity. The FDA halted the trial once the adverse effect had been reported by the clinical trial group. Mohr died on July 24.

Since the death of Jesse Gelsinger, a patient in a gene therapy trial in 1999, the field has been dogged by setbacks.

Carol Kauffman, from the University of Michigan, a speaker on the panel, said that in addition to histoplasmosis, the autopsy also revealed severe sepsis and other symptoms often seen in AIDS patients.

There have been 40 known cases of histoplasmosis in patients undergoing anti-tumor necrosis factor therapy.


Neil.