No Easy Answers in Gene Therapy Death

Jocelyn is a staff writer for Science magazine.

BETHESDA, MARYLAND--An investigation into whether gene therapy killed a 36-year-old woman in an arthritis trial has so far come up empty. At a meeting today, the National Institutes of Health's (NIH's) Recombinant DNA Advisory Committee (RAC) ruled out some hypotheses but came to no firm conclusions about what role, if any, gene therapy played in the woman's death.

The murky bottom line eased concerns of researchers who have worried that gene therapy, which has been blamed for two deaths in the past 8 years, would be linked to a third. Results presented at the meeting did not challenge the consensus that the popular vector used, adeno-associated virus (AAV), is relatively safe (ScienceNOW, 26 July). However, questions about the design and ethics of the trial have cast a negative light on the field, particularly gene therapy for non-life-threatening diseases. Concluded Arthur Nienhuis, president of the American Society of Gene Therapy: "We see areas in which we need to be concerned."

The tragedy involved Jolee Mohr of Springfield, Illinois, who was married with a 5-year-old daughter. She had suffered from rheumatoid arthritis since she was 21, and through her rheumatologist, she enrolled in a phase I/II safety arthritis trial sponsored by Targeted Genetics Corp. in Seattle, Washington. The study involved injecting into joints an AAV that carried a gene coding for a protein that inhibits a proinflammatory cytokine called tumor necrosis factor α (TNF-α). Mohr received an initial injection in her right knee in February and a second injection on 2 July.

The evening of the second injection, Mohr developed a fever and chills. Ten days later, she was admitted to her local hospital and eventually transported to the University of Chicago Hospital, where she died after massive organ failure on 24 July. The Food and Drug Administration immediately put the trial on hold.

The main cause of death was apparently Histoplasma capsulatum, a fungus endemic in the Midwest that normally does not cause serious infection, University of Chicago doctors said at the RAC meeting. Mohr's liver, brain, lungs, and other tissues were "loaded with" the organism, which was not picked up in lab tests during her hospitalization, reported pathologist John Hart of the University of Chicago Medical Center. In addition, she had an abdominal hematoma, or a blood clot, that weighed more than 3.5 kilograms and was pressing on her other organs.

Tests of Mohr's stored blood have revealed that she had a mild Histomplasma infection the day she received the second injection. Exactly why her immune system was unable to fight off the fungus is not yet clear. Because Mohr tested positive for herpes simplex virus (HSV), some had suggested that its proteins, along with wild AAV, could have allowed the AAV vector to replicate and weaken her immune system. But the levels of HSV in Mohr's tissues and blood did not support this possibility, suggested scientists at the RAC meeting. And although AAV vector did escape from the injected joint to other tissues, these levels were extremely low, making it unlikely the virus was replicating.

A more likely culprit is a drug she was taking. Named Humira (adalimumab), the drug is also a TNF-α blocker and has been associated with Histoplasma infections. Whereas Humira alone could have caused the immune suppression, another possibility is that Humira combined with the TNF-α blocker encoded by the gene therapy pushed Mohr over the edge. Tests so far have not answered this question.

More definitive results should be available by the next RAC meeting in December, said chair Howard Federoff of Georgetown University in Washington, D.C. But as Scott Strome of the University of Maryland Medical Center in Baltimore, Maryland, put it, "I don't know that we can ever be certain of the role gene therapy played." Meanwhile, however, Federoff and others say the case raises questions about the ethics of the study, including whether Mohr realized that patients weren't expected to benefit. Her distraught husband, Robb Mohr, told the RAC panel that "how she ever got signed up is still beyond my belief."

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