Federal regulators have given a green light to a gene-therapy arthritis trial that was halted last summer after a patient died. New tests indicate that the therapy played no role in the death. The decision comes as a relief to gene-therapy researchers who had worried about a potential new setback for their field.
The trial conducted by Targeted Genetics Corp. was shut down after the 24 July death of 36-year-old Jolee Mohr of Taylorville, Illinois, who received a gene-therapy injection to treat her rheumatoid arthritis in one knee 3 weeks earlier (Science, 3 August). At a September meeting of the federal Recombinant DNA Advisory Committee (RAC), experts noted that Mohr apparently died mainly from a fungal infection called histoplasmosis that her immune system was unable to fight off (ScienceNOW, 17 September). Mohr's immune system may have been compromised by an arthritis drug she was taking, Humira, which blocks an inflammatory molecule called tumor necrosis factor α (TNF-α). The protein produced by the gene therapy is also a TNF-α blocker, and if it spread beyond Mohr's knee, the combination with Humira may have left her vulnerable to the fungus.
That did not happen, according to Targeted Genetics. The company points to new test results from an investigation by the company and outside researchers, which were presented at the American College of Rheumatology annual meeting earlier this month. The level of TNF-α blocker detected in Mohr's blood with a binding assay was "well within the normal range expected" from the dose of Humira she was taking, says President and CEO H. Stewart Parker. The new tests also ruled out the idea that the gene-therapy vector, adeno-associated virus, replicated in Mohr's body. Although DNA from the vector turned up in other tissues, the amounts were extremely low. Today, the company announced that the U.S. Food and Drug Administration has lifted the hold on the trial.
Others agree that the case is closed. "It does not look like the gene therapy played a role to the best of our knowledge," says physician Kyle Hogarth of the University of Chicago in Illinois, who treated Mohr and took part in the investigation. However, Hogarth questions whether it makes sense to enroll patients who are already taking TNF-α blockers in the study, because it's difficult to distinguish between the effects of the gene-therapy product and the drugs. Parker disagrees, noting that rheumatologists say "there is a significant unmet need" for treatments for patients with joints that do not respond to the systemic drugs.
The company now plans to resume the trial of 127 patients but will not give a second dose to as many as 35 awaiting patients if they have a fever, as Mohr did. "We are being conservative," says Parker. She says the only change to the informed-consent document will be to note the earlier death. RAC will issue its final conclusions about the case at a meeting next week. RAC Chair Howard Federoff of Georgetown University in Washington, D.C., declined to comment in advance of the meeting.