Gene therapy fallout

Jesse Gelsinger thought he could help change the world. The teenager hoped that by enrolling in a cutting-edge gene therapy study at the University of Pennsylvania, he could end the suffering of people plagued with inherited diseases similar to his own. However, before researchers could even finish the study, Gelsinger was dead, the field of gene therapy was turned upside down and Penn was the object of intense nationwide scrutiny. Yesterday marked the first anniversary of Gelsinger's death -- the first reported fatality in the 10-year history of clinical gene therapy trials. While experts in the field have said that the researchers are not directly to blame for the the Tucson, Ariz., teen's death, during the past year the University has reviewed and reformed its research protocols, and Penn's Institute for Human Gene Therapy -- where Gelsinger was a patient -- has fallen from its prominent perch atop the field to being restricted to research on animals and cell cultures. Following Gelsinger's death, the U.S. Food and Drug Administration launched an investigation and suspended all of Penn's clinical gene therapy trials in January and refused to lift the ban in March, after alleging that the IHGT engaged in patterns of negligence. But IHGT director James M. Wilson -- a onetime star who was recruited by top Penn administrators to start the nation's first gene therapy institute in 1993 -- has consistently defended his work and maintained that there was nothing he or his colleagues could have done to prevent Gelsinger's death. But the negative attention paid to Wilson, the IHGT and Penn administrators, attention that also unleashed extensive debate about the entire area of medical research on humans, was called "an embarrassment" by University President Judith Rodin. "Penn's reputation is not fundamentally marred by a single incident or a single accident," Rodin insisted. But, "it's made us realistic about the consequences of our missteps." Gelsinger suffered from Ornithine Transcarbamylase Deficiency (OTC), a rare inherited liver disorder that inhibits the body's ability to produce enzymes that break down ammonia, a by-product of protein digestion. He died four days after being infused with a viral vector that would bring functioning genes to his liver. The potentially corrective genes could have produced the missing enzymes, but instead the infusion initiated a response that officials said ultimately led to organ failure and death. Penn is no longer manufacturing the vectors -- used to transfer the genes into a subject -- for human research, according to Provost Robert Barchi. However, he added, "The IHGT is still manufacturing vectors for things that have nothing to do with human research." According to Stephen Eck, co-director of the cancer gene therapy programs at the IHGT, Penn "didn't want the liability for manufacturing the viruses, now that there are other commercial resources" that can make the vectors instead. Eck maintained however, that there was no evidence the viruses produced at Penn for DNA packaging were unsafe. Penn's decision to stop manufacturing its own vectors came along with changes in oversight for its research, and an attitude that the Institute could not sacrifice safety and reputation for a leading position in the field. "It has given us the opportunity to really examine everything we're doing," Rodin said. The University has reviewed its policies based on recommendations made by an external review committee, appointed by Rodin to examine the school's human gene therapy research protocols after the ban was placed, and Barchi's special committee of faculty members who are reviewing all of Penn's human subject research. Rodin said officials plan to expand the monitoring of the Internal Review Board for all of Penn's research interests. "There's no question that Penn will be the strongest, the tightest, the most reviewed," Rodin said. In an extensive response to the FDA's allegations in February, IHGT officials directly addressed and defended each of the agency's 18 observations -- which included charges that researchers failed to fully inform patients of the study's risks; included patients such as Gelsinger who were ineligible to participate; failed to notify the FDA of deaths of two laboratory monkeys and the liver toxicity of a third on time; and enrolled Gelsinger despite high ammonia levels. "There's no question that there were breaches, there were breakdowns in the protocol," Medical School Senior Vice Dean Richard Tannen admitted last fall. But Tannen added that he doesn't believe any of the concerns the FDA expressed in any way led to the tragic outcome. Paul Gelsinger, Jesse's father, originally stood by Penn researchers, but when he testified in front of the U.S. Senate Subcommittee on Public Health in February, he looked back and said, "I was fairly naive to have been as trusting as I was" of the Penn researchers. Speaking for his client last week, attorney Alan Milstein said that Paul Gelsinger "places the blame up and down the line," including the researchers and administration at Penn. He also faults the Recombinant DNA Advisory Committee and the FDA, "who were instrumental in approving the study which never should have been approved." Interest has also evolved on the increasing connections between researchers at academic institutions -- who may additionally stand to benefit financially from the success of their experiments -- with private companies. Wilson was also director of Genovo, Inc., which until recently provided about 20 percent of the Institute's funding. The University also had stock in the company. Physicians at Penn insist that the reputations of the Penn Health System and the School of Medicine have not suffered due to this year's developments at the IHGT. "We have taken hits and performed admirably," said Stanley Goldfarb, chairman of the Department of Medicine, noting that the school's research funding has increased by 30 percent this past year. On Penn's new standing in the gene therapy research field, Eck said, "Gene therapy is now a huge field. It is going to be impossible for Penn to be the leader in everything." Eck compared leading the gene therapy field to leading the entire field of producing drugs: "No one can cover that much."

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