Gene study at Penn under fire

An 18-year-old participant in the study died last month. The cause of his death remains unknown. An experimental gene-therapy treatment conducted by Penn researchers that ended with the death of one of its patients was seriously flawed in its design and motivations, The Washington Post reported over the weekend. According to the highly critical article, the scientists in charge of the study -- which used a genetically altered virus to counteract a deficiency in a liver enzyme -- ignored side effects from animal studies, improperly obtained consent from test subjects, used healthy patients instead of sick ones and were motivated by a financial stake in the success of the treatment. The researchers, led by James Wilson, director of Penn's Institute for Human Gene Therapy, said the article was both inaccurate and upsetting. "We were disheartened by The Washington Post's misleading representation of our motivations and actions regarding the development and implementation of our gene-therapy clinical trial," the researchers said in a statement. The study included patients like 18-year-old Jesse Gelsinger, who had a less severe form of the enzyme deficiency that is usually treated with drugs and a controlled diet. News of Gelsinger's September 17 death at the Hospital of the University of Pennsylvania, which was the first reported in any gene-therapy experiment, was broken by the Post and made national headlines. "A close look at the Penn research provides a rare snapshot of that subtle scientific and ethical landscape known as the cutting edge of medicine," the Post article reads. "And it resurrects old questions about whether the Penn experiment ever should have begun." The Post article criticized the study -- which was put on hold after Gelsinger's death -- by saying that it was driven by Wilson's financial concerns. Wilson founded a private gene-therapy company called Genovo in 1992, and the article alleges that his research on liver-directed gene therapy was motivated by the potential financial rewards that he would receive through the company for a successful treatment. Wilson denied these allegations and added that the financial relationship between the researchers and the company was fully explained on the consent form signed by each patient. Besides Wilson's "financial stake" in the experiment, the Post also claims that his reputation as one of the leading scientists in his field led regulators to overlook problems in the study. But Mark Batshaw, the principal investigator in the study said that it was he, not Wilson, who was in charge of patient care, adding that he has no connection to Genovo at all. "It's fair to talk about issues of money and the effect it could have on trials, but in this case it was barking up the wrong tree," said Batshaw, who is chairperson of pediatrics at George Washington University and chief academic officer of the Children's National Medical Center in Washington, D.C. "Our intent was always pure, and it was made to seem different than that." Other consent issues were discussed by the Post article, including an allegation that volunteers' consent was not obtained through their physicians. In addition, the Post claimed that "early indications of toxicity" were ignored by the research team -- led by Wilson, Batshaw and Penn surgeon Steven Raper -- and that information about those findings was left off the consent form as well. The scientists say that all relevant risk factors were included in the consent form, and that all information gained from the pre-clinical work was considered in the final design of the study. Batshaw said the outside studies indicating negative side effects have not yet been published, so it would have been difficult for the researchers to consider the findings. He added that the Post exaggerated the severity of the treatment's side effects. In addition, any changes in the study were made gradually, and not as attempts to undermine the federal regulators who supervise this kind of research, he said, adding that everything was done with "lots of oversight." The gene therapy study was conducted on healthy patients -- those whose symptoms of enzyme deficiency were held in check by drugs and a controlled diet -- and not on babies with the disease who were fatally ill, because informed consent cannot be obtained from parents of a dying baby, the researchers said. The Post article, however, contended that this type of high-risk research should only be done on the most seriously ill patients, not on the healthiest of affected individuals. Batshaw said that since the Penn experiment was a Phase I trial, it is geared at testing the safety of a new treatment, not at curing anyone. The study used a virus to carry genes that would produce the liver enzyme ornithine transcarbamylase, known as OTC. Patients in the study lacked the proper levels of OTC -- meaning that they cannot break down ammonia, a by-product of protein digestion. The most severe form of the disease is fatal soon after birth. According to the researchers, placing healthy OTC genes in an altered adenovirus -- the same type of virus that causes the common cold -- and injecting it into the liver of a patient who cannot make the enzyme on his own should trigger the production of functioning enzymes and boost complete protein digestion. Gelsinger was the 18th patient to participate in the Penn study, and, along with one other person who had no adverse reactions to the treatment, received the highest dose of altered adenovirus. The cause of Gelsinger's death has not been definitively linked to the virus and remains unknown. All data gained from an investigation into the study will be made public at a December 9 meeting with the Washington, D.C.-based National Institutes of Health, which oversees all Phase I studies.