Question:    In September 1999, Jesse Gelsinger died during a gene therapy trial at the University of Pennsylvania. His was the first reported death due to gene therapy. What impact has his death had on gene therapy research?

Reply:
Background
           Jesse Gelsinger, from Arizona, was born with ornithine transcarbamylase (OTC) deficiency. A mutation in the OTC gene results in an inability to break down ammonia, a normal by-product of metabolism, which builds up and can be fatal. About half of the people born with this disorder die soon after birth. Jesse Gelsinger's disease was mild and he was able to control it through diet and drugs.
           In 1999, 18-year-old Jesse enrolled in a gene therapy trial at the University of Pennsylvania. The gene therapy trial, headed by Drs. James Wilson, Mark Batshaw and Steven Raper, was to determine the safety of their gene therapy method. They were testing the safety of the treatment on adults with mild forms of the disease, however these volunteers would not get any long-term benefit from the therapy. If the therapy proved safe, then they intended to use the therapy to treat newborns born with severe forms of the disease.
           The trial used an adenovirus vector to deliver the normal OTC gene to volunteers in the trial. The adenovirus, the class of virus that causes colds, pinkeye and pneumonia, was to deliver the normal OTC gene into the liver cells which would then make OTC and be able to break down ammonia. However, adenovirus has been shown to trigger intense immune reactions and induce life threatening inflammatory responses. The research team at the University of Pennsylvania modified the adenovirus to make it less inflammatory in the hopes of making it safer to use as a deliverer in gene therapy. However, monkeys treated with the same adenovirus had had immune reactions to the virus and died during experiments.
           In September 1999, Jesse Gelsinger, the 18th volunteer in this trial, received the highest research dose of virus administered in this trial. Within hours of receiving the treatment, Jesse became ill. Four days later, Jesse died from massive organ failure caused by an over-reaction of his immune system to the adenovirus. On September 17, 1999, Jesse Gelsinger became the first reported person to die from gene therapy.

Issues

           Jesse Gelsinger's death has prompted investigations in the gene therapy trial and brought current regulation of gene therapy experiments under scrutiny. Following his death, regulators halted eight other gene therapy trials at U Penn. When investigating Jesse's death, the FDA found 18 instances where researchers failed to follow the rules designed to protect volunteers from harm.
           Benefits versus risks.   Many have questioned why healthy individuals, who had their disease under control, were used as volunteers in this trial. Typically, risky experimental trials are performed on the sickest population; individuals with no other treatment options. For those who are desperately ill, the risks of a new treatment can be justified. However, in this trial the healthiest population was enrolled as volunteers, those who were able to manage their disease through conventional treatment. Because these patients' livers are already stressed due to their disease, it was very risky to treat them with a therapy proven to cause liver damage. Since the volunteers stood no chance of any lasting benefit from the therapy, the risks far outweighed the benefits in this trial.
           Informed Consent.   The rules of informed consent require that the risks and benefits of an experiment be clearly explained to volunteers in understandable language. If during the trial, volunteers experience serious side effects, all participants are to be informed and re-consent to participation in the study. In the U Penn study, the consent form approved by the NIH notified participants that monkey had died from similar treatments. However, the final consent form distributed to volunteers omitted any mention of the monkey deaths. In addition, while several volunteers in this trial had experienced elevated liver enzymes and adverse reactions to the treatment the consent form was not amended to include these reactions. Instead, the researchers continued increasing the dose, despite warning signs, including one volunteer who suffered severe liver damage. Because the consent form did not inform potential volunteers about these adverse effects, participants were unable to make informed decisions regarding the risks of participating in this trial.
           Recruitment.   Also brought into question was the methods used to recruit participants to the study. The NIH committee that approved the trial had insisted that patients only be recruited through physicians because they felt patients would be easily coerced into participating in risky study if recruited directly. However, Batshaw wrote a piece about the study and recruited volunteers through a patient advocacy newsletter and Web page.
           Financial Incentive.   Also in question is whether financial incentives caused researchers to continue the study despite the risks. Dr. Wilson, one of the researchers, has financial interest in Genovo, Inc., a private company he helped found. In 1995 Biogen Inc. paid Genovo $37 million for the right to market any liver-related therapies developed by Genovo, which also has rights to any discoveries made by Wilson. While Wilson denies that this agreement influenced his decisions regarding the trial, many are uncomfortable with the close connections between industry and research. 43% of the gene therapy protocols approved in the past three years have had corporate sponsors. Some feel that the financial incentive for gene therapy advancement may cloud researchers judgements regarding safety of gene therapy trials.

Impact

           Regulation.   As a result of Jesse Gelsinger's death, the regulation of gene therapy trials is being investigated by a Congressional committee, the NIH and FDA. Preliminary findings indicate that the current monitoring systems are too lax. Following Jesse Gelsinger's death, the NIH contacted all gene therapy trials under its jurisdiction and asked them for reports of all adverse effects experienced in the trials. They found 691 instances of serious side effects over the past seven years, only 39 of which had been reported to the NIH according to regulations. The NIH requires all deaths and adverse effects from gene therapy trials to be reported, regardless of cause, so that it can review data and detect trends or unexpected toxicities and warn experimenters. However, researchers are less willing to report adverse effects to the NIH because they make this information public whereas the FDA keeps it confidential.
           The FDA has changed their guidelines regarding gene therapy trials as a result of Jesse Gelsinger's death. They now require research institutions to submit monitoring plans that detail how the researchers will protect their human subjects. The FDA will ensure that these plans are followed. Previously, this was left up to institutional internal review boards and was not monitored by any federal agency. In an effort to improve monitoring, the FDA will also conduct on-site inspections of clinical trials.
           Participation.  It is hard to judge whether Jesse Gelsinger's death has impacted participation in other gene therapy trials. Some researchers report that enrollment in trials has dropped since his death. Others report that they have increased, saying their volunteers report they fear a moratorium on gene therapy and want to receive treatment before any bans.
           The high hopes for gene therapy have yet to be realized; after a decade of research, gene therapy has not resulted in a single cure. Jesse Gelsinger's death has called into question the scientific integrity of gene therapy trials. Many feel the field of gene therapy is moving too fast; trials on humans are happening before therapies have been well tested in animal models. And while many questioned the efficacy of gene therapy, until Jesse Gelinger's death most researchers felt the treatment was benign. This assumption is no longer valid and calls for reconsideration of the risks and benefits of gene therapy trials.