Report: Patient in gene therapy test died of lung failure

Jesse Gelsinger, 18, died as a result of his participation in a HUP gene therapy trial. Two and a half months after the death of an 18-year-old patient in a Penn gene therapy experiment, researchers have determined that the modified cold virus used in the study triggered a deadly immune response that led to organ failure and death. The death of Jesse Gelsinger on September 17 drew national attention to Penn's Institute for Human Gene Therapy and aroused debate on the ethics of this type of study. It was the first known death connected to gene therapy. The experiment used a genetically altered adenovirus -- a cold virus lacking the cold-causing genes -- to counteract a deficiency in a liver enzyme. A preliminary report based on an autopsy and laboratory experiments was released yesterday, indicating that the Tucson, Ariz., native's death was due primarily to oxygen deprivation caused by a lung disorder called Adult Respiratory Distress Syndrome. A full report on the investigation will be presented to the Recombinant DNA Advisory Committee of the National Institutes of Health in Washington, D.C., in a public forum next Wednesday through Friday. Investigators -- led by IHGT Director James M. Wilson -- say that Gelsinger had an immediate immune reaction to the gene injection, which was followed by liver injury and blood coagulation. Although these symptoms began to improve after two days, ARDS set in and was irreversible. They believe that the original injection of the virus on September 13 set off the fatal response four days later, but they do not know precisely what it is about the injection that caused it. According to a statement released by the University of Pennsylvania Health System, human error -- which would have been the simplest explanation for the death -- was not found in a review of the dosages given to each patient and tests of the manufacture of the gene product. They say that there was no information available that could have predicted the death. Earlier patients and animal studies had suggested that liver inflammation and blood coagulation could be possible side effects, but a lung disorder was not seen in any of the other patients or studies. The researchers did find that Gelsinger had abnormal bone marrow, but it is unclear whether the problem was related to the treatment, or was a pre-existing abnormality. "The researchers remain committed to fully evaluating all potential leads," the statement released yesterday said. "The purpose of these efforts is to understand the precise nature of Mr. Gelsinger's unfortunate death, and to share the knowledge gained with the research community and the public in order to prevent another such occurrence." Gelsinger had ornithine transcarbamylase, or OTC, deficiency, a genetic disorder that left his liver unable to break down ammonia, a poisonous by-product of protein digestion. Gelsinger had a mild form of the disease; the most severe forms are fatal soon after birth. In the experiment -- which has been placed on hold until all of the data are reviewed and presented to the NIH -- a gene that produces the functioning OTC enzyme is inserted into a deactivated cold virus and then injected directly into the liver, theoretically producing functioning enzymes for the recipient. Gelsinger's death has drawn much scrutiny to the 9-year-old field of medicine, particularly since Gelsinger was the first reported gene therapy fatality. Also, gene therapy is usually saved for patients whose diseases' severity leaves them few other options. Gelsinger -- like the rest of the patients in the Penn study -- was relatively healthy, as his symptoms were kept in check with drugs and a low-protein diet. A recent Washington Post article raised serious questions about Wilson's motives for the study, pointing out his financial ties to a private gene therapy company that would have profited from a successful series of trials. The article also questioned whether patients in the study were properly informed of its risks. Wilson and other Penn officials have denied the allegations.