Probe into HUP death continues

Officials are trying to determine why an 18-year-old gene therapy patient died at HUP last month. Two weeks after the death of a patient undergoing experimental gene therapy treatment brought Penn under national scrutiny, officials at Penn's Institute for Human Gene Therapy -- one of the country's leading authorities in the burgeoning field -- are trying to figure out what went wrong. The patient, 18-year-old Jesse Gelsinger, was one of 18 participants in a Penn experiment testing the safety of using a genetically altered virus to stimulate enzyme production in the liver. Gelsinger died of organ failure on September 17, four days after receiving the new genes. News of his death broke last Wednesday and made headlines nationwide. The two-year-old study is now on hold until all the data can be reviewed and presented to the U.S. Food and Drug Administration and the National Institutes of Health. Despite the national attention that is now focused on gene therapy in general, and Penn in particular, officials say Gelsinger's death -- which has not been definitively linked to the genetically altered virus -- is not a reason to stop gene therapy trials. "If we don't do something? we won't progress in the field," said Joe Hughes, senior associate director for Translational Clinical Research at the IHGT. Gelsinger would have felt the same way, Associate Director for Clinical Research Programs Lisa Speicher said. "He had a great attitude when he came in and he really wanted to help other people with the disease," she said. Speicher added that incidents like this are one of the setbacks of this type of study, and "you take two steps forward and one step back." "If we knew the answers, the disease would be cured already," she said. Gelsinger had an enzyme disorder called ornithine transcarbamylase deficiency, which prevented his liver from breaking down ammonia, a poisonous by-product of protein digestion. Bioethicists and medical professionals around the country have been prompted to reconsider the ramifications of gene therapy, a relatively new area of medicine that is already the focus of much scrutiny. Jeffrey Kahn, director of the Center for Bioethics at the University of Minnesota, said Gelsinger's death raises questions about "how to understand the tradeoff between a potential cure and taking on what may be significant risks for someone who is otherwise very healthy." Officials are doing a thorough study into the cause of death and "hope that people would withhold judgement about this" until they find out what happened, said Mark Batshaw, one of the physicians who initiated the study. He now works in Washington, D.C., as the chief academic officer for the Children's National Medical Center and heads the Pediatrics Department at George Washington University. Researchers have already determined that the genes were not contaminated and they say that the dosage Gelsinger received has been used successfully on patients in other studies. The results of the investigation into Gelsinger's death will be presented to the FDA on November 1, and more results will be presented to the NIH in an open forum in early December. "We have to find out whether Jesse had an idiosyncratic response to the virus that was unique to him or whether we had reached the toxic level" of gene infusion, Batshaw said. In the Penn study, genes that produce OTC were inserted into an adenovirus -- a virus that causes flu-like symptoms -- and injected straight into the liver. Scientists expected the OTC gene to trigger the production of a functioning OTC enzyme, therefore allowing the body to fully digest protein. The experiment was not intended to cure the patients -- and was not used on seriously ill patients -- but rather to test the maximum safe dosage for newborns afflicted with the disorder. Outside scientists have raised concern about the delivery method used in the study -- through an artery that goes straight to the liver, rather than the more common intravenous method -- but Hughes said this did not cause the complications. Another controversial aspect of the study was that unlike traditional gene therapy trials, in which patients are so sick that gene therapy is a last resort, this study was done on fairly healthy individuals. But IHGT Director James M. Wilson said this was the only way to perform the experiment, since most OTC cases are found in newborn males, who, when afflicted, rarely survive more than a couple of days --Eand aren't suitable subjects for the study because they cannot give informed consent. But patients like Gelsinger have a less serious mutation of the gene, and are thus able to control the disease's symptoms by medication and a low-protein diet to live much longer. Gelsinger, a native of Tucson, Ariz., was the second patient in the sixth group of the study and received the highest dose of the virus. Other than fever and other cold symptoms, none of the patients -- including the other person who got the same high dose as Gelsinger -- had any adverse reaction to the treatment. Approximately 50 trials using the adenovirus are currently being conducted nationwide. With the exception of this study and another one with a similar delivery method, all of Penn's gene therapy trials are continuing as planned.