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1st appeared
22
February
2000
Gene Therapy Death Has Triggered Scrutiny of Clinical Trials A San Jose Mercury News article that ran on the Associated Press last week erroneously stated that three gene therapy experiments at UCSF were part of the same study that led to the death last September of Jesse Gelsinger, an 18-year-old patient treated for a rare liver disease at the University of Pennsylvania. In fact, no patients have received the same gene therapy at UCSF, although one local patient who participated in the Pennsylvania clinical trial was monitored at UCSF following treatment. Her participation concluded on schedule before the trial was stopped by the National Institutes of Health (NIH) and by the Food and Drug Administration (FDA). "I am concerned that progress in treating deadly liver disease will be slowed if gene therapy trials do not go forward," says Philip Rosenthal, the liver specialist who monitored the patient. Patients with the liver disease, called ornithine transcarbamylase (OTC) deficiency, frequently are granted high priority on the waiting list for liver transplants, according to Rosenthal, and donor livers are perpetually in short supply. "I would like to see the day when we do not have to perform liver transplants on these patients," Rosenthal says. Gelsinger, the University of Pennsylvania patient, died four days after initial injection of the gene therapy drug into his hepatic artery, a major blood vessel feeding the liver. He died of massive organ failure blamed on a serious inflammatory response to treatment. The Pennsylvania team, led by James Wilson, had previously treated 17 patients in the same clinical trial. Gelsinger’s death was the first reported treatment-associated death to result from gene therapy in the U.S. The treatment approach has been used in an effort to heal more than 4,000 patients over the past decade with a variety of usually life-threatening diseases. Gene therapy remains entirely experimental--there is no gene therapy that has been approved as a standard treatment for any disease. Nonetheless clinical researchers insist that it remains a promising strategy for improving patients’ responses to fatal disease. Patients treated in the Pennsylvania study lacked normal amounts of OTC, an enzyme needed to break down ammonia, a waste product of food (protein) digestion. Ammonia levels in the blood can build up and become toxic to these patients. The therapy was designed to insert normal copies of the gene encoding the protein into liver cells, where it would be switched on to produce the necessary enzyme. Concerns about Use of Virus Gelsinger’s death raised questions about a disabled common cold-like virus called adenovirus, one of several gene-delivery vehicles used in gene therapy trials to ferry genes into cells targeted for disease treatment. The immunological reactions that frequently occur in response to adenovirus gene delivery in humans have been well documented for many years. The timing and dosage of virally delivered therapy is adjusted to minimize immune reactions. Adenovirus is used in more than one-quarter of the more than 372 gene therapy trials registered with the NIH. All gene-delivery vehicles have advantages and disadvantages, and none are viewed as ideal. Researchers at UCSF and elsewhere are investigating ways to develop improved techniques for getting therapeutic genes into patients’ cells. After Gelsinger’s death, the NIH carried out a comprehensive review of 70 adenovirus-based clinical trials involving more than 1,200 patients. The strategy used by the Pennsylvania researchers for getting genes into liver cells was first tested in cancer studies at UCSF by oncologist Alan Venook and surgeon Robert Warren, and later adopted by the Pennsylvania researchers to treat an entirely different liver disease.
Liver cells possess docking sites for adenovirus, further enhancing drug delivery, Venook notes. Efficient drug delivery is especially crucial in gene therapy for cancer, Venook explains, because it is important to get genes into a high percentage of cancer cells in order to stop tumor growth. "Every patient had some side effects—fevers, aches and pain," Venook said. "But there was no evidence of significant liver damage. We had no question about it being safe the way we were doing it." After patients receive their first dose of the therapy, the researchers now surgically implant a pump to deliver additional doses of the therapeutic genes. It is not yet clear if sufficient amounts of p53 is being produced or whether the gene therapy will be effective, but biopsies taken at the time of surgery reveal that the gene is being taken up by liver cells, Venook says. The use of adenovirus to deliver OTC to the liver, as was attempted in the Pennsylvania study, "makes perfect sense," Venook says. In comparison to gene therapy for cancer, fewer cells would need to incorporate and turn on the gene in order to produce a therapeutic amount of the needed enzyme. However, Venook theorizes that Gelsinger, due to a worsening of his liver disease, may have been compromised in his ability to metabolize the waste byproducts of an adenovirus-induced immune response. Because the trials use a similar dosing of adenovirus and the same route of drug administration as were used in the Pennsylvania trial, last October the FDA placed a "clinical hold" on two of the UCSF research team’s cancer treatment studies—prohibiting new patient enrollment—in order to again review data from the earlier Phase I trial. One of the studies that was put on hold is a multi-center Phase II trial of the same therapy, sponsored by Schering-Plough. The second is a Phase I study, also sponsored by Schering Plough, in which the gene therapy is used to target primary liver tumors. Warren went to the NIH in December to present findings during a meeting conducted by the agency’s Recombinant DNA Advisory Committee, which oversees all gene therapy trials at institutions receiving NIH support. Robert Consalvo, director of external affairs for Schering Plough, notes that 61 patients had already received p53 gene therapy through hepatic artery delivery to the liver at the time the trials were put on hold. The FDA lifted the hold on December 15, according to Consalvo. An FDA spokesperson noted that no problems related to toxicity similar to what was observed in the Gelsinger case were seen in the Schering Plough trials. Shortly before the hold was lifted, on December 8, a front-page article in the Washington Post reported that the FDA had uncovered improprieties in the conduct of the Pennsylvania study, including failure to report treatment side effects and the inclusion of Gelsinger in the trial even though his ammonia levels had risen above what was permitted by the approved experimental protocol. Patients will once again be able to enroll in the liver tumor trials at UCSF, pending approval by UCSF’s Committee for Human Research (CHR) of a revised informed consent form that advises potential enrollees of the death resulting from adenoviral gene delivery in the Pennsylvania study. Gene Therapy at UCSF Continued
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Venook
and Warren designed their protocol to treat patients with liver cancer
or an inoperable liver metastasis of colon cancer. In phase I trials
to determine safety and therapeutic dose, they injected adenovirus harboring
a gene called p53 through a catheter into the hepatic arteries of 34
patients with inoperable liver metastasis in which this growth-controlling
gene was absent. Life expectancy for patients with this type of liver
metastasis is roughly one year.