Death in a Gene Therapy Trial - What Went Wrong?

The death of an Arizona teenager on September 17th, 2000 in a University of Pennsylvania sponsored gene therapy clinical trial brought the decision-makers in the viral gene therapy field to Washington, D.C. for a meeting of the recombinant DNA advisory committee (RAC).  At issue was the future of gene therapy clinical trial design and the implementation of clinical protocols.  On the hot seat was the University of Pennsylvania Institute for Human Gene Therapy.

Jesse Gelsinger , an 18 year old Arizona man, suffered from an inherited disorder called deficiency of ornithine transcarbamylase (OTC).  OTC deficiency is a genetic error, which effects urea metabolism and effects one out of every 30,000 children.  OTC is the second enzyme in the urea cycle and catalyzes the conversion of ornithine and carbamoyl phosphate to citrullinne.  The urea cycle is a pathway in which nitrogen, a waste product of protein metabolism, is removed from the blood, converted to urea and removed from the body in urine.  In urea cycle disorders the nitrogen accumulates in the form of ammonia and is not removed from the body where it causes irreversible brain damage and/or death.  OTC has been localized to Xp21.1 and manifests at birth in males and during childhood in females. OTC deficiency is managed by a diet low in protein and high in calories. The level of nitrogen is controlled by converting the nitrogen to a secretable compound by use of sodium benzoate and sodium phenylacetate, and also by dialysis.

The E1-deleted, E2A-temperature-sensitive adenovirus vector expressing the human OTC enzyme was infused directly into the hepatic vein over two hours.  Jesse was the 18th patient enrolled in the study and was one of two patients that received the highest dose in the study.  The maximum dose was three hundred times the amount given to the initial patients.  The other patient received the maximum dose just before with no adverse side effects.

Researchers unexpectedly found significant amounts of the adenovirus vector in the lymph nodes, spleen, and bone marrow. They also found Jesse's bone marrow to be stem cell depleted. This has led some scientists to believe that an existing condition might have been responsible for the rapid and extreme immune reaction. Other scientists believe that administering the vector into the hepatic artery is the culprit.

The cause of death, as first reported in the Philadelphia Inquirer, appears to be a buildup of IL-6 (Jesse's level was 5 times that of other subjects), which caused adult respiratory distress syndrome (ARDS).  The peculiarity of the death is that IL-10, which has been shown to suppress IL-6 production (Dokter, Koopman, and Vellenga 1996), and also TNFalpha production (Pollice, et al 1998), was also elevated but was not effective in bringing down the level of IL-6 (there was obviously some problem with Th1 to Th2 cytokine balance or regulation).  The other patient that received the highest dose of adenovirus in the trial also had spikes of IL-6 and IL-10, but the IL-6 values returned to normal whereas for some unknown reasons Jesse's did not.

In the opinion of the Food and Drug Administration (FDA), there were many errors in judgment during the implementation of this clinical trial, although it is unclear if any of them could have a causative relationship to the ARDS.  When Jesse entered the trial he was not eligible.  His liver function was abnormal.  Although the liver function was brought within range approximately 2 weeks before dosing, the investigators were reported to have changed their own inclusion criteria without proper FDA approval.  In addition, the trial members were not properly informed of the pre-clinical data. When patients enter a trial such as this they sign what is called an informed-consent form. This form is supposed to contain detailed information about the procedure as well as certain pre-clinical data.  The informed-consent form should have stated that primates had died after receiving a similar treatment, although these primates received 50 times the highest dose administered in the phase I/II human trial. Finally. The protocol was reportedly violated in that two other patients experienced grade III toxicity, which should have led to stopping the trial at a lower dosage level.  The trial is now halted, along with any other treatment utilizing this high of a vector dose.  This also calls into question the use of adenovirus when delivered systemically (IV).  Most adenoviral trials in progress utilize injection directly into the tissue of interest.

Several years ago many people hyped gene therapy to be the next great medical advance with the capability to cure most major inherited diseases and offer unique ways to deliver therapeutic proteins.  To date, over 4,000 people have participated in over 350 gene therapy clinical protocols (25% with adenovirus), with at best limited success.  Of the people treated by gene therapy, this is reportedly the first death to occur as a direct result of the therapy.

At this point in time adverse reactions are not always made public.  They must be reported to the FDA, but they are considered proprietary information.  Only trials receiving federal funding are required to report adverse effects to the RAC and are made public.  One would think such negative publicity would cause investors to flee the gene therapy industry, however that appears not to be the case.  A quick survey of stocks in viral and non-viral gene therapy companies have increased in value by 64% since the news first broke in the Washington Post on September 29th, 1999.  This has been consistent with an overall surge in biotechnology stocks in the last 1-2 months, with genomics stocks leading the way (the AMEX biotechnology index has risen ~22% since November 30th, and the NASDAQ biotechnology index has risen ~38% since September 29th).

Hopefully, a couple of items should come out of this tragedy. A clear definition of the responsibilities of the RAC and FDA with a distinct delineation between the two organizations. Also, there is a need for a clear policy for reporting gene therapy trials which includes full disclosure of adverse effects while protecting corporate intellectual property and patient confidentiality