Gene Therapy to Treat Disease - Biotechnology and Your Health: Pharmaceutical Applications - page 92

trials using a retroviral vector to treat X-SCID and convened an
expert committee to review the data and give advice as to whether to
make the hold permanent. The committee suggested that the FDA
permit the use of such vectors only for X-SCID patients with no other
treatment option, such as a bone marrow transplant from a relative.
This failure was another blow for gene therapy. The unexpected
problem has made researchers focus on better understanding and con-
trolling where a payload gene is inserted in the target cells' genome.
Death of a Gene Therapy Volunteer
In 1999, Jesse Gelsinger, an 18-year-old from Arizona with a
mild form of an inherited deficiency of the liver enzyme ornithine
transcarbamylase ( OTC ), died during a gene clinical trial at the
University of Pennsylvania, triggering a tightening of the review
process and oversight of such research. He was enrolled in an early
stage trial to determine the safety of treating OTC deficiency by
delivering an adenovirus vector that carried the gene for OTC to the
liver. Severe forms of OTC deficiency can result in brain swelling,
coma, and death soon after birth, but mild forms can be controlled
with changes in diet and with drug treatment.
Although Gelsinger had the mild form of OTC deficiency,
he volunteered for a University of Pennsylvania trial to test the
safety and efficacy of increasing doses of an OTC vector because
he wanted to help severely affected newborns. He died four days
after the vector was injected into a blood vessel in his liver. An
autopsy showed that he died of a severe inflammatory response
to the adenoviral vector, which led to a blood reaction that caused
most of his organs to shut down.
The media coverage of Gelsinger's death was extensive, and
investigations by federal agencies discovered several serious lapses
in following the rules for conducting human trials. The University
of Pennsylvania clinical gene therapy unit had failed to disclose to
university safety monitors, to federal regulators, and to Gelsinger