Atlanta, GA (11/10/99)- The report of the first fatality associated
with an experimental gene therapy treatment should serve as a reminder that
considerable research remains to be done before the safety and efficacy of
these therapies can be demonstrated, note researchers in the field.
University of Pennsylvania researchers reported the death recently of an
18-year-old patient, Jesse Gelsinger, who had been receiving an experimental
gene therapy to correct a single gene enzyme deficiency called ornithine transcarbamoylase
deficiency. He had received the highest dose of a the gene/viral vector combination
allowed in the protocol. Within 24 hours of receiving the gene therapy, he
developed fever, nausea and back pain. He subsequently developed respiratory
distress syndrome and died. While the cause of death is still being investigated,
researchers believe it was probably some sort of immune or allergic reaction
to the adenoviral
vector used to deliver the gene.
University of Pennsylvania case brought increased scrutiny to other ongoing
gene therapy clinical trials. The Washington Post accused two of the leading
researchers in the field, Dr. Jeffrey Isner at Tufts University and Dr. Ron
Crystal at Cornell University of concealing information about several deaths
that had occurred in trials they were involved in. Both researchers contested
the charges, saying that all regulatory requirements were met.
left: Dr. Jeffrey
Dr. Isner has been a pioneer in the use of VEGF gene therapy for the treatment
of peripheral vascular disease, a disease in which clogging of the leg arteries
interferes with walking. VEGF (vascular endothelial growth factor) is a naturally
occurring protein that encourages the growth of new blood vessels. It is being
investigated in several trials as a potential treatment for peripheral vascular
and cardiovascular disease. Dr. Isner has reported promising data from his
clinical trials showing significant improvements in patients ability to walk
after receiving the treatments. In a press conference at the annual meeting
of the American Heart Association, Dr. Isner reported that the two deaths
that had occurred in VEGF clinical trials were not related to the gene therapy,a
conclusion shared by the FDA. These patients are very sick to begin with,
and can only be enrolled in gene therapy trials when all other treatments
have failed. Moreover, Dr. Isner's work does not involve the use of an adenoviral
vector. Rather, his studies have all used naked DNA delivered directly to
the patients diseased blood vessels.
Dr. Ron Crystal's work does involve
the use of adenoviral vectors in patients with advanced cardiovascular disease.
Dr. Crystal maintains that none of four deaths in the trials he directed were
caused by the gene therapy. In the first place, these patients are very sick
to begin with, he told a symposium during the AHA conference. In the second
place, the dose of adenovirus used in his studies is at least 1000 times less
than that used in the University of Pennsylvania case.
New Gene Therapy Approach Shows Promise
Researchers from Harvard University reported promising results with a new
gene therapy technique for treatment of peripheral vascular disease at the
American Heart Association meeting. Patients with this disease are currently
treated with surgery in which pieces of healthy vein are grafted to the diseased
area, restoring blood flow. The Harvard researchers wanted to know what would
happen if they first soaked the vein grafts in a solution containing DNA engineered
to inhibit clogging of the vessels.
"As many as half of all bypass surgeries fail five to ten years after the
operation because the vessels used to bypass the clogged arteries become blocked
themselves. Further research is needed, but this procedure could end up having
a major impact not only on long term success of all types of bypass surgery,
but also on the cost of treating graft blockages," says Michael J. Mann, M.D.,
Brigham and Women's Hospital.
Seventeen patients received the DNA-soaked vessels and sixteen patients had
conventional bypass surgery without the gene therapy. One year after treatment,
the patients who had received the gene therapy had less than half of the failures
of patients who received surgery alone. A failure was defined as the blockage
of the graft or a need for another procedure.
"These results are very encouraging and could represent a new treatment that
would vastly improve the long-term success rate of all bypass procedures,"
says study co-author Victor J. Dzau, M.D., professor of medicine at Harvard
Medical School and chief of medicine at Brigham and Women's Hospital, Boston.
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