in a Gene Therapy Trial - What Went Wrong?
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
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
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