A YEAR after 18-year-old Jesse Gelsinger died following experimental gene
therapy, researchers are beginning to understand what went wrong. Their work may
help to prevent similar tragedies in the future.
Savio Woo of the Mount Sinai School of Medicine in New York opened the
conference by recounting how Gelsinger died after he was injected with an
adenovirus carrying a gene to treat his liver disorder. The incident sent shock
waves through the field, and similar trials were quickly halted.
Federal agencies criticised the leader of the trial, James Wilson of the
University of Pennsylvania, for not reporting adverse reactions in other
patients, for example
(快猫短视频, 18 December 1999, p 9).
But during the investigation, the National Institutes of Health鈥檚 Recombinant DNA
Advisory Committee learned that many other researchers had also failed to notify
them of complications in gene therapy trials.
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The manner of Gelsinger鈥檚 death took scientists by surprise in a number of
ways. Although the virus was injected directly into his liver, it infiltrated
several other organs as well. And while liver inflammation was considered the
most likely side effect, Gelsinger died from a widespread inflammatory reaction.
Closer examination showed his blood had high levels of IL-6, a protein that
promotes inflammation.
Now Wilson and his colleagues have done experiments in mice and monkeys to
help them understand what went wrong. They found that in both animals, the
infused virus left the liver and reached high levels in the spleen, lymph nodes
and bone marrow. Even within the liver, the virus tended to accumulate in the
Kupffer cells, which interact with the immune system, rather than in the main
kind of liver cell, hepatocytes鈥攚hich were the intended targets.
At least one of these unintended hosts contributed towards inflammation.
Spleen cells in mice treated with the modified adenovirus produced IL-6 within
hours. 鈥淭hey were cranking out this protein even without us tickling them to do
that,鈥� says Wilson. 鈥淯nfortunately, until we saw this reaction in the human, we
didn鈥檛 know what to focus on in the mouse or monkey.鈥�
Wilson thinks that altering the viruses that deliver genes so they interact
less with cells that release IL-6 and other immunostimulatory molecules could
make therapy much safer. Following Wilson鈥檚 talk, Woo urged his colleagues to
take these lessons to heart: 鈥淲e all need to learn a lot of science from this
patient,鈥� he said.
