AFTER the death of Jesse Gelsinger last year from the gene therapy that was
meant to cure his liver disorder, hundreds of previously unreported
complications in clinical trails of the procedure came to light. Gene therapy
seemed doomed.
But the setback is only temporary, says Inder Verma of the Salk Institute for
Biological Sciences in La Jolla, California. The problems did not stem from a
fundamental flaw in the technology itself, but from the way it was applied, he
says. 鈥淚n terms of basic science, we have done very well.鈥� According to Verma,
the key to the success of gene therapy, which may ultimately be used to treat
everything from cancer to haemophilia to diabetes, is finding a safe and
reliable way of carrying genes into patients鈥攊n scientific jargon, a good
vector.
One of the biggest obstacles to vectors is the human immune system. When
Verma鈥檚 group engineered a cold virus to deliver a gene that codes for factor
IX, a protein needed by haemophiliacs, the immune cells of the mice and dogs
they tested it on attacked both the virus and the foreign protein. Gelsinger鈥檚
death also seems to have involved a severe immune reaction. 鈥淔or me, the biggest
question is `What are the immunological challenges?'鈥� Verma says.
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The ideal gene therapy vector must meet three conditions. It must provoke
little or no immune reaction, infect both dividing and non-dividing cells, and
be easy to generate in large quantities in the lab. One potential answer, which
Verma first proposed in 1996, shocked many of his colleagues. 鈥淓veryone said `Oh
my God, AIDS virus, are you nuts?'鈥� he recalls. But he maintains that a
modified, pared-down form of HIV could fulfil all three of his criteria.
Already, Verma has shown that modified HIV can deliver a therapeutic gene to
haematopoietic stem cells, which generate the blood and immune cells. Some
vectors can only deliver genes to dividing cells, so these stem cells are hard
to infect because they divide so rarely. But Verma鈥檚 HIV vector had no trouble
transferring the gene for green fluorescent protein into cultured human
haematopoietic stem cells. For over 24 weeks, between 5 and 15 per cent of the
cells continued to generate the foreign protein (Science, vol 283, p 682).
Another promising new way to get genes into cells is the adeno-associated
virus, or AAV. It causes no known human disease, and genes transferred to
cultured cells this way are expressed for a long time. An AAV carrying the
factor IX gene has been given to three volunteers with haemophilia B. So far
none has shown ill effects, and two have been able to reduce their injections of
factor IX (Nature Genetics, vol 24, p 257). The only apparent drawback to AAV is
that it is difficult to produce in large quantities.
None of this will matter unless scientists can restore public confidence in
the technology. The problem, according to Verma, is that the successes in animal
research have been completely overshadowed by the failures in human trials. 鈥淲e
went too fast into the clinical trials. The enthusiasm hasn鈥檛 been borne out,鈥�
he says. But with a more cautious approach, he thinks gene therapy will prove
indispensable. 鈥淩arely comes a technology which can have such a vast impact on
public health,鈥� he says.
