Here's an article in today's WSJ about AAV vectors:
A Harmless Virus Shows Promise,
May Revive Hopes for Gene Therapy
By ROBERT LANGRETH
Staff Reporter of THE WALL STREET JOURNAL
An apparently harmless virus that's shaped like a soccer ball may give a
boost to the beleaguered field of gene therapy.
Since researchers began injecting patients with new genes to replace
damaged ones about a decade ago, their biggest challenge has been
devising a delivery vehicle that is safe, capable of bearing sufficient
quantities of healthy genes and able to target specific parts of the body.
Last year's death of a young man from Arizona, Jesse Gelsinger, in a
University of Pennsylvania gene-therapy experiment highlighted the
potential danger of one of the most commonly used means of delivery --
adenovirus, a genetically engineered form of the cold virus. Attacked by
the body's immune system, adenovirus causes side effects that are usually
temporary flu-like symptoms. In the Gelsinger case, however, the side
effects fatally crippled the patient's lungs.
Mr. Gelsinger's death brought about a regulatory crackdown, including
stricter oversight of gene-therapy experiments at the University of
Pennsylvania and elsewhere. But it also sparked a race to create
gene-delivery vehicles that don't provoke an immune response.
A leading contender: the spherical
adeno-associated virus, known as AAV. A
number of biotechnology companies are
testing AAV, and some have had results that show promise for patients
suffering from a form of hemophilia.
This month, scientists with the Children's Hospital of Philadelphia, working
with the tiny biotech firm Avigen Inc. of Alameda, Calif., reported that two
of the first three hemophilia patients treated with minute quantities of
AAV-borne genes showed signs of improvement. The outcome suggested
that the virus was effective in getting the genes where they needed to be,
without major side effects.
Noting that the results are very preliminary, the Children's Hospital
scientists were excited nonetheless because the experiment was meant to
evaluate only the safety of the experimental therapy, not its effectiveness.
Elsewhere, Targeted Genetics Corp., based in Seattle, expects to begin
tests of AAV gene therapy involving patients suffering from a more
common form of hemophilia in a year. Cell Genesys Inc., Foster City,
Calif., is considering a similar AAV patient trial.
Scientists are focusing on hemophilia because it is viewed as one of the
most straightforward diseases to treat with gene therapy. People with
hemophilia are missing a gene needed to make one of two key proteins
needed for the blood to clot. Up to several times a week, they must inject
themselves with genetically engineered versions of the protein to prevent
spontaneous internal bleeding. But these medications are expensive and
often don't prevent crippling joint problems caused by internal bleeding.
With gene therapy, researchers are hoping to use AAV to replace this
defective gene with healthy new ones, so that patients can produce enough
clotting protein on their own.
This method doesn't have to be particularly efficient to work: If the new
genes produce a mere 5% of normal levels of clotting protein, it should be
enough to alleviate most symptoms. By contrast, when dealing with some
other diseases, most or all of the defective cells have to be corrected for
the treatment to work.
Avigen's hemophilia results "are tantalizingly encouraging," says Savio
Woo, president of the American Society of Gene Therapy. Still, the
hemophilia tests are far from a sure thing, and a failure could raise the
question of whether any gene-therapy breakthrough is possible using
currently available technologies. Moreover, even if the AAV concept
works, it may be limited to a handful of diseases and not be useful in
gene-therapy treatments targeting acute diseases such as artery blockage
or advanced cancer.
Some scientists argue that none of the existing gene-therapy technologies
are not yet ready for prime time. Merck & Co., for example, has spent
years trying to perfect a gene-delivery approach involving an improved,
second-generation adenovirus, but the company has decided against
patient tests soon. "We think there is a lot more work that needs to be
done" on improving gene-delivery and manufacturing techniques before
such tests begin, says Roger Perlmutter, who heads discovery research for
the drug giant.
Meanwhile, Chiron Corp., Emeryville, Calif., is continuing a hemophilia
gene-therapy trial -- one that doesn't use AAV -- but recently curtailed
much of its other gene-therapy research effort to reduce spending.
The first approach to gene therapy entailed removing defective cells before
the new genes could be put in. That was a logistical quagmire, and so
scientists started looking for ways new genes could be directly injected into
the body.
What they came up with was the adenovirus, a respiratory bug that causes
the common cold. With one injection in the lung, liver, or muscle, it can
quickly infect millions of cells.
By the early 1990s, many scientists across the country rushed to test this
method for terminal cancer, cystic fibrosis, and heart disease, using
genetically engineered adenoviruses that can't replicate inside the body.
But the downside of adenovirus soon became apparent. Besides the risk of
out-of-control side effects, there was the fact that the immune system
typically kills cells injected with new adenovirus-borne genes within several
weeks, thus limiting the treatment's effectiveness.
A handful of scientists recognized the problems of adenovirus early on and
focused their energies on AAV. One was Dr. Carter of Targeted Genetics.
Another was Avigen's founder, John Monahan. He created Avigen in 1992
after another gene-therapy company he had worked for showed no
interest in pursuing AAV gene therapy.
At the time, little was known about AAV, and there was great skepticism
about the method. All viruses are primitive in that they can't reproduce on
their own, requiring help from human or animal cells. But AAV is so
primitive that it cannot reproduce except in the presence of adenovirus --
hence the name adeno-associated virus. With this limitation, critics said it
would be impossible to manufacture AAV in commercial quantities.
Researchers at Avigen and Targeted Genetics spent years engineering a
way to manufacture AAV. They removed all the viral genes from its center,
leaving an empty viral shell to which a payload of genes to treat hemophilia
or cystic fibrosis could be added. Both companies now say they have
perfected production methods to make enough AAV for human testing.
Meanwhile, in the early 1990s, two academic researchers -- Katherine
High of Children's Hospital and Mark Kay of Stanford University School
of Medicine -- had independently become fascinated with treating
hemophilia patients by gene therapy. Both tried various approaches that
didn't work, and both eventually turned to AAV in frustration.
To their amazement, it worked. "I couldn't believe the data at first," recalls
Dr. Kay about the first time he used AAV to deliver blood-clotting genes
to lab mice. "It was the first time I have done an experiment that had
worked so well I couldn't see what the glitch would be going forward."
Last winter, teams led by Dr. High and Dr. Kay stunned scientists by
showing that a single series of AAV injections could essentially cure dogs
of hemophilia for months at a time. Today, two years after the initial
injections, these dogs are still producing high levels of blood proteins, with
no obvious side effects, Dr. High says.
The big question is whether the AAV method can work in people. Drs.
High and Kay have teamed up with Avigen to test AAV in patients with
hemophilia B, while Targeted Genetics is gearing up for human trials of
AAV gene therapy for the more common form of the disease, hemophilia
A.
Scientists are cautious because so many previous gene-therapy treatments
that worked in animals have failed in people. Although the Avigen results
seem promising for hemophilia patients, much larger trials are needed
before the effectiveness of AAV can be assessed with certainty.
Write to Robert Langreth at robert.langreth@wsj.com |
