03/29/2000
The Wall Street Journal
Page B1
(Copyright (c) 2000, Dow Jones & Company, Inc.)
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 Barrie 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.
---
Delivering New Genes into the Body
For gene therapy to be successful, researchers need a safe and
efficient way to deliver healthy new genes into the human body. One of
the more promising new vehicles is a genetically engineered version of
AAV, a harmless virus. Here is how AAV gene therapy would work for
treating hemophilia.
1 In the lab, scientists first remove the viral genes from the AAV
virus.
2 In place of the viral genes, the human gene -- in this case a gene
that produces blood-clotting proteins -- is inserted inside the virus.
3 The gene-bearing viruses are delivered into the leg muscle or
liver. The viral shell protects the clotting gene and helps transport
it to a cell.
4 Once inside a muscle cell, if all goes well, the new genes will
eventually start producing blood-clotting proteins, alleviating the
symptoms of the disease.
Sources: Avigen; WSJ research |
