Washington, DC (12/11/98)- The apparent success of a hemophilia gene
therapy experiment with dogs suggests the chances are good for similar success
in humans, report researchers.
Scientists
at The Children's Hospital of Philadelphia conducted an experimental protocol
involving dogs with a genetic defect predisposing them to develop hemophilia
B, a blood clotting disorder. Functional genes capable of producing the clotting
factor known as Factor IX were attached to an adeno-associated
virus vector and injected into
the leg muscles of the animals. The theory was that the genetically modified
virus would carry the missing gene to muscle cells, which in turn would take
up the gene and begin producing the clotting factor and releasing it into
the blood stream.
Sure
enough, the treatment produced lasting improvement in the animals. After
the gene therapy, blood-clotting times dropped from more than an hour's time
to 15 to 20 minutes. Normal clotting time in healthy animals is about six
minutes. It took about two months for the genes to maximize expression of
the missing protein. The researchers were encouraged to find that expression
levels remained stable for more than a year after the one-time treatment.
Moreover, no side effects or limiting immune responses occurred as a result
of treatment.
"The gene transfer strategy that we used resulted in sustained expression
of Factor IX at levels adequate to show improvement in two different blood
coagulation assays. Many gene transfer strategies that seemed promising in
mice failed to show efficacy in large-animal models. However, our success
with large animal models here increases our expectation that similar effects
may be seen in humans," said Katherine High, M.D., Director of Research of
the Hematology Division at The Children's Hospital.
A team of researchers
at Stanford University School of Medicine reported similar findings with a
slightly different approach. The researchers infused the Factor IX gene into
the blood vessels leading to the liver, first in mice, then in dogs. This
approach improved blood clotting in the hemophiliac animals for up to 17 months
in mice and for up to eight months in dogs.
"This is something
that we've worked out in the lab that has a high potential of working in people,"
said Mark Kay, MD, PhD, associate professor of pediatrics and genetics, director
of Stanford's program in human gene therapy.
Hemophilia is one of a small number of diseases
that are caused by a single, known genetic defect. This makes it an ideal
candidate for gene therapy approaches. Current treatments for hemophilia involve
intravenous infusions of expensive versions of missing clotting factors into
the bloodstream. Some of these blood products are derived from pooled blood,
while others are produced using recombinant DNA technology. Researchers would
like to avoid using factors derived from blood banks because of a risk of
transmitting disease including hepatitis and HIV.
Both teams are
now collaborating to move the research along to clinical trials for human
hemophilia B. They have already
filed an application with the Food and Drug Administration to begin the first
phase of clinical trials in 10 to 20 adult patients with hemophilia B.
The research appears in the January 1999 edition
of the journal Nature Medicine.
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