Katherine High, M.D., of The Children's Hospital of Philadelphia, Addresses
           Progress and Prospects for Genetic Treatment of Disease

    PHILADELPHIA, Feb. 28 /PRNewswire/ -- Researchers are advancing on the
goal of successfully using gene therapy to treat the crippling bleeding
disorder hemophilia, according to Katherine A. High, M.D., a hematologist at
The Children's Hospital of Philadelphia and one of the world's preeminent
experts in the field of gene therapy. Dr. High is currently involved in
clinical trials seeking to improve blood clotting in patients with hemophilia
B by using a genetically engineered virus to deliver beneficial genes.
Dr. High delivered a Science Innovation Lecture to the American Association
for the Advancement of Science recently in Boston.
    "While current clinical studies look promising," she said, "the experience
of the first decade of gene therapy, which began in 1990, has led researchers
to temper their expectations of quick results. The practical problems of
delivering therapeutic genes, efficiently producing clinical benefits, and
avoiding toxic side effects have often disappointed researchers and patients
with the disease, both of whom are hoping to find a cure or treatment."
    Gene therapy is a novel form of disease treatment because the active agent
is a sequence of DNA instead of the proteins or small molecules that are
currently used as drugs, said Dr. High.  Hemophilia is among the diseases that
lend themselves more readily to gene therapy because even small increases in
the clotting factor that is deficient in a patient's blood can improve the
disease from a severe form to a much milder form, and result in great
improvements in quality of life for hemophilia sufferers.
    Currently, patients with severe hemophilia receive frequent, intravenous
infusions of manufactured engineered clotting factor.  However, these
treatments are expensive and inconvenient, and sometimes stimulate an immune
reaction that neutralizes the benefits of treatment.  Because a single
defective gene causes hemophilia B, gene therapy involves inserting a normal
version of the gene, which makes a normal protein -- the clotting factor. (The
two common forms of hemophilia are hemophilia A and hemophilia B. While
symptoms of both forms are clinically identical for patients, hemophilia A
affects clotting factor VIII, while hemophilia B affects factor IX.)
    Dr. High's involvement in gene therapy began with her earlier pioneering
investigations of the genetics of hemophilia, including her studies in mice
and dogs. The animals have served as well-understood models for studying
hemophilia and possible gene therapies. "An advantage hemophilia has as a
target for gene therapy," she added, "is that we can more thoroughly test the
effectiveness of promising approaches in small and large animals before
proceeding to human trials." In 1999, her team announced that gene therapy
achieved long-term improvement of naturally occurring hemophilia in dogs. That
work produced levels of clotting factor in the dogs that would be therapeutic
if achieved in humans.
    Dr. High's approach uses a genetically engineered virus called adeno-
associated virus (AAV) as a vector, or delivery vehicle, to carry genes into a
patient's cells. In partnership with Stanford University School of Medicine,
Children's Hospital carried out early-stage clinical trials in adult patients
with hemophilia B. In those trials, the researchers showed in 2000 that the
introduced gene induced patients' cells to produce clotting factor IX, the
blood-based protein that is highly deficient in patients with the severe form
of the disease. There were no serious side effects of the treatment, which
delivered the gene by direct injection into the patients' leg and arm muscles.
    Last year, The Children's Hospital of Philadelphia and Stanford
University, in conjunction with the biotechnology company Avigen, Inc., began
clinical trials that infuse the gene therapy product directly to patients'
livers. Earlier animal studies by the teams at both hospitals suggested that a
liver-directed approach, aided by improved genetic engineering of the gene
package, could more efficiently produce clotting factor from a given amount of
gene product. "Our goal is to determine if we can achieve the same therapeutic
results for human patients that we found in hemophilic dogs," she said.
    The path of the hemophilia clinical research has not been free of
obstacles. The liver-directed gene therapy trials were halted briefly when
portions of the AAV vector were found in a patient's semen. This result did
not persist beyond a few weeks, and new safety studies indicated that gene
transfer probably does not occur in the sperm cells. Gene therapy researchers
must strictly avoid altering the DNA of germ line cells, such as sperm, to
avoid the potential of transferring unknown effects to a patient's children.
In response to the safety studies, the U.S. Food and Drug Administration
permitted the liver-directed clinical trial to resume in December 2001.
    Both of the hemophilia B gene therapy clinical trials have been
collaborations among Dr. High, geneticist Mark Kay, M.D., Ph.D., of Stanford
University School of Medicine and Avigen, Inc., which is based in Alameda,
Cal.  Catherine S. Manno, M.D., is the principal investigator of the trials at
Children's Hospital, while Bert Glader, M.D., Ph.D. is the principal
investigator at Stanford.
    The hemophilia gene therapy trials have been closely watched because they
may represent a milestone in genetic-based medicine, with implications for
many other genetic and acquired diseases. Dr. High adds that only 20 years
ago, drugs based on recombinant technology, such as insulin, growth hormone
and clotting factors, seemed a daunting challenge for medical researchers, but
are now standard weapons in physicians' toolboxes. "Advances in research and
technology suggest that gene therapy will also become a successful and
powerful method for treating human disease," she added.
    Founded in 1855 as the nation's first pediatric hospital, The Children's
Hospital of Philadelphia is ranked today as the best pediatric hospital in the
nation by a comprehensive Child Magazine survey. Its pediatric research
program is among the largest in the country, ranking second in National
Institutes of Health funding.

    Contact: John Ascenzi
             215-590-7332
             Ascenzi@email.chop.edu


                    MAKE YOUR OPINION COUNT -  Click Here
               http://tbutton.prnewswire.com/prn/11690X34349628

SOURCE  The Children's Hospital of Philadelphia