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PR for HIV Vector Use from NY Times

        January 19, 1999
        Scientists Enlist H.I.V. to Fight Other Ills

        By ANDREW POLLACK

            SAN DIEGO, Calif. -- In a bold but potentially frightening
effort to turn one of the world's most
            virulent killers into a cure, scientists and biotechnology
companies are trying to tame the AIDS
        virus and harness it to treat disease. 

        The scientists say they have stripped the human immunodeficiency
virus of its ability to cause disease,
        while leaving intact its ability to infect human cells. Such a
crippled virus, they say, could be used to
        deliver genes into human cells for gene therapy. 

        Several university scientists and biotechnology companies hope to
begin
        clinical trials using the modified HIV viruses to carry genes that
they hope can
        be used to treat diseases such as cancer and hemophilia. At least
one attempt
        will even be made to use the modified HIV, the virus that causes
AIDS, to treat
        AIDS itself. 

        "It would be ironic to cure AIDS with the AIDS virus," said Dr.
Inder M.
        Verma, a professor at The Salk Institute for Biological Studies
here, who has
        pioneered the effort to harness HIV for gene therapy. But he added,
"There is a
        saying that diamond cuts diamond." 

        Verma and others involved in such research say it is virtually
inconceivable that
        anyone treated using the crippled HIV could get AIDS as a result.
The gene
        carrier, which is known as a vector, not only is missing the HIV
genes that cause
        disease but also lacks the ability to replicate and spread in the
body, they say. 

        But some experts note that in rare instances, disabled viruses can
recombine with genetic material
        from other viruses or from the person's own cells to regain the
ability to replicate. And even if the
        actual risks are low, patients are likely to be afraid, and
regulators cautious, about injecting patients
        with even a modified AIDS virus. 

        "It's a human pathogen that's caused a terrible pandemic, so one
needs to be thoughtful about using it,
        even in a crippled form," said Dr. Eric Poeschla, an assistant
professor of medicine at the University
        of California at San Diego. 

        The Food and Drug Administration, whose approval is required for
gene therapy trials, agreed.
        "There are a number of scientific questions and safety issues to be
addressed before any of that could
        go forward," Dr. Philip Noguchi, the director of the agency's
division of cellular and gene therapies,
        said in an interview. "We don't quite know what we should be
concerned about because the biological
        understanding has not been developed yet." 

        The National Institutes of Health held a meeting of experts last
March to explore the use of HIV
        vectors for gene therapy, which involves inserting genes for a
particular function into a patient's cells.
        But Noguchi said a wider, more open public hearing would be held
before his agency would consider
        approving the first such trial. "The public hasn't really weighed
in with its own opinion," he said. 

        It is the very infectiousness of HIV that makes it attractive for
gene therapy, which so far has not lived
        up to its expectations. People with hemophilia, for instance, have
an inherited genetic defect that
        prevents them from making a crucial protein needed for blood
clotting. But if enough of the patient's
        cells could be provided with the proper gene, the patient could
manufacture his own blood clotting
        factor. 

        To deliver the genes of interest, scientists generally insert them
into debilitated viruses, because
        viruses spread by delivering their own genetic material into the
cells of their target. But gene therapy,
        which has been tried for about a decade, has in general failed
because it has been impossible to
        deliver enough of the genes, and get them to work long enough, to
make enough of the required protein.

        In many cases the viral gene carriers are attacked and destroyed by
the body's immune system. Some
        of the viruses used so far allow for only transient production of
the protein because they do not
        incorporate the genes they carry into the chromosomes of the target
cells. 

        One of the most commonly used vectors, derived from mouse leukemia
virus, can deliver genes into
        chromosomes, where, it is hoped, they will operate for a long time.
But this vector can do this only
        when cells are dividing, making it difficult to treat diseases in
the brain, liver, heart and other organs
        in which cells divide rarely if at all. And a promising new vector,
based on adeno-associated viruses,
        appears safe and somewhat effective, but is limited in the size of
the genes it can carry. HIV, on the
        other hand, is both cunning at evading the body's immune defenses
and can carry large genes. Most
        important, it is one of a small class of viruses, known as
lentiviruses, that can incorporate genes into
        the chromosomes even of nondividing cells. 

        "Lentiviral vectors are really a new hope in the field of gene
therapy," said Dr. Philippe LeBoulch,
        assistant professor of medicine at Harvard University and chief
scientific officer of Genetix
        Pharmaceuticals Inc., a privately held Massachusetts company
planning to use HIV-based vectors in
        gene therapy. 

        Verma's lab has used the vector to incorporate genes into the
brain, liver, muscle, bone marrow and
        retinal cells of rats or mice. The genes seem to function for months. 

        Still, others say, it is not clear whether the HIV vectors will be
efficient enough to make gene therapy
        work. "They are still going to have to struggle to get genes into
people, even using an HIV vector,"
        said Poeschla of the University of California. 

        Besides being infectious, the AIDS virus has been extensively
studied, so that scientists know how to
        modify it. "We know every nucleotide down to the last base," Verma
said. 

        His laboratory's latest vector removes six of the nine genes in the
AIDS virus. One big change that is
        required is that of the virus' protein coat, which determines which
cells it can attach to. The AIDS
        virus mainly infects certain white blood cells known as T cells. So
scientists have replaced the HIV
        protein coat with that of a cattle virus that seems to be able to
infect many different types of human
        cells. 

        The only genes taken from the HIV itself to make the vector are
those that govern the process by which
        the viral genetic material is incorporated into the chromosome of
the target cell. These genes are put
        into cells known as packaging cells, which produce the actual
vectors. 

        The vectors themselves -- the particles that would be injected into
a patient -- contain the viral
        proteins needed to incorporate the therapeutic gene into the
patient's chromosomes, but they do not
        contain the genes that direct the creation of those proteins. So
after it incorporates the gene into one
        cell, the viral particle cannot go on to direct the cell to produce
more viruses. 

              Copyright 1999 The New York Times Company