FROM:  AScribe Newswire
 March 29, 2002 Friday 1:57 PM Eastern Time

HEADLINE: Rats With Partial Parkinson's Damage in Brain Show Complete
Functional Recovery After Gene Therapy

" GAINESVILLE, Fla., March 29 [AScribe Newswire] -- Scientists report
this week
they have demonstrated that the injection of two corrective genes into a
specific brain region generated significant restoration of normal limb
movement
in rats with a chemical-induced form of Parkinson's disease.

   The findings - by a team of researchers from the University of Florida
in
Gainesville and Lund University in Lund, Sweden - are published in the
current
online version of the journal of the Proceedings of the National Academy
of
Sciences.

   Neuroscientists Anders Bjorklund of Sweden and Ronald Mandel with UF
said the
strategy that proved effective in the rodents is not a cure for
Parkinson's
disease, but is expected to lead to a better method for delaying and
controlling
symptoms of the progressively disabling condition. About 1 million
Americans are
affected by Parkinson's disease, which occurs most often between the ages
of 65
and 90.

   "We found that the simultaneous delivery of two selected genes,
coupled with
a powerful gene-activating agent, works like a pump to prime the
production of
L-dopa, which is then converted into dopamine by appropriate nerve cells
in the
brain," said Mandel, a professor of neuroscience with UF's Evelyn F.  and
William L. McKnight Brain Institute and the UF Genetics Institute.
Dopamine is
a neurotransmitter chemical that plays a lead role in coordinating limb
movements.

   Limb impairments were completely reversed in rats that had near-total
Parkinsonian lesions on only one side of the brain, meaning that some of
their
dopamine-producing cells remained intact. These partial lesions mimic the
kind
of damage [progressive death of L-dopa-producing cells] found in people
with the
disease, according to the scientists. Even in the rats with complete
destruction
of dopamine-producing cells, the delivery of gene therapy resulted in a
limited
amount of restored motor function.

   "Quite frankly, I was surprised by this successful outcome, since our
previous experiments in the same animal model failed to result in
restored motor
function," said Mandel.

   One key to success, he said, was to figure out how much L-dopa the
corrective
genes need to generate to produce long-lasting functional effects. "Our
team was
first to determine this critical threshold," he said.  The experiment
that
 helped the rats regain motor function involved a single injection of two
different genes, each packaged separately along with the selected gene
promoter
in a gene-transport molecule [vector]. Both genes code for enzymes
essential to
triggering production of L-dopa. Based on prior discoveries by Dr.
Bjorklund,
the researchers injected these genes into the striatal region of the
forebrain,
the destination point of dopamine-producing cells. When the injected
vectors
land in this area, they deposit their payload of genes, which are "turned
on" by
the gene-promoter [a selected segment of DNA] to initiate L-dopa
production.

   Mandel said videotapes of the rats moving about in tall clear-glass
cylinders
provide the most visible demonstration of the spontaneous behavior
regained
after gene therapy. Initial tapes show healthy rats standing up and
exploring
the sides of the cylinder with their front paws while walking around on
their
hind legs. In the next tapes, taken after the induction of Parkinsonian
lesions,
the rats can be seen dragging one limp and rigid front paw while walking
around
and exploring their environment with the normal front limb. Then, in
videos
taken after gene therapy, the same rats demonstrate normal function of
both
front paws.

   The vector used for the studies was the apparently harmless
adeno-associated
virus, or AAV, developed at UF as a gene carrier in the early 1980s by
Nicholas
Muzyczka, an eminent scholar with the UF Genetics Institute and a
co-researcher
in the Parkinson's study, and Dr. Kenneth Berns, molecular biologist. UF
holds
the patent on use of the AAV vector in the brain.  Mandel said the
effectiveness
of gene therapy in the Parkinsonian rats generates hope that the therapy
can
eventually be applied in humans, with the potential to double the time a
person
with Parkinson's disease will respond well to standard medications.
Typically a
patient responds well to medication for three to five years, but the
beneficial
effects gradually diminish because side effects begin to reduce the
therapeutic
value of the drug.

   "Before the U.S. Food and Drug Administration may approve this type of
therapy for human testing, we have to solve a critically important
problem,"
said Muzyczka, who also is co-director of the Powell Gene Therapy Center
at UF.
"The gene promoter we're now using stays turned on continually, resulting
in
continuous dopamine production unlike the way our bodies adjust this
production
to meet our needs. We need a gene regulator that functions more like a
rheostat
to turn dopamine production on and off as needed to sustain normal limb
movement."

   UF researchers now are investigating several promising candidate gene
promoters. Muzyczka said he is optimistic that human application may
occur in
about five years.

   "We anticipate gene therapy will offer a way to help patients with
Parkinson's disease live many years longer free of disabling symptoms,"
Mandel
said. "There is no reason why gene therapy couldn't also be given in
addition to
medication and surgical procedures such as pallidotomy, or deep-brain
stimulation."

   The research reported in the journal results from more than four years
of
studies involving nearly 200 rats. Funding came from the Swedish Medical
Research Council, and the Knut and Alice Wallenberg Foundation."

CONTACT:
For more information contact: Arline Phillips-Han,
352/392-9542, E-mail: [log in to unmask]

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