Cocktails of genes & neurotrophics promising
Gene Therapy Effective in Primate Models
of Parkinson's Disease
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WESTPORT, CT (Reuters Health) Oct 27 - Lentiviral
delivery of the gene for glial cell line-derived
neurotrophic factor (GDNF) improved markers
of Parkinson's disease (PD) in two rhesus
monkey models, according to a report in the
October 27th issue of Science.
GDNF has potent trophic effects on the dopaminergic
nigral neurons implicated in PD, but intraventricular
administration of GDNF failed to improve
parkinsonian symptoms in one PD patient.
The authors attribute that failure to ineffective
delivery of GDNF.
Dr. Jeffrey H. Kordower from Rush Presbyterian-St.
Luke's Medical Center in Chicago and an international
team of researchers examined whether lentiviral
delivery of GDNF (lenti-GDNF) could reverse
the changes associated with nigrostriatal
degeneration in two different rhesus monkey
models.
In an aged monkey model, lenti-GDNF injection
resulted in intense GDNF immunoreactivity
within the striatum, as well as anterograde
transport of the trophic factor along its
projection pathways, the authors report.
Moreover, several markers of dopaminergic
function were increased after lenti-GDNF
delivery.
In young rhesus monkeys rendered hemiparkinsonian
by unilateral injection of MPTP, performance
as measured by a modified parkinsonian clinical
rating scale improved during the 3-month
period following lenti-GDNF injection, the
researchers note. Most lenti-GDNF-treated
animals also improved their performance on
an operant hand-reach task. Control monkeys,
however, experienced no such changes in performance.
Post-mortem studies confirmed the enhanced
expression of GDNF signal in the caudate
nucleus, putamen, and substantia nigra of
lenti-GDNF-treated monkeys, but in none of
the control animals, the report indicates.
Tyrosine hydroxylase-positive fibers throughout
the nigrostriatal pathway were also enhanced
by lenti-GDNF treatment.
Two young adult rhesus monkeys sacrificed
8 months after lenti-GDNF injection continued
to show enhanced GDNF immunoreactivity in
the area of injection, the investigators
observe.
"Our study demonstrates that delivery
of GDNF cDNA into the nigrostriatal system
using a lentiviral vector system can potently
reverse the structural and functional effects
of dopamine insufficiency in nonhuman primate
models of aging and early Parkinson's disease,"
the authors conclude.
These findings indicate that "lentiviral
delivery of GDNF may provide potent clinical
benefits for patients with PD," they
add. "For lenti-GDNF therapy to be a
practical clinical approach, studies determining
the regions of GDNF delivery critical to
reverse progressive nigrostriatal degeneration
are needed."
"Cocktails of genes encoding a medley
of neurotrophic factors, delivered by safe
inducible vectors to target areas in the
brain and spinal cord, hold promise as a
treatment not only for PD but also for an
entire spectrum of other central nervous
system disorders," suggests Dr. Lars
Olson from Karolinska Institute in Stockholm,
Sweden in a related commentary.
Science 2000;290:721-724,767-773.