Parkinson's Disease; Gene Therapy for
Parkinson's Disease Demonstrated in Rat
Model
January 20, 1998
Gene Therapy Weekly via Individual Inc. : Midbrain injection of recombinant
adeno-associated virus (rAAV) encoding rat glial cell line-derived
neurotrophic factor
(GDNF) protects rats in a degeneration model of Parkinson's disease (PD).
GDNF is a potent neurotrophic molecule for nigral dopaminergic neurons.
Currently,
there is no treatment for PD that impedes the progress of the disease. A
trophic
molecule capable of halting on-going degeneration of the dopaminergic
neurons of the
substantia nigra (SN) would be valuable for the treatment of PD.
To take advantage of the dopaminergic neurotrophic activity of GDNF for
PD, R.J.
Mandel and colleagues from Cell Genesys, Inc., Foster City, California,
addressed
several protein delivery issues using a somatic gene therapy approach in
the Sauer and
Oertel (Neurosciences 1994;59:401-15) progressive 6-hydroxydopamine
(6-OHDA)-induced degeneration model of PD in rats (" Midbrain Injection of
Recombinant Adeno-Associated Virus Encoding Rat Glial Cell Line-Derived
Neurotrophic Factor Protects Nigral Neurons in a Progressive
6-Hydroxydopamine-Induced Degeneration Model of Parkinson's Disease in
Rats, "
Proceedings of the National Academy of Sciences, December 9,
1997;94(25):14083-8).
"The present study uses a viral vector derived from the nonpathogenic human
parvovirus, adeno-associated virus (AAV), to deliver rat GDNF (rGDNF)
directly to the
nigra by using the Sauer and Oertel progressive degeneration model in
rats," stated
Mandel et al. "The data demonstrate that the levels of rGDNF produced
after intranigral
injection of rAAV-rGDNF are sufficient to spare nearly 100 percent of the
neurons from
a 6-OHDA lesion, which normally induces 50 percent nigral cell loss, and
that rGDNF
gene expression persists for at least 10 weeks."
In the striatal 6-OHDA lesion model, nigrostriatal dopaminergic cells die
progressively
between one and four weeks after lesion initiation. Mandel et al.
demonstrated that
GDNF delivered near the SN via rAAV injections was able to protect nigral
dopamine
(DA) cells from 6-OHDA-induced degeneration when administered three weeks
before
6-OHDA.
"The data regarding a GDNF-based gene therapy presented herein suggest that
therapeutic nigral protein delivery via in vivo injection of an
appropriately safe vector
may be a viable strategy for the treatment of PD, " concluded Mandel et
al. "The present
data indicate that expression of relatively low levels of GDNF are
sufficient to provide
significant protection against 6-OHDA-induced nigrostriatal degeneration.
"Thus, vector-mediated delivery of GDNF may fulfill most of the
requirements necessary
to qualify as a therapeutic strategy for PD: 1) biological efficacy, 2)
long-term
expression, and 3) lack of toxicity coupled with a wide therapeutic window."
The corresponding author for this study is R.J. Mandel, Department of Gene
Therapy
Applications, Cell Genesys, Inc., 342 Lakeside Drive, Foster City,
California 94404.
- by Michelle Marble
John Stafford -- http://pw2.netcom.com/~johnws/index.html --
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