Recombinant adeno-associated viral vector-mediated glial cell line-derived neurotrophic factor gene transfer protects nigral dopamine neurons after onset of progressive degeneration in a rat model of Parkinson's disease.
Previous work has demonstrated that viral vector mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF), when administered prior to a striatal injection of the specific neurotoxin, 6-hydroxydopamine (6-OHDA), can protect nigral dopamine (DA) neurons from cell death. When considering gene therapy for Parkinson's disease (PD), vector delivery prior to the onset of neuropathology is not possible and chronic delivery will likely be necessary in a GDNF-based PD therapy. The present study was undertaken to determine if GDNF delivered via a recombinant adeno-associated viral vector (rAAV) could affect nigral DA cell survival when initiated just after the administration of striatal 6-OHDA. The onset of rAAV-mediated GDNF transgene expression near the substantia nigra was determined to begin somewhere between 1 and 7 days after the 6-OHDA injection and subsequent vector administration. The cell survival data indicate that rAAV-GDNF delivery results in a highly significant sparing of nigral DA neurons. These data indicate that a single delivery of rAAV encoding GDNF is efficacious when delivered after the onset of progressive degeneration in a rat model of PD.
Mandel
R J
RJ
Department of Neuroscience, University of Florida Brain Institute, University of Florida College of Medicine, Gainesville 32610-0244, USA. rmandel@ufbi.ufl.edu
Snyder
R O
RO
Leff
S E
SE
D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004298:Dopamine / Q000032:analysis*; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007763:Lac Operon; D008297:Male; D009410:Nerve Degeneration; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013378:Substantia Nigra / Q000473:pathology*; D013565:Sympatholytics / Q000633:toxicity
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine