title: Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
abstract: Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.
authors.affiliation: Department of Neurological Sciences, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. jkordowe@rush.edu
authors.forename: J H
authors.initials: JH
authors.lastname: Kordower
authors.forename: M E
authors.initials: ME
authors.lastname: Emborg
authors.forename: J
authors.initials: J
authors.lastname: Bloch
authors.forename: S Y
authors.initials: SY
authors.lastname: Ma
authors.forename: Y
authors.initials: Y
authors.lastname: Chu
authors.forename: L
authors.initials: L
authors.lastname: Leventhal
authors.forename: J
authors.initials: J
authors.lastname: McBride
authors.forename: E Y
authors.initials: EY
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Palfi
authors.forename: B Z
authors.initials: BZ
authors.lastname: Roitberg
authors.forename: W D
authors.initials: WD
authors.lastname: Brown
authors.forename: J E
authors.initials: JE
authors.lastname: Holden
authors.forename: R
authors.initials: R
authors.lastname: Pyzalski
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.forename: P
authors.initials: P
authors.lastname: Carvey
authors.forename: Z
authors.initials: Z
authors.lastname: Ling
authors.forename: D
authors.initials: D
authors.lastname: Trono
authors.forename: P
authors.initials: P
authors.lastname: Hantraye
authors.forename: N
authors.initials: N
authors.lastname: Déglon
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000375:Aging; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016086:Lentivirus / Q000235:genetics; D008253:Macaca mulatta; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000517:prevention & control*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D009474:Neurons / Q000201:enzymology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D011597:Psychomotor Performance; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine