Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
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.
Kordower
J H
JH
Department of Neurological Sciences, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. jkordowe@rush.edu
Emborg
M E
ME
Bloch
J
J
Ma
S Y
SY
Chu
Y
Y
Leventhal
L
L
McBride
J
J
Chen
E Y
EY
Palfi
S
S
Roitberg
B Z
BZ
Brown
W D
WD
Holden
J E
JE
Pyzalski
R
R
Taylor
M D
MD
Carvey
P
P
Ling
Z
Z
Trono
D
D
Hantraye
P
P
Déglon
N
N
Aebischer
P
P
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
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