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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Aging
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Animals
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Antigens, CD / analysis
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Dihydroxyphenylalanine / analogs & derivatives*
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Dihydroxyphenylalanine / metabolism
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Disease Models, Animal
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Dopamine / metabolism*
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Female
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Gene Expression
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Genetic Therapy*
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Genetic Vectors
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Glial Cell Line-Derived Neurotrophic Factor
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Lentivirus / genetics
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Macaca mulatta
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Neostriatum / metabolism
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Neostriatum / pathology
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Nerve Degeneration / prevention & control*
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Nerve Growth Factors*
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / therapeutic use
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Neurons / enzymology
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Parkinson Disease / physiopathology
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Parkinson Disease / therapy*
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / physiopathology
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Parkinsonian Disorders / therapy
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Psychomotor Performance
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Antigens, CD
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Glial Cell Line-Derived Neurotrophic Factor
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Nerve Growth Factors
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Nerve Tissue Proteins
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fluorodopa F 18
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Dihydroxyphenylalanine
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase
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Dopamine