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.

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

“…[5][6][7][8][9][10][11][12] However, when GDNF is administered with a delay after the insult, sparing of DA neurons is only marginal and the magnitude of functional recovery probably reflects the number of DA neurons still surviving and maintaining nigrostriatal connections. 10,[23][24][25] In contrast with previous studies 10,26 in which three or four deposits of 6-OHDA were injected to create more extensive striatal lesions, 6-OHDA was injected at only one site in our model and less damage might have been incurred to nigrostriatal connections.…”

“…DOI: 10.1038/sj/gt/3301682 (Ad) or lentiviral vectors protects nigral DA neurons while regenerating the nigrostriatal pathway in rodent and primate models of PD when administered before or shortly after an injection of neurotoxin. [5][6][7][8][9][10][11][12] However, the effectiveness of chronically delivered GDNF gene via AAV vector in a later phase of the degenerative process has not previously been documented. PD is a disorder characterized by progressive DA degeneration, and substantial numbers of DA neurons are depleted before the obvious appearance of symptoms.…”

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

“…80). Intrastriatal delivery of LV-GDNF was effective in reducing 6-OHDAinduced damage to nigrostriatal neurons, protecting nigral dopaminergic neuronal cell bodies and resulting in sprouting of their lesioned axons along the nigrostriatal pathway (Ref.…”

Neurotrophic factors for the treatment of Parkinson's disease

“…Lentiviral vectors have the capacity to deliver large transgenes and they can integrate efficiently into non-dividing cells. Delivery of the human GDNF gene using lentiviral vectors in MPTP-lesioned and aged rhesus monkeys achieved long-term gene expression and significant functional benefits [54]. Kordower and colleagues administered lentiviral-GDNF to the striatum and substantia nigra of nonlesioned aged monkeys and MPTP-treated young monkeys and found extensive expression of GDNF in all of the brains.…”