Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for adult nigral dopamine neurons in vivo. GDNF has both protective and restorative effects on the nigro-striatal dopaminergic (DA) system in animal models of Parkinson disease. Appropriate administration of this factor is essential for the success of its clinical application. Since it cannot cross the blood-brain barrier, a gene transfer method may be appropriate for delivery of the trophic factor to DA cells. We have constructed a recombinant adenovirus (Ad) encoding GDNF and injected it into rat striatum to make use of its ability to infect neurons and to be retrogradely transported by DA neurons. Ad-GDNF was found to drive production of large amounts of GDNF, as quantified by ELISA. The GDNF produced after gene transfer was biologically active: it increased the survival and differentiation of DA neurons in vitro. To test the efficacy of the Ad-mediated GDNF gene transfer in vivo, we used a progressive lesion model of Parkinson disease. Rats received injections unilaterally into their striatum first of Ad and then 6 days later of 6-hydroxydopamine. We found that mesencephalic nigral dopamine neurons of animals treated with the Ad-GDNF were protected, whereas those of animals treated with the Ad-␤-galactosidase were not. This protection was associated with a difference in motor function: amphetamine-induced turning was much lower in animals that received the Ad-GDNF than in the animals that received Ad-␤-galactosidase. This finding may have implications for the development of a treatment for Parkinson disease based on the use of neurotrophic factors.

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.…”

Neurotrophic factors for the treatment of Parkinson's disease

“…Gene therapy approaches have been applied to achieve long-term and targeted delivery of GDNF to the injured nigrostriatal pathway. Adenoviral vector delivery of GDNF into or close to the substantia nigra [46,47] or into the striatum [48,49] of rats with intrastriatal 6-OHDA lesions resulted in significant motor improvements and protection of nigral dopaminergic neurones. Adenoviral-delivered GDNF induced behavioural and neuroprotective effects when injected into the substantia nigra, but not into the striatum, in rats that had intrastriatal 6-OHDA lesions [50].…”

Gene therapy in the CNS

“…[10][11][12][13][14] Fifth, the cell specificity of gene transfer within the nervous system (to neurons versus glia, and specific phenotypes of each) will depend on use of targeted vectors, which selectively infect particular cell types, cellspecific promoters, [15][16][17][18] and routing through neuronal projections in the brain. [19][20][21] Finally, for effective application of viral vector-mediated gene transfer for therapy, lack of toxicity and immune response will be essential, with the exception of brain tumors where these responses may be part of the therapeutic paradigm. 22 Although the brain is considered to have poor immunologic surveillance, inflammatory and immunological responses do occur, as documented with adenovirus (Ad) vectors, 8,23 and can cause damage to normal neural tissue.…”