Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy

Abstract

Glial cell line-derived neurotrophic factor (GDNF) supports growth and survival of dopaminergic (DA) neurons. A replication-defective adenoviral (Ad) vector encoding human GDNF injected near the rat substantia nigra was found to protect DA neurons from the progressive degeneration induced by the neurotoxin 6-hydroxydopamine (6-OHDA) injected into the striatum. Ad GDNF gene therapy reduced loss of DA neurons approximately threefold 6 weeks after 6-OHDA lesion, as compared with no treatment or injection of Ad lacZ or Ad mGDNF (encoding a biologically inactive deletion mutant GDNF). These results suggest that Ad vector-mediated GDNF gene therapy may slow the DA neuronal cell loss in humans with Parkinson's disease.

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].…”

Viral vectors for in vivo gene transfer in Parkinson's disease: Properties and clinical grade production

“…rAd was one of the earliest viral vectors used with success in the brain (Le Gal La Salle et al, 1993) and in animal models of PD (Barkats et al, 1998;Choi-Lundberg et al, 1997). Wild type Ad (wt-Ad) commonly infects humans and is known to cause respiratory infections, conjunctivitis, and gastroenteritis (Shenk, 1996).…”

“…Recombinant adenovirus (rAd), recombinant adenoassociated viruses (rAAV), herpes simplex viruses (HSV) and lentiviruses (Lv) are currently most utilized viral vectors that have been demonstrated to reliably transfer DNA in animal models of PD (Azzouz et al, 2002;Bilang-Bleuel et al, 1997;Choi-Lundberg et al, 1997;Corti et al, 1999;Kordower et al, 2000). Currently, there are at least 3 early stage clinical trials testing the safety of vector-delivery of genes to treat PD (http://www.gemcris.od.nih.gov/).…”