ADENOVIRAL VECTOR-MEDIATED GDNF GENE-THERAPY IN A RODENT LESION MODELOF LATE-STAGE PARKINSONS-DISEASE

A recombinant adenoviral vector encoding the human glial cell line-der ived neurotrophic factor (GDNF) gene (Ad-GDNF) was used to express the neurotrophic factor GDNF in the unilaterally 6-hydroxydopamine (6-OHD A) denervated substantia nigra (SN) of adult rats ten weeks following the 6-OHDA injection. 6-OHDA lesions significantly increased apomorphi ne-induced (contralateral) rotations and reduced striatal and nigral d opamine (DA) levels by 99% and 70%, respectively. Ad-GDNF significantl y (P < 0.01) decreased (by 30-40%) apomorphine-induced rotations in le sioned rats for up to two weeks following a single injection. Locomoto r activity, assessed 7 days following the Ad-GDNF injection, was also significantly (P < 0.05) increased (by 300-400%). Two weeks after the Ad-GDNF injection, locomotor activity was still significantly increase d compared to the Ad-beta-gal-injected 6-OHDA lesioned (control) group . Additionally, in Ad-GDNF-injected rats, there was a significant decr ease (10-13%) in weight gain which persisted for approximately two wee ks following the injection. Consisitent with the behavioral changes, l evels of DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were elevated (by 98% and 65%, respectively) in the SN, but not the striat um of Ad-GDNF-injected rats. Overall, a single Ad-GDNF injection had s ignificant effects for 2-3 weeks following administration. These resul ts suggest that virally delivered GDNF promotes the recovery of nigral dopaminergic tone (i.e.: increased DA and DOPAC levels) and improves behavioral performance (i.e.: decreased rotations, increased locomotio n) in rodents with extensive nigrostriatal dopaminergic denervation. M oreover, our results suggest that viral delivery of trophic factors ma y be used eventually to treat neurodegenerative diseases such as Parki nson's disease. (C) 1997 Elsevier Science B.V.