Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor

Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substa ntia nigra (SN), protects SN dopaminergic (DA) neuronal soma from B-hydroxy dopamine (6-OHDA)-induced degeneration. In the present study, the effects o f Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could b e assessed without relying on DA phenotypic markers, fluorogold (FG) was in fused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF o r control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, ve hicle, or no injection) was injected unilaterally into the striatum near on e BG site. Progressive degeneration of DA neurons was initiated 7 days late r by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHD A, Ad GDNF prevented the death of 40% of susceptible DA neurons that projec ted to the lesion site. Ad GDNF prevented the development of behavioral asy mmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical sw faces and amphetamine-induce d rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatu m for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate tha t Ad GDNF can sustain increased levels of biosynthesized GDNF in the termin al region of DA neurons for at least 7 weeks and that this GDNF slows the d egeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene th erapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD. (C) 1998 Academic Press .