Lentiviral vectors as a gene delivery system in the mouse midbrain: Cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF

Local delivery of therapeutic molecules represents one of the limiting fact ors for the treatment of neurodegenerative disorders. In vivo gene transfer using viral vectors constitutes a powerful strategy to overcome this limit ation. The aim of the present study was to validate the lentiviral vector a s a gene delivery system in the mouse midbrain in the perspective of screen ing biotherapeutic molecules in mouse models of Parkinson's disease. A prel iminary study with a LacZ-encoding vector injected above the substantia nig ra of C57BL/6j mice indicated that lentiviral vectors can infect approximat ely 40,000 cells and diffuse over long distances. Based on these results, g lial cell line-derived neurotrophic factor (GDNF) was assessed as a neuropr otective molecule in a 6-hydroxydopamine model of Parkinson's disease. Lent iviral vectors carrying the cDNA for GDNF or mutated GDNF were unilaterally injected above the substantia nigra of C57BL/6j mice. Two weeks later, the animals were lesioned ipsilaterally with 6-hydroxydopamine into the striat um. Apomorphine-induced rotation was significantly decreased in the GDNF-in jected group compared to control animals. Moreover, GDNF efficiently protec ted 69.5% of the tyrosine hydroxylase-positive cells in the substantia nigr a against B-hydroxydopamine-induced toxicity compared to 33.1% with control mutated GDNF. These data indicate that lentiviral vectors constitute a pow erful gene delivery system for the screening of therapeutic molecules in mo use models of Parkinson's disease. (C) 2000 Academic Press.