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 factors for the treatment of neurodegenerative disorders. In vivo gene transfer using viral vectors constitutes a powerful strategy to overcome this limitation. The aim of the present study was to validate the lentiviral vector as a gene delivery system in the mouse midbrain in the perspective of screening biotherapeutic molecules in mouse models of Parkinson's disease. A preliminary study with a LacZ-encoding vector injected above the substantia nigra of C57BL/6j mice indicated that lentiviral vectors can infect approximately 40,000 cells and diffuse over long distances. Based on these results, glial cell line-derived neurotrophic factor (GDNF) was assessed as a neuroprotective molecule in a 6-hydroxydopamine model of Parkinson's disease. Lentiviral 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 striatum. Apomorphine-induced rotation was significantly decreased in the GDNF-injected group compared to control animals. Moreover, GDNF efficiently protected 69.5% of the tyrosine hydroxylase-positive cells in the substantia nigra against 6-hydroxydopamine-induced toxicity compared to 33.1% with control mutated GDNF. These data indicate that lentiviral vectors constitute a powerful gene delivery system for the screening of therapeutic molecules in mouse models of Parkinson's disease.
Keywords: Animals ; Apomorphine/pharmacology ; Cell Count/drug effects ; Corpus Striatum/chemistry/metabolism/pathology ; Dopamine/analysis ; Gene Therapy/ methods ; Genes ; Reporter ; Genetic Vectors/genetics/ pharmacology ; Glial Cell Line-Derived Neurotrophic Factor ; Lentivirus/genetics ; Male ; Mesencephalon/ drug effects/metabolism/pathology ; Mice ; Mice ; Inbred C57BL ; Microinjections ; Motor Activity/drug effects ; Nerve Growth Factors ; Nerve Tissue Proteins/administration & dosage/ biosynthesis/genetics ; Oxidopamine ; Parkinson Disease ; Secondary/chemically induced/pathology/ therapy ; Substantia Nigra/chemistry/metabolism/pathology ; Tyrosine 3-Monooxygenase/analysis
Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Record created on 2007-03-09, modified on 2016-08-08