title: 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.
abstract: 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.
authors.affiliation: Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: J C
authors.initials: JC
authors.lastname: Bensadoun
authors.forename: N
authors.initials: N
authors.lastname: Déglon
authors.forename: J L
authors.initials: JL
authors.lastname: Tseng
authors.forename: J L
authors.initials: JL
authors.lastname: Ridet
authors.forename: A D
authors.initials: AD
authors.lastname: Zurn
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000032:analysis; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D013378:Substantia Nigra / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine