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

• Published in: Experimental neurology Vol. 164; no. 1; pp. 15 - 24
• Main Authors: Bensadoun, Jean-Charles, Déglon, Nicole, Tseng, Jack L., Ridet, Jean-Luc, Zurn, Anne D., Aebischer, Patrick
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.07.2000; Elsevier
• Subjects: animal model; Animals; Apomorphine - pharmacology; Biological and medical sciences; Cell Count - drug effects; Corpus Striatum - chemistry; Corpus Striatum - metabolism; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - analysis; GDNF; Genes, Reporter; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - pharmacology; Glial Cell Line-Derived Neurotrophic Factor; lentivirus; Lentivirus - genetics; Male; Medical sciences; Mesencephalon - drug effects; Mesencephalon - metabolism; Mesencephalon - pathology; Mice; Mice, Inbred C57BL; Microinjections; midbrain; Motor Activity - drug effects; mouse; Nerve Growth Factors; Nerve Tissue Proteins - administration & dosage; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurology; Oxidopamine; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - pathology; Parkinson Disease, Secondary - therapy; Parkinson's disease; Substantia Nigra - chemistry; Substantia Nigra - metabolism; Substantia Nigra - pathology; Tyrosine 3-Monooxygenase - analysis; mouse; midbrain; Parkinson's disease; GDNF; animal model; lentivirus; Animal model; Nervous system diseases; Rodentia; Retroviridae; Parkinson disease; Midbrain; Lentivirus; Cerebral disorder; Genetic transfer; Virus; In vivo; Vertebrata; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Degenerative disease; Gene therapy; Vector; Extrapyramidal syndrome
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.2000.7409

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.