title: Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington's disease.
abstract: Neurodegenerative diseases represent promising targets for gene therapy approaches provided effective transfer vectors. In the present study, we evaluated the effectiveness of LacZ-expressing lentiviral vectors with two different internal promoters, the mouse phosphoglycerate kinase 1 (PGK) and cytomegalovirus (CMV), to infect striatal cells. The intrastriatal injection of lenti-beta-Gal vectors lead to 207, 400 +/- 11,500 and 303,100 +/- 4,300 infected cells in adult rats, respectively. Importantly, the beta-galactosidase activity was higher in striatal extracts from PGK-LacZ-injected animals as compared to CMV-LacZ animals. The efficacy of the system was further examined with a potential therapeutic gene for the treatment of Huntington's disease, the human ciliary neurotrophic factor (CNTF). PGK-LacZ- or PGK-CNTF-expressing viruses were stereotaxically injected into the striatum of rats, 3 weeks later the animals were unilaterally lesioned with 180 nmol of quinolinic acid (QA). Control animals displayed 148 +/- 43 apomorphine-induced rotations ipsilateral to the lesion 5 days postlesion as compared to 26 +/- 22 turns/45 min in the CNTF-treated group. The extent of the striatal damage was significantly diminished in the CNTF-treated rats as indicated by the 52 +/- 9.7% decrease of the lesion volume and the sparing of DARPP-32, ChAT and NADPH-d neuronal populations. These results further establish that lentiviruses may represent an efficient gene delivery system for the screening of therapeutic molecules in Huntington's disease.
authors.affiliation: Division of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland.
authors.forename: L P
authors.initials: LP
authors.lastname: de Almeida
authors.forename: D
authors.initials: D
authors.lastname: Zala
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
authors.forename: N
authors.initials: N
authors.lastname: Déglon
mesh_terms: D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006816:Huntington Disease / Q000139:chemically induced / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D018696:Neuroprotective Agents; D010735:Phosphoglycerate Kinase / Q000235:genetics; D011401:Promoter Regions, Genetic; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D020934:Ciliary Neurotrophic Factor; D018696:Neuroprotective Agents; D010735:Phosphoglycerate Kinase; D001616:beta-Galactosidase; D017378:Quinolinic Acid