Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease

• Published in: Neurobiology of disease Vol. 8; no. 3; pp. 433 - 446
• Main Authors: de Almeida, L.Pereira, Zala, D., Aebischer, P., Déglon, N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2001; Elsevier
• Subjects: Animals; beta-Galactosidase - genetics; ciliary neurotrophic factor; Ciliary Neurotrophic Factor - genetics; Cytomegalovirus; Cytomegalovirus - genetics; Disease Models, Animal; Female; Gene Expression; gene therapy; Genetic Therapy - methods; Genetic Vectors; Huntington Disease - chemically induced; Huntington Disease - therapy; Huntington's disease; lentiviral vector; Lentivirus; Lentivirus - genetics; Neuroprotective Agents; Phosphoglycerate Kinase - genetics; Promoter Regions, Genetic; Quinolinic Acid; quinolinic acid lesion model; Rats; Rats, Wistar; gene therapy; quinolinic acid lesion model; Huntington's disease; lentiviral vector; ciliary neurotrophic factor
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1006/nbdi.2001.0388

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-β-Gal vectors lead to 207, 400 ± 11,500 and 303,100 ± 4,300 infected cells in adult rats, respectively. Importantly, the β-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.