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

• Main Authors: L.Pereira de Almeida, D. Zala, P. Aebischer, N. Déglon
• Format: Article
• Language: English
• Published: Elsevier 2001-06-01
• Series: Neurobiology of Disease
• Subjects: Huntington's disease; lentiviral vector; gene therapy; ciliary neurotrophic factor; quinolinic acid lesion model
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996101903882

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.