Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington's disease.
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.
de Almeida
L P
LP
Division of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland.
Zala
D
D
Aebischer
P
P
Déglon
N
N
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
D020934:Ciliary Neurotrophic Factor; D018696:Neuroprotective Agents; D010735:Phosphoglycerate Kinase; D001616:beta-Galactosidase; D017378:Quinolinic Acid