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 app roaches provided effective transfer vectors. In the present study, we evalu ated the effectiveness of LacZ-expressing lentiviral vectors with two diffe rent internal promoters, the mouse phosphoglycerate kinase 1 (PGK) and cyto megalovirus (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 -galactos idase activity was higher in striatal extracts from PGK-LacZ-injected anima ls 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-C NTF-expressing viruses were stereotaxically injected into the striatum of r ats, 3 weeks later the animals were unilaterally lesioned with 180 nmol of quinolinic acid (QA). Control animals displayed 148 +/- 43 apomorphine-indu ced 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 b y 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 th at lentiviruses may represent an efficient gene delivery system for the scr eening of therapeutic molecules in Huntington's disease. (C) 2001 Academic Press.