Publication

Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington's disease

Patrick Aebischer, Nicole Déglon, Diana Zala
2001
Journal Articles

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.

Official source

https://infoscience.epfl.ch/entities/publication/b463cd03-cd6d-4c73-a87a-075e042e550c

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Patrick Aebischer, Nicole Déglon, Diana Zala
2001
Journal Articles

Abstract

Official source

https://infoscience.epfl.ch/entities/publication/b463cd03-cd6d-4c73-a87a-075e042e550c

About this result

Related concepts (19)

Gene therapy

Gene therapy is a medical technology which aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA was performed in 1980, by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Gene therapy of the human retina

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness. In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber's congenital amaurosis had been successfully treated using gene therapy with adeno-associated virus (AAV). In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA.

Neurotrophic factors

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories.

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