Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS

Speaker: 羅志文               Time: 2005/09/21 13:10-14:00

Commentator: 蕭璦莉 老師     Place: Room 601

Abstract:

Amyotrophic lateral sclerosis (ALS) is the most common adult motor disease. This disease’s primary hallmark is the selective dysfunction and death of the motoneurons¹. Mutation in Cu/Zn superoxide dismutase (SOD1) is one of the causes of familial ALS, but the relationship between the SOD1 mutation and ALS is unclear. So far as we know, the SOD1-mediated toxicity in ALS is not due to loss of function but instead to gain of one or more toxic properties². Therefore, an attractive therapeutic approach for ALS is to reduce the level of mutant SOD1 gene expression. In this paper, the authors knocked down the human mutant SOD1 gene expression in SOD1^G93A ALS mice by lentiviral vectors which encode a short hairpin RNA (shRNA) specific to human SOD1 gene (Lt-shSOD1). They showed that the virus can efficiently reduce SOD1 protein and RNA levels, and protect SOD1^G93A motoneurons from NO-induced death in vitro. Furthermore, in vivo, they demonstrated that SOD1^G93A ALS mice restored some motoneuron functions and delayed the pathogenesis of ALS by intraspinal injection of Lt-shSOD1 viruses. Thus, lentiviral vector encoding shRNA is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutation³.

References:

1.      Bruijn LI et al. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 27:723-49 (2004)

2.      Raoul C et al. Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. Neuron. 35:1067-83 (2002)

3.      Raoul C et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med. 11:423-428 (2005)