Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a ...

• Autor(es): Alves, Sandro ; Nascimento-Ferreira, Isabel ; Auregan, Gwennaëlle ; Hassig, Raymonde ; Dufour, Noëlle ; Brouillet, Emmanuel ; Lima, Maria C. Pedroso de ; Hantraye, Philippe ; Almeida, Luís Pereira de ; Déglon, Nicole
• Data: 2008
• Identificador Persistente: http://hdl.handle.net/10316/12776
• Origem: Estudo Geral - Universidade de Coimbra
• Tipo de Documento: Artigo
• Idioma: Inglês

Descrição

Recent studies have demonstrated that RNAi is a promising approach for treating autosomal dominant disorders. However, discrimination between wild-type and mutant transcripts is essential, to preserve wild-type expression and function. A single nucleotide polymorphism (SNP) is present in more than 70% of patients with Machado-Joseph disease (MJD). We investigated whether this SNP could be used to inactivate mutant ataxin-3 selectively. Lentiviral-mediated silencing of mutant human ataxin-3 was demonstrated in vitro and in a rat model of MJD in vivo. The allele-specific silencing of ataxin-3 significantly decreased the severity of the neuropathological abnormalities associated with MJD. These data demonstrate that RNAi has potential for use in MJD treatment and constitute the first proof-of-principle for allele-specific silencing in the central nervous system