Article: article from journal or magazin.
Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: epublish
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.
Alleles, Animals, Base Sequence, Brain/metabolism, Cell Line, DNA Primers, Disease Models, Animal, Gene Silencing, Humans, Machado-Joseph Disease/genetics, Machado-Joseph Disease/physiopathology, Male, Mutation, Nerve Tissue Proteins/genetics, Polymorphism, Single Nucleotide, RNA/genetics, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction
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