Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease.
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.
Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
Sandro
S
Alves
Isabel
I
Nascimento-Ferreira
Gwennaëlle
G
Auregan
Raymonde
R
Hassig
Noëlle
N
Dufour
Emmanuel
E
Brouillet
Maria C
MC
Pedroso de Lima
Philippe
P
Hantraye
Luís
L
Pereira de Almeida
Nicole
N
Déglon
D000483:Alleles; D000818:Animals; D000067699:Ataxin-3; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D009419:Nerve Tissue Proteins; D012313:RNA; D000067699:Ataxin-3; C511593:Atxn3 protein, rat