In vivo application of an RNAi strategy for the selective suppression of a mutant allele

Human Gene Therapy
Takayuki KuboderaTakanori Yokota

Abstract

Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our metho...Continue Reading

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Citations

May 24, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Waldy San SebastianKrystof S Bankiewicz
Feb 2, 2012·Expert Reviews in Molecular Medicine·Lauren M Watson, Matthew J A Wood
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Jun 3, 2017·Nucleic Acids Research·Helen J CurtisMiguel A Varela
Mar 16, 2013·Human Genetics·Tamara MartínezCovadonga Pañeda

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Methods Mentioned

BETA
transgenic
transfection
PCR
electrophoresis
reverse transcription-PCR
Assay

Software Mentioned

Image J

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