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Five siRNAs Targeting Three SNPs May Provide Therapy for Three-Quarters of Huntington's Disease Patients

2009; Elsevier BV; Volume: 19; Issue: 9 Linguagem: Inglês

10.1016/j.cub.2009.03.030

1879-0445

Edith L. Pfister, Lori Kennington, Juerg Straubhaar, Sujata Wagh, Wanzhou Liu, Marian DiFiglia, G. Bernhard Landwehrmeyer, Jean‐Paul Vonsattel, Phillip D. Zamore, Neil Aronin,

RNA Research and Splicing

Among dominant neurodegenerative disorders, Huntington's disease (HD) is perhaps the best candidate for treatment with small interfering RNAs (siRNAs) [1Xia H. Mao Q. Eliason S.L. Harper S.Q. Martins I.H. Orr H.T. Paulson H.L. Yang L. Kotin R.M. Davidson B.L. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.Nat. Med. 2004; 10: 816-820Crossref PubMed Scopus (568) Google Scholar, 2Machida Y. Okada T. Kurosawa M. Oyama F. Ozawa K. Nukina N. rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse.Biochem. Biophys. Res. Commun. 2006; 343: 190-197Crossref PubMed Scopus (111) Google Scholar, 3Wang Y.L. Liu W. Wada E. Murata M. Wada K. Kanazawa I. Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA.Neurosci. Res. 2005; 53: 241-249Crossref PubMed Scopus (151) Google Scholar, 4Xia X. Zhou H. Huang Y. Xu Z. 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Designing siRNA that distinguish between genes that differ by a single nucleotide.PLoS Genet. 2006; 2: e140Crossref PubMed Scopus (202) Google Scholar, 16Ding H. Schwarz D.S. Keene A. Affar E.-B. Fenton L. Xia X. Shi Y. Zamore P.D. Xu Z. Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis.Aging Cell. 2003; 2: 209-217Crossref PubMed Scopus (149) Google Scholar, 17Dahlgren C. Zhang H.Y. Du Q. Grahn M. Norstedt G. Wahlestedt C. Liang Z. Analysis of siRNA specificity on targets with double-nucleotide mismatches.Nucleic Acids Res. 2008; 36: e53Crossref PubMed Scopus (57) Google Scholar, 18Du Q. Thonberg H. Wang J. Wahlestedt C. Liang Z. A systematic analysis of the silencing effects of an active siRNA at all single-nucleotide mismatched target sites.Nucleic Acids Res. 2005; 33: 1671-1677Crossref PubMed Scopus (189) Google Scholar, 19Miller V.M. Gouvion C.M. Davidson B.L. Paulson H.L. Targeting Alzheimer's disease genes with RNA interference: An efficient strategy for silencing mutant alleles.Nucleic Acids Res. 2004; 32: 661-668Crossref PubMed Scopus (136) Google Scholar]. We sequenced 22 predicted SNP sites in 225 human samples corresponding to HD and control subjects. We find that 48% of our patient population is heterozygous at a single SNP site; one isoform of this SNP is associated with HD. Several other SNP sites are frequently heterozygous. Consequently, five allele-specific siRNAs, corresponding to just three SNP sites, could be used to treat three-quarters of the United States and European HD patient populations. We have designed and validated selective siRNAs for the three SNP sites, laying the foundation for allele-specific RNA interference (RNAi) therapy for HD.