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

• Published in: Current biology Vol. 19; no. 9; pp. 774 - 778
• Main Authors: Pfister, Edith L., Kennington, Lori, Straubhaar, Juerg, Wagh, Sujata, Liu, Wanzhou, DiFiglia, Marian, Landwehrmeyer, Bernhard, Vonsattel, Jean-Paul, Zamore, Phillip D., Aronin, Neil
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 12.05.2009
• Subjects: DNA; Genetic Carrier Screening; Genetic Therapy - methods; Humans; HUMDISEASE; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - therapy; Nerve Tissue Proteins - genetics; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide - genetics; RNA; RNA Interference; RNA, Small Interfering - genetics; Sequence Analysis, DNA; RNA; DNA; HUMDISEASE
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2009.03.030

Among dominant neurodegenerative disorders, Huntington's disease (HD) is perhaps the best candidate for treatment with small interfering RNAs (siRNAs) [1–9]. Invariably fatal, HD is caused by expansion of a CAG repeat in the Huntingtin gene, creating an extended polyglutamine tract that makes the Huntingtin protein toxic [10]. Silencing mutant Huntingtin messenger RNA (mRNA) should provide therapeutic benefit, but normal Huntingtin likely contributes to neuronal function [11–13]. No siRNA strategy can yet distinguish among the normal and disease Huntingtin alleles and other mRNAs containing CAG repeats [14]. siRNAs targeting the disease isoform of a heterozygous single-nucleotide polymorphism (SNP) in Huntingtin provide an alternative [15–19]. 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.