Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients
Department of Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Endocrinology and Metabolism
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
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 . 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 . 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.
DOI of Published Version
Curr Biol. 2009 May 12;19(9):774-8. Epub 2009 Apr 9. Link to article on publisher's site
Current biology : CB
Pfister, Edith L.; Kennington, Lori A.; Straubhaar, Juerg R.; Wagh, Sujata; Liu, Wanzhou; DiFiglia, Marian; Landwehrmeyer, Bernhard; Vonsattel, Jean-Paul; Zamore, Phillip D.; and Aronin, Neil, "Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients" (2009). GSBS Student Publications. 1620.