Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients

Student Author(s)

Edith Pfister

Academic Program


UMMS Affiliation

Department of Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Endocrinology and Metabolism

Publication Date


Document Type



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 [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.

DOI of Published Version



Curr Biol. 2009 May 12;19(9):774-8. Epub 2009 Apr 9. Link to article on publisher's site

Journal/Book/Conference Title

Current biology : CB

Related Resources

Link to Article in PubMed

PubMed ID