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

Curr Biol. 2009 May 12;19(9):774-8. doi: 10.1016/j.cub.2009.03.030. Epub 2009 Apr 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Carrier Screening
  • Genetic Therapy / methods*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / therapy*
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • RNA Interference*
  • RNA, Small Interfering / genetics*
  • Sequence Analysis, DNA


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Small Interfering