Tailor-made RNAi knockdown against triplet repeat disease-causing alleles

Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21731-6. doi: 10.1073/pnas.1012153107. Epub 2010 Nov 22.

Abstract

Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease allele-specific RNAi are quite difficult. In this study we developed a pull-down method to rapidly identify coding SNP (cSNP) haplotypes of triple repeat, disease-causing alleles, and we demonstrated disease allele-specific RNAi that targeted cSNP sites in mutant Huntingtin alleles, each of which possessed a different cSNP haplotype. Therefore, the methods presented here allow for allele-specific RNAi knockdown against disease-causing alleles by using siRNAs specific to disease-linked cSNP haplotypes, and advanced progress toward tailor-made RNAi treatments for triplet repeat diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Gene Knockdown Techniques*
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Haplotypes
  • HeLa Cells
  • Humans
  • Huntingtin Protein
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • RNA Interference*
  • RNA, Small Interfering / genetics
  • Trinucleotide Repeats*

Substances

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