Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models

Nat Commun. 2022 Oct 3;13(1):5802. doi: 10.1038/s41467-022-33061-x.


Small interfering RNAs are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing of gene expression in vivo. We recently demonstrated that siRNA chemical architectures can be optimized to provide efficient delivery to the CNS, enabling development of CNS-targeted therapeutics. Many genetically-defined neurodegenerative disorders are dominant, favoring selective silencing of the mutant allele. In some cases, successfully targeting the mutant allele requires targeting single nucleotide polymorphism (SNP) heterozygosities. Here, we use Huntington's disease (HD) as a model. The optimized compound exhibits selective silencing of mutant huntingtin protein in patient-derived cells and throughout the HD mouse brain, demonstrating SNP-based allele-specific RNAi silencing of gene expression in vivo in the CNS. Targeting a disease-causing allele using RNAi-based therapies could be helpful in a range of dominant CNS disorders where maintaining wild-type expression is essential.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Chemical Engineering
  • Gene Silencing
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease* / genetics
  • Huntington Disease* / metabolism
  • Huntington Disease* / therapy
  • Mice
  • Nerve Tissue Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism


  • Huntingtin Protein
  • Nerve Tissue Proteins
  • RNA, Small Interfering