Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism

Jiaxin Hu, Jing Liu, David R. Corey

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


Inhibiting expression of huntingtin (HTT) protein is a promising strategy for treating Huntington's disease (HD), but indiscriminant inhibition of both wild-type and mutant alleles may lead to toxicity. An ideal silencing agent would block expression of mutant HTT while leaving expression of wild-type HTT intact. We observe that fully complementary duplex RNAs targeting the expanded CAG repeat within HTT mRNA block expression of both alleles. Switching the RNAi mechanism toward that used by miRNAs by introducing one or more mismatched bases into these duplex RNAs leads to potent (<10 nM) and highly selective (>30-fold relative to wild-type HTT) inhibition of mutant HTT expression in patient-derived cells. Potent, allele selective inhibition of HTT by mismatched RNAs provides a new option for developing HD therapeutics.

Original languageEnglish (US)
Pages (from-to)1183-1188
Number of pages6
JournalChemistry and Biology
Issue number11
StatePublished - Nov 24 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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