Chemistry & Biology
Volume 17, Issue 11, 24 November 2010, Pages 1183-1188
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Brief Communication
Allele-Selective Inhibition of Huntingtin Expression by Switching to an miRNA-like RNAi Mechanism

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Summary

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.

Highlights

► Allele-selective inhibition of human HTT expression ► Switching the mechanism of RNAi enhances selectivity ► Selective duplex RNAs are a promising approach to therapy for HD

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