title: Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism.
abstract: 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.
authors.affiliation: The Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
mesh_terms: D000483:Alleles; D020137:Base Pair Mismatch; D001483:Base Sequence; D002460:Cell Line; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000628:therapy; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering