Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cell. 2012 Aug 31;150(5):895-908. doi: 10.1016/j.cell.2012.08.002.

Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression.

Author information

  • 1Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.

Abstract

Mutant huntingtin (HTT) protein causes Huntington disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single-stranded antisense oligonucleotides with the efficiency of RNAi. Here, we describe RNAi by single-stranded siRNAs (ss-siRNAs). ss-siRNAs are potent (>100-fold more than unmodified RNA) and allele-selective (>30-fold) inhibitors of mutant HTT expression in cells derived from HD patients. Strategic placement of mismatched bases mimics micro-RNA recognition and optimizes discrimination between mutant and wild-type alleles. ss-siRNAs require Argonaute protein and function through the RNAi pathway. Intraventricular infusion of ss-siRNA produced selective silencing of the mutant HTT allele throughout the brain in a mouse HD model. These data demonstrate that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development.

Copyright © 2012 Elsevier Inc. All rights reserved.

Comment in

PMID:
22939619
[PubMed - indexed for MEDLINE]
PMCID:
PMC3444165
Free PMC Article

Images from this publication.See all images (7)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk