Di-valent SiRNA-mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington's Disease

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2023 May 13

PMID 37177784

Authors

Daniel OReilly

Jillian Belgrad

Chantal Ferguson

Ashley Summers

Ellen Sapp

Cassandra McHugh

Ella Mathews

Adel Boudi

Julianna Buchwald

Socheata Ly

Dimas Moreno

Raymond Furgal

Eric Luu

Zachary Kennedy

Vignesh Hariharan

Kathryn Monopoli

X William Yang

Jeffery Carroll

Marian DiFiglia

Neil Aronin

Anastasia Khvorova

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.

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