Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.
Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Despite multiple clinical trials, huntingtin (HTT)-lowering strategies have yet to show meaningful clinical benefit. Both somatic expansion and toxic HTT species are key molecular drivers of HD, yet therapeutic strategies targeting these pathways have never been directly compared or evaluated in combination. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MutS homolog 3 (MSH3), a critical regulator of somatic expansion, HTT, or both in Q111 HD mice (>110 CAGs), which develop robust expansion, mutant HTT inclusions, and transcriptional dysregulation by 12 months. Long-term MSH3 silencing blocked somatic expansion, reduced inclusions, and normalized gene expression. HTT silencing alone had a limited effect, whereas combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based cosilencing of MSH3 and HTT as a disease-modifying strategy for HD.