Somatic CRISPR editing of Msh3 mitigates Huntington's disease pathology in mice

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansion in the Huntingtin (HTT) gene.
• Somatic CAG repeat expansion in neurons drives disease progression and clinical onset.
• MSH3 is a key protein driving somatic CAG expansion and a potential therapeutic target.

Purpose of the Study:

• To investigate the therapeutic potential of targeting MSH3 in Huntington's disease.
• To evaluate the impact of MSH3 inhibition at different disease stages.
• To understand the mechanism by which MSH3 contributes to HD pathogenesis.

Main Methods:

• Somatic CRISPR-Cas9 gene editing was used to knock out MSH3 in HttQ111 mice at various ages (6, 16, 24 weeks).
• CAG expansion, huntingtin pathology, and transcriptional dysregulation were assessed.
• The production of the exon 1 HTT transcript was analyzed.

Main Results:

• MSH3 knockout significantly slowed striatal CAG expansion across all intervention ages.
• Earlier MSH3 targeting demonstrated a greater reduction in pathology and transcriptional dysregulation.
• MSH3 inhibition suppressed the production of the pathogenic exon 1 HTT transcript.

Conclusions:

• Targeting MSH3 is a promising disease-modifying strategy for Huntington's disease.
• The timing of MSH3 intervention significantly influences therapeutic effectiveness.
• Understanding MSH3's role provides critical preclinical data for developing MSH3-targeted therapies for HD.