Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
• Somatic repeat expansion, mediated by the mismatch repair (MMR) pathway, accelerates HD onset, particularly in striatal neurons.
• MSH3 is identified as a crucial MMR component influencing HD progression and a potential therapeutic target.

Purpose of the Study:

• To develop and evaluate a short interfering RNA (siRNA) therapy targeting MSH3 for Huntington's disease.
• To assess the efficacy of MSH3 silencing in preventing CAG repeat expansion in HD mouse models.
• To determine the safety profile of the MSH3-targeting siRNA therapy regarding other MMR genes and microsatellite instability.

Main Methods:

• Developed a chemically modified siRNA to silence MSH3 expression in vitro and in vivo.
• Utilized a di-valent scaffold for siRNA synthesis to enhance stability and delivery.
• Administered siRNA therapy to two mouse models of Huntington's disease and analyzed CAG repeat expansion in the striatum.

Main Results:

• The developed siRNA effectively silenced Msh3 expression in vitro and in vivo.
• siRNA-mediated MSH3 silencing significantly blocked CAG repeat expansion in the striatum of HD mouse models.
• The treatment did not affect tumor-associated microsatellite instability or the expression of other MMR genes, indicating specificity.

Conclusions:

• MSH3 is a critical driver of somatic CAG repeat expansion in Huntington's disease.
• siRNA-mediated MSH3 silencing presents a promising and potentially safe therapeutic strategy for Huntington's disease.
• This approach may also be applicable to other repeat expansion disorders.