H013 Validation of MSH3 as a therapeutic target for Huntington’s disease

Background The CAG repeat mutation for Huntington’s disease expands in vulnerable brain regions with age. The age of symptom onset is influenced by somatic CAG repeat expansion genetic modifiers, which include variants in mismatch repair pathways genes. Knocking out the mismatch repair gene MSH3 in mouse models of Huntington’s disease prevents somatic CAG repeat expansion, and therapeutic treatments targeting MSH3 are currently under development. Aims To investigate when best to treat with Msh3 targeting therapeutics to ensure maximum efficacy. Methods We used a genetic approach to ablate (HdhQ111:Msh3-/-) and reduce to 50% (HdhQ111:Msh3+/-), Msh3 expression in the HdhQ111 mouse model. Alongside this we also treated HdhQ111 mice with two Msh3 targeting ASOs by ICV administration at 3 months of age. Striatal phenotypes were investigated at 7 and 14 months. Results Ablation of Msh3 prevented somatic expansion, and both Msh3 reduction and ASO treatment decreased the rate of expansion, at both ages studied. Ablation of Msh3 resulted in the greatest delay in HTT aggregation, but both approaches reduced nuclear inclusions and ameliorated extra-nuclear inclusions. This resulted in a significant reduction in levels of transcriptional dysregulation seen in HdhQ111:Msh3+/- and HdhQ111:Msh3-/- striata, however the ASO interventions only had a limited effect on the number of dysregulated genes. Conclusions This parallel analysis of genetic and interventional approaches has shed further light on the pathogenic CAG repeat threshold in brain and highlighted the importance of administering therapeutics targeting somatic CAG instability as early as possible, for maximum benefit.