A002 A CAG repeat threshold for therapeutics targeting somatic instability in mouse models of Huntington’s disease

Background The Huntington’s disease (HD) mutation is a CAG repeat expansion that encodes for an expanded polyglutamine tract. The CAG repeat is unstable, and expansions of hundreds of CAGs have been detected in HD post-mortem brains. Mismatch repair genes, including MSH3, known to modify somatic expansion, have been identified as genetic modifiers. Therefore, the CAG repeat expansion is required for pathogenesis, and the pathogenic repeat threshold in brain is unknown. Aims Potential treatments targeting MSH3 are under development. We used mouse models of Huntington’s disease to determine the maximum benefit of targeting Msh3. Methods We used a genetic approach to both ablate Msh3 expression and reduce it to 50% in the zQ175 and HdhQ111 HD mouse models, with CAG expansions of 185 and 111, respectively. The impact on striatal phenotypes was investigated. Results Ablation of Msh3 expression prevented CAG repeat expansion, while reducing expression by 50% decreased the rate of expansion, in both mouse models. Crucially, in zQ175 mice, the lack of somatic expansion had no effect on striatal huntingtin aggregation nor on striatal transcriptional dysregulation. Conclusions This indicates that the pathogenic consequences of a CAG repeat of 185 cannot be accelerated by further expansion of the CAG repeat, and targeting somatic expansion at this stage cannot ameliorate striatal pathology. Analysis of these phenotypes in HdhQ111:Msh3 mice is ongoing and will further elucidate the treatable threshold of pathogenic CAG repeats. These data underlie the importance of administering treatments targeting somatic expansion as early as possible. Funding The CHDI Foundation, UKDRI and Wellcome Trust.