Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment.

Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the huntingtin (HTT) gene. Genetic modifiers of disease onset and progression in HD implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a leading therapeutic target. To inform development of an SI-targeting therapy, we generated a computational model that uses HD patient data to infer therapeutic effects of reducing SI. To target SI experimentally, we designed an artificial microRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described medium spiny neuron (MSN)-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved 48–94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs). Predictive modeling indicates this level of knockdown would delay motor symptom onset by more than 5 years in most HD gene-positive individuals, with many predicted to experience delays exceeding 50 years. Applied to a representative patient, the model predicts 50–120 % slowing of HD progression as measured by change from baseline in the composite Unified Huntington Disease Rating Scale (cUHDRS). Finally, AAV-DB-3.miMSH3 reduced Msh3 mRNA and protein by up to 27% and 40%, respectively, and SI by up to 46% in HdhQ111 mice. Cumulatively, the preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy for HD.