Natural history study and statistical modelling of disease progression in a preclinical model of myotubular myopathy

Generating reliable preclinical data in animal models of disease is essential in therapy development. Here we perform statistical analysis and joint longitudinal-survival modelling of the progressive phenotype observed in Mtm1^−/y knock-out mice, a faithful model for myotubular myopathy (XLMTM). Analysis of historical data was used to generate a model for phenotype progression, which was then confirmed with phenotypic data from a new colony of mice derived via in vitro fertilization in an independent animal house, highlighting the reproducibility of disease phenotype in Mtm1^−/y mice. This combined data was then used to refine the phenotypic parameters analyzed in these mice, and improve the model generated for expected disease progression. The disease progression model was then used to test therapeutic efficacy of Dnm2 targeting. Dnm2 reduction by antisense oligonucleotides blocked or postponed disease development, and resulted in a significant dose-dependent improvement outside the expected disease progression in untreated Mtm1^−/y mice. This provides an example of optimizing disease analysis and testing therapeutic efficacy in a preclinical model, that can be applied by scientists testing therapeutic approaches using neuromuscular disease models in different laboratories.