A combinatorial approach to ALS therapies in the PrP.TDP43-315 model of ALS; complications and tribulations

Effective treatment for sporadic amyotrophic lateral sclerosis has been steadily advancing towards combinatorial therapies. For many years, riluzole was the only approved drug and it offered modest benefits. In 2017, edaravone was approved for ALS and became the first drug to be used in combination with riluzole. In the present study, we have attempted to build on the concepts of combinatorial therapy by testing novel drug combinations in a transgenic mouse model. Mice that express A315T mutant TDP43, using the mouse prion promoter, have been reported to develop many of the symptoms of ALS, including paralysis. Aberrant TDP43 function is a common feature in sporadic ALS, and thus TDP43 transgenic models may recapitulate disease processes that occur in humans with sporadic ALS. Although the PrP.TDP43-A315T model has been reported to develop abnormalities in gut motility that contribute to early mortality, recent studies indicated that gut motility issues could be mitigated by feeding mice with gel-based diets rather than the standard dry chow. In the present study, we have attempted to use the PrP.TDP43-A315T model to test whether we could identify a drug combination that synergized to extend life span in this model substantially. The drug combinations were built around the existing drug modalities, adding additional drugs that had indications of utility from the literature. To mitigate gut motility issues, we fed the mice gel-based diets with or without added drug combinations. Although the gel-based diets extended life expectancy in PrP.TDP43-A315T mice, most of the animals still developed gut motility abnormalities that may have contributed to early mortality. None of the drug combinations we tested extended life expectancy in this model substantially.