The effect of coadministration of D156844 and AR42 (REC-2282) on the survival and motor phenotype of mice with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is characterized by degeneration of spinal motor neurons and is a leading genetic cause of pediatric death worldwide. SMA results from the loss of or pathological variant in the survival motor neuron 1 (SMN1) gene. Disease severity is dependent on the number of copies of the orthologous SMN2 gene, which is nearly identical to SMN1 except for some key nucleotide differences. As disease severity is inversely related to SMN2 copy number, most SMA therapeutics trials have focused on identifying ways to increase SMN2 expression at different levels of gene regulation. Other studies have investigated compounds which protect affected motor neurons and their target muscles in an SMN-independent manner. In this study, we examined the therapeutic efficacy of the effect of a combination regimen of the SMN2 inducer D156844 and the neuroprotective agent AR42 (REC-2282) on the disease progression and survival in the SMNΔ7 SMA mouse model. The dual administration of D156844 and AR42 results in an additive improvement in the survival of these mice as well as delaying disease endstage. Additionally, coadministration of D156844 and AR42 produced improvements in motor phenotype in SMNΔ7 SMA mice. This study provides further evidence underlying the potential benefit of a combination therapeutics approach to treating SMA.