Evaluation of dynamin 2 knockdown as a therapeutic strategy for RYR1 related myopathy.

Abstract

RYR1 congenital myopathies, due to pathogenic variants in the RYR1 gene, are the most common subtype of nondystrophic myopathy. At present, there are no therapies for this condition. RYR1 myopathies share features with centronuclear myopathy (CNM), as RYR1 dysfunction is an important common pathologic endpoint of these conditions. Knockdown of dynamin 2 (DNM2) using an antisense oligonucleotide based strategy has shown efficacy in mouse models of CNM, including restoration of RYR1 function. Based on this, we sought to test whether Dnm2 knockdown could also ameliorate the phenotype of a mouse model of recessive RYR1 congenital myopathy, which exhibits a marked reduction in Ryr1 expression and function. To accomplish this, we administered an antisense oligonucleotide (ASO) targeting Dnm2 RNA or a scrambled ASO to a mouse model of the disease, and then measured the impact on multiple functional and pathologic endpoints. While we successfully achieved Dnm2 RNA knockdown with this treatment, no benefit was observed in any parameters measured. We thus conclude that lowering DNM2 transcript levels are unlikely to be a promising strategy for treating RYR1 congenital myopathy.