Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models

In this paper, we demonstrate that dantrolene and Rycals S107 and ARM210 ( proprietary compounds from ARMGO pharma/ SERVIER) potentiate AO-mediated exon skipping of exon 44 or exon 45 in patient-derived myotube cultures with appropriate mutations. Further, dantrolene is shown to boost AO-mediated exon skipping in patientderived, induced cardiomyocyte cultures. Our findings further validate the ryanodine receptors (RyR) as the likely target responsible for exon skip boosting and demonstrate potential applicability beyond exon 51 skipping. These data provide preclinical support of dantrolene trial as an adjuvant to AO-mediated exon-skipping therapy in humans and identify a novel Rycal, ARM210, for development as a potential exon-skipping booster. Further, they highlight the value of mutation-specific DMD culture models for basic discovery, preclinical drug screening and translation of personalized genetic medicines. ARM210 is currently under clinical investigation as a stand alone compound for the treatment of various skeletal muscle related diseases (DMD, RyR1-related myopathies, Sarcopenia and Cachexia). Our data suggest that this compound could also be used as a combination therapy with antisense oligonucleotides therapies for DMD.

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