DMD TREATMENT: ANIMAL MODELS: P.206Effects of sarconeos (API BIO101) on in vivo and in vitro models of Duchenne muscular dystrophy

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Duchenne muscular dystrophy (DMD), is an inherited muscular disease, characterized by progressive muscle weakness and cardiomyopathy leading to premature death. It is believed that DMD is notably characterized by a systemic mitochondrial defect central to disease etiology. Sarconeos (API BIO101) is a first in class Mas activator currently in clinical development (phase 2b) for sarcopenia. Twelve-week-old C57BL10-mdx mice were orally treated with vehicle or BIO101 at 50mg/kg*day for 8 weeks. Immortalized human skeletal muscle cells KM571 derived from DMD patient (exon 52 mutated) were also employed and treated with various doses of BIO101 ranging from 1 to 5 µM. Myoblast differentiation was investigated by fluorescent microscopy. Signalling pathways activation status was assessed by western blot. Oxygen consumption rate was measured using a Seahorse XF Analyzer. BIO101 treatment significantly improved physical performances of C57BL10-mdx mice when compared to vehicle-treated mdx animals: running distance (2.4-fold increase); TA muscle maximal isometric force (+ 15%, p<0.01). KM571 human myotubes exposed to BIO101 for two days displayed an improved basal and maximal mitochondrial respiration (+20% in OCR, p<0.01). Additionally, BIO101 stimulated KM571 differentiation according to increased myofibers diameter, number of nuclei per myotube and fusion index (+21%, p<0.001, +34%, p<0.01 and +7%, p<0.01, respectively) consistently with a rapid and significant activation of AKT/mTOR and MAPK signalling pathways both involved in muscle anabolism. Our study demonstrates that sarconeos (API BIO101), increases muscle performance consistently with improved mitochondrial respiration and anabolism. These results warrant further investigations notably on mitochondrial biogenesis and energy metabolism. Sarconeos, for which Orphan disease designation applications have been lodged could offer a new option, alone or in combination with gene therapies, for the treatment of DMD.