P.318 - AT-300, a calcium modulator, improves muscle force production and decreases muscle degeneration in D2-mdx model of Duchenne muscular dystrophy

Abstract

AT-300 is a peptide, a new class of drugs that selectively modulate mechanosensitive cation channels. These channels are involved in disease progression in DMD and murine models. The objective of these investigations was to determine AT-300 1)PK in mouse muscle and 2) acute and 6 weeks in vivo efficacy in the D2-mdx. PK and efficacy testing were conducted on DBA/2J and D2-mdx murine model of DMD at 6–9 weeks of age. Efficacy was measured in situ with a muscle lever system. Isometric torque after 20 eccentric contractions of the hind limb plantar flexors was compared to baseline and to controls. Muscle was evaluated with Evans Blue dye as an indicator of sarcolemmal damage. Additionally, histological analysis was performed to determine numbers of central nuclei, muscle cell morphometry and quantitation of fibrosis. Skeletal and cardiac muscle concentrations increased with increasing dosage, time and exercise activity. Target concentration was readily achieved within 7 days. Kidney concentrations were high and appeared to saturate at higher dosage and activity levels. There was a very low brain concentration. AT-300 showed a much higher affinity for binding sites in the tissue (possibly membrane association) than to serum protein and resistance to enzymatic digestion. AT-300 protects skeletal muscle to EC injury by ~50% compared to the untreated group. Body weight loss was significantly less in treated vs. control mice after 6 weeks treatment, also showing preservation of muscle fiber cross-sectional area. AT-300 partially prevented muscle force drop after eccentric contraction. There was no difference in treated mice on EBD incorporation, central nucleation, and interstitial fibrosis. AT-300 protects against decrease muscle force loss in vivo caused by eccentric contraction injury and reduces muscle degeneration. Longer studies are needed to assess the full effects of AT-300 in dystrophic muscle.