G.P.90

• Published in: Neuromuscular disorders : NMD 2014-10, Vol.24 (9), p.821-822
• Main Authors: Capogrosso, R.F, Cozzoli, A, Giustino, A, Mantuano, P, Massari, A.M, Conte, E, Cannone, M, Bellis, M. De, Liantonio, A, Camerino, G.M, De Luca, A
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.104

The progressive myofiber degeneration in Duchenne muscular dystrophy (DMD) is caused by the complex cascade of events triggered by the absence of dystrophin. Studies in the mdx mouse model of DMD have shown that pathology-related post-translational modifications of the Ryanodine receptor subtype 1 (RyR1) result in the dissociation of the stabilizing subunit calstabin1, leading to “leaky” channels and altered Ca2 + homeostasis, a key event in DMD (Bellinger, Nat Med 2009). S48168, also known as ARM210, is a small molecule stabilizer of the calstabin-RyR channel complex that prevents Ca2+ leak without altering RyR1 post-translational modifications. We assessed the effects of 4 weeks oral administration of S48168 (10 and 50 mg/kg/day) on treadmill-exercised mdx mice, starting at 4–5 weeks of age. A functional improvement was observed in vivo in S48168 -treated mdx mice, with a 50% recovery score of maximal forelimb force at 50 mg/kg. Both doses prevented the decline in running performance, observed in vehicle-treated mdx mice, as assessed in an exhaustion test. Ex vivo assessment showed a dose-dependent improvement of diaphragm specific force, with a significant 30% increase of maximal force (100–140 Hz) at 50 mg/kg, while minor, if any, effects were observed in hind-limb EDL muscle. However, and consistently with the S48168 mechanism of action, the mechanical threshold EDL myofibers, an index of calcium handling during contraction, was significantly shifted toward the wild type (wt) values at the highest dose. In parallel, the resting cytosolic calcium level in FDB myofibers was significantly reduced by 25% in the S48168-treated mice. S48168 did not lower CK or LDH plasma levels. However a reduction of damaged area was detected in diaphragm and in gastrocnemius muscle of 50 mg/kg treated mdx mice. Dose-proportional increases in plasma and muscle drug content were also observed, without any signs of toxicity. These results support S48168 as a potential therapy for DMD.