Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.
Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.
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DOI：
10.1096/fj.201700182rrr
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
De Luca A
中科院分区：
文献类型：
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作者：
Capogrosso RF;Mantuano P;Uaesoontrachoon K;Cozzoli A;Giustino A;Dow T;Srinivassane S;Filipovic M;Bell C;Vandermeulen J;Massari AM;De Bellis M;Conte E;Pierno S;Camerino GM;Liantonio A;Nagaraju K;De Luca A
肌纤维缺乏肌营养不良蛋白进行长期改变的Ca 2+稳态，部分原因是泄漏的Ca 2+释放ryanodine（RyR）通道。S48168/ARM210是一种RyR钙释放通道稳定剂（Rycal化合物），预期可增强钙稳定蛋白与RyR通道复合物的再结合，并可能减轻肌营养不良蛋白缺陷骨骼肌和心肌中的病理性Ca2+渗漏。本研究通过由2个独立实验室平行进行的首次概念验证、短期（4周）、1期给药，随后进行12周给药（2期），系统研究了S48168/ARM210对mdx小鼠表型的影响。给mdx小鼠饮水中加入两种不同浓度（50或10 mg/kg/d）的S48168/ARM 210，分别给药4和12 wk。小鼠每周进行两次跑步机训练（12 m/min，持续30 min），以揭示轻度疾病。该测试之后是体内前肢和后肢握力和疲劳性测量、离体趾长伸肌（EDL）和膈肌（DIA）力收缩测量以及组织学和生化分析。4周和12周后，治疗导致功能（握力、DIA和EDL肌肉的离体力产生）以及组织学改善，无不良反应。此外，钙稳态的细胞生物标志物水平增加。因此，这些数据表明，S48168/ARM210在测试的剂量水平下可能是治疗杜氏肌营养不良症（DMD）的安全治疗选择。卡波格罗索河F.、Mantuano，P.，Uaesoontrachoon，K.，Cozzoli，A.，Giustino，A.，Dow，T.，Srinivassane，S.，Filipovic，M.，贝尔角，Vandermeulen，J.，Massari，A. M.，De Bellis，M.，孔戴，E.，Pierno，S.，卡梅里诺湾M.，Liantonio，A.，Nagaraju，K.，德卢卡A。Ryanodine通道复合物稳定剂化合物S48168/ARM210作为抗肌萎缩蛋白缺陷型mdx小鼠的疾病修饰剂：概念验证研究和疗效的独立验证。
Muscle fibers lacking dystrophin undergo a long-term alteration of Ca2+ homeostasis, partially caused by a leaky Ca2+ release ryanodine (RyR) channel. S48168/ARM210, an RyR calcium release channel stabilizer (a Rycal compound), is expected to enhance the rebinding of calstabin to the RyR channel complex and possibly alleviate the pathologic Ca2+ leakage in dystrophin-deficient skeletal and cardiac muscle. This study systematically investigated the effect of S48168/ARM210 on the phenotype of mdx mice by means of a first proof-of-concept, short (4 wk), phase 1 treatment, followed by a 12-wk treatment (phase 2) performed in parallel by 2 independent laboratories. The mdx mice were treated with S48168/ARM210 at two different concentrations (50 or 10 mg/kg/d) in their drinking water for 4 and 12 wk, respectively. The mice were subjected to treadmill sessions twice per week (12 m/min for 30 min) to unmask the mild disease. This testing was followed by in vivo forelimb and hindlimb grip strength and fatigability measurement, ex vivo extensor digitorum longus (EDL) and diaphragm (DIA) force contraction measurement and histologic and biochemical analysis. The treatments resulted in functional (grip strength, ex vivo force production in DIA and EDL muscles) as well as histologic improvement after 4 and 12 wk, with no adverse effects. Furthermore, levels of cellular biomarkers of calcium homeostasis increased. Therefore, these data suggest that S48168/ARM210 may be a safe therapeutic option, at the dose levels tested, for the treatment of Duchenne muscular dystrophy (DMD).—Capogrosso, R. F., Mantuano, P., Uaesoontrachoon, K., Cozzoli, A., Giustino, A., Dow, T., Srinivassane, S., Filipovic, M., Bell, C., Vandermeulen, J., Massari, A. M., De Bellis, M., Conte, E., Pierno, S., Camerino, G. M., Liantonio, A., Nagaraju, K., De Luca, A. Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.