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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
Author(s) -
Capogrosso Roberta Francesca,
Mantuano Paola,
Uaesoontrachoon Kitipong,
Cozzoli Anna,
Giustino Arcangela,
Dow Todd,
Srinivassane Sadish,
Filipovic Marina,
Bell Christina,
Vandermeulen Jack,
Massari Ada Maria,
De Bellis Michela,
Conte Elena,
Pierno Sabata,
Camerino Giulia Maria,
Liantonio Antonella,
Nagaraju Kanneboyina,
De Luca Annamaria
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700182rrr
Subject(s) - nova scotia , library science , humanities , art , geography , computer science , archaeology
Muscle fibers lacking dystrophin undergo a long‐term alteration of Ca 2+ homeostasis, partially caused by aleaky Ca 2+ 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 Ca 2+ 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. FASEB J. 32, 1025–1043 (2018). www.fasebj.org