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 Journal : Official Publication of the Federation of American Societies for Experimental Biology
Roberta Francesca CapogrossoAnnamaria De Luca

Abstract

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 ...Continue Reading

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Citations

Nov 9, 2018·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Tokunbor A LawalKatherine G Meilleur
Jan 26, 2021·European Journal of Medicinal Chemistry·Jesus M AizpuruaAinara Vallejo-Illarramendi
Feb 20, 2021·Nature Reviews. Disease Primers·Dongsheng DuanAnnemieke Aartsma-Rus
Jan 26, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Nalinda B WasalaDongsheng Duan
Nov 5, 2019·Molecular Therapy. Nucleic Acids·Florian BarthélémyM Carrie Miceli
Apr 27, 2021·Frontiers in Physiology·Satvik MareeduGopal J Babu
Aug 6, 2021·Free Radical Biology & Medicine·Richa RathorSom Nath Singh
Aug 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Paola MantuanoAnnamaria De Luca

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Methods Mentioned

BETA
force measurements
PCR
Assay
force measurement
force contraction measurements

Software Mentioned

AcqKnowledge
TREAT
Image J
Stata
NMD

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