Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse

Abstract

BackgroundDuchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle. There is significant evidence demonstrating that increasing levels of the dystrophin-related protein, utrophin, in mouse models results in sarcolemmal bound utrophin and prevents the muscular dystrophy pathology. The aim of this work was to develop a small molecule which increases the levels of utrophin in muscle and thus has therapeutic potential.Methodology and Principal FindingsWe describe the in vivo activity of SMT C1100; the first orally bioavailable small molecule utrophin upregulator. Once-a-day daily-dosing with SMT C1100 reduces a number of the pathological effects of dystrophin deficiency. Treatment results in reduced pathology, better muscle physiology leading to an increase in overall strength, and an ability to resist fatigue after forced exercise; a surrogate for the six minute walk test currently recommended as the pivotal outcome measure in human trials for DMD.Conclusions and SignificanceThis study demonstrates proof-of-principle for the use of in vitro screening methods in allowing identification of pharmacological agents for utrophin transcriptional upregulation. The best compound identified, SMT C1100, demonstrated significant disease modifying effects in DMD models. Our data warrant the full evaluation of this compound in clinical trials in DMD patients.

Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of α1-syntrophin and PLC/PKC in SOCE regulation

“…␣ 1 -Syntrophin seems to be sufficient to regulate abnormal cation entry triggered by SR store depletion in the absence of dystrophin. As already experimented with utrophin, upregulation of ␣ 1 -syntrophin could be used for compensating the absence of dystrophin (55). Furthermore, ␣ 1 -syntrophin presents the advantage of being already expressed in DMD muscle cells, which excludes the risk of immune response in treated patients.…”

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…The use of SMT C1100 translated into improvement of muscle morphology and functionality, with utrophin detected also in heart and diaphragm in mdx mice [43]. A phase I clinical trial showed that SMT C1100 is safe and well tolerated [44].…”

Reawakening Atlas: Chemical Approaches To Repair or Replace Dysfunctional Musculature

“…However, optimism should be cautious, in light of the recent clinical trials failure of Ataluren, a small-molecular agent designed to make ribosomes become less sensitive to, or possibly ignore premature stop codons, despite promising preclinical data. 98,99 Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy diagnosed in adults and also causes cataracts, heart defects, endocrine problems, and poor muscle relaxation. 100 DM1 is caused by expanded trinucleotide repeats in the 3′ untranslated region (3′UTR) of the mRNA of dystrophia myotonica protein kinase (DMPK), which binds and sequesters the protein muscle blind-like1 (MBL1) and produces mRNA slicing defects in a number of genes.…”