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Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Others: Utrophin is a protein that is expressed at neuromuscular and musculotendinous junctions. It shows homology to dystrophin. Upregulation of utrophin may be able to compensate for some of the effects of dystrophin loss.Inducing muscle hypertrophy by upregulating genes involved in muscle growth, such as insulin-like growth factor 1 (IGF-1) or L-arginine, may help to fight muscle wasting.Blocking the effect of myostatin as a negative regulator of muscle mass could have a similar beneficial effect.
Genetics
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Jane A. Hurst, Richard H. Scott
Supportive management of muscular weakness and prevention of contractures should be provided, including physiotherapy and nocturnal respiratory support. Children should be under surveillance for, and management of, cardiac failure using standard therapies. Gene therapy and upregulation of the dystrophin-related protein utrophin are therapeutic hopes for the future.
Common therapeutic advances for Duchenne muscular dystrophy (DMD)
Published in International Journal of Neuroscience, 2021
Arash Salmaninejad, Yousef Jafari Abarghan, Saeed Bozorg Qomi, Hadi Bayat, Meysam Yousefi, Sara Azhdari, Samaneh Talebi, Majid Mojarrad
A new orally bioavailable drug, SMT C1100, recently is developed (Table 1). This drug can successfully upregulate the expression of utrophin in DMD patients and mdx mice. It is represented that in vivo activity of SMT C1100 is able to increase utrophin mRNA level by 2-fold and consequently increase utrophin protein in the heart, diaphragm and skeletal muscles [91]. It is also demonstrated that using SMT C1100 beside Prednisone has an interactive effect [91]. SMT C1100 has completely passed the phase I trial and now it is proceeding phase II. It is reported that increasing 4 percent in the expression level of dystrophin is sufficient for noticeable survival and demands the emphasize on SMT C1100 drug for evaluation in DMD patients [92]. SMT C1100 decreases the serum creatine kinases (CK) level, muscle fibrosis, necrosis and membrane damage in skeletal muscle. In addition, SMT C1100 is safe and well-tolerated among healthy volunteers. SMT022357 is another chemical compound of SMT C1100 family. This chemical molecule closely related to the SMT C1100 structurally. SMT022357 treatment increases utrophin level and results in pathophysiological improvement in the muscles of the mdx mouse (Table 1) [5]. Furthermore, some other commonly utrophin modulation pre-clinical strategies are summarized in Table 1.
The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy
Published in Expert Opinion on Orphan Drugs, 2018
Simon Guiraud, David Roblin, Davies. E. Kay
Nearly 30 years after the discovery of the utrophin gene, the characterization of the gene and protein organization revealed a high homology to dystrophin, disrupted in DMD. Utrophin is an autosomal, structural, and functional paralog of dystrophin able to compensate for the lack of dystrophin in different animal models of DMD. Utrophin modulation approach has the potential to offer a universal treatment to all DMD patients regardless of their genetic defect. Despite a high level of structural identity, utrophin and dystrophin differ in their spatiotemporal expression. Utrophin is ubiquitously expressed mainly in embryonic tissue and is primarily restricted to the neuromuscular junction in adult muscle. Utrophin is also expressed in cardiac fibers and in regenerating skeletal muscle fibers. Dystrophin is expressed in the skeletal, cardiac, and smooth muscles in adult. Some sequence differences between the two proteins underlie functional differences in binding partners and explain that utrophin may not be able to recapitulate all the functions of dystrophin. Thus, utrophin modulation strategy may lead to a mild BMD phenotype. The ongoing clinical trials of utrophin modulation will test this hypothesis. This approach to therapy is still very attractive since both exon skipping and AAV-mediated gene therapy with dystrophin minigenes will also lead to a BMD phenotype.
Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy
Published in Expert Opinion on Pharmacotherapy, 2022
Kelsie D. Kracht, Nicole L. Eichorn, Daniel J. Berlau
Utrophin is an autosomal paralogue of dystrophin and is thought to act as a substitute for dystrophin deficiency in DMD [100]. Ezutromid inhibits the aryl hydrocarbon (AhR) receptor to increase the production of utrophin and was previously under investigation as a utrophin modulator [90]. Ezutromid (SMT-C1100) went on to a phase 2 trial but was unfortunately discontinued due to its rapid clearance from the body [101]. Further development of utrophin modulation has evolved into the gene therapy, GALGT2, which upregulate utrophin expression [102]. One benefit of pursuing this drug class is that all patients with DMD could see benefits regardless of their specific dystrophin mutation.