Abstract
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.
Highlights
Duchenne muscular dystrophy (DMD) is a lethal pediatric muscle disorder, affecting 1 out of 5000 males born worldwide [1]
In a recent analysis including 7149 DMD patients [8], large mutations were identified in approximately 79% of the patients, in which large deletions account for 68% and large duplications are responsible for the rest 11%
To interact with ribosome, which leads to insertion of an alternative amino acids at the point of Theoretically, it is applicable to all nonsense mutations, which represent up to 10% of all DMD cases
Summary
Duchenne muscular dystrophy (DMD) is a lethal pediatric muscle disorder, affecting 1 out of 5000 males born worldwide [1]. Dystrophin is a cytoskeletal protein that connects the dystrophin-associated protein complex (DAPC) and the intracellular cytoskeleton c-actin [4] It contains four functional domains: actin-binding amino-terminal domain (ABD), a central rod domain, a cysteine-rich domain, and a carboxy-terminal domain [5]. Given that DMD mutations lead to dystrophin deficiency, therapies that restore dystrophin expression have been developed to meet clinical needs. Previous studies of DMD pathogenesis mainly focused on muscle wasting caused by dystrophin deficiency in myofibers, whereas recent findings suggest that DMD may be a stem cell disease [6]. We summarize new evidence of DMD pathogenesis and highlight therapies targeting the DMD gene defects in both muscle fibers and myogenic stem cells
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