Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

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.

Keywords: Duchenne muscular dystrophy; cell transplantation; dystrophin restoration; gene therapy; pathogenesis.

Figure 1

Dystrophin gene with exon mutation spots and their corresponding domains. (A) The structure of dystrophin gene. Dystrophin gene contains 79 exons. N-terminal domain (NT): exon 2–8; Central rod domain: exon 9–61; Cysteine-rich domain (CR): exon 64–70; C-terminal domain (CT): exon 71–79. The arrow shape of the adjacent exons shows open reading frame (ORF) compatibility. The CR and CT domains comprise the WW domain, EF hand and ZZ domains. (B) The schematic of dystrophin protein structure and dystrophin-sarcolemma interaction. In skeletal muscle, central rod domain 1–3 and 10–12, CR, CT binds to the sarcolemma, termed membrane binding domains (MBDs). In cardiac muscle, R10–12 do not bind to the sarcolemma. The N-terminal domain contains the primary actin binding domain which connects F-actin. The CR and first half of the CT bind to transmembrane β-dystroglycan. CT contains the dystrobrevin- and syntrophin-binding sites, which bind to the two transmembrane proteins on sarcolemma. The NT, CR, and CT are considered essential for dystrophin function. R: rod domain. H: hinge.

Figure 2

How intrinsic DMD gene deficit affects satellite cells (SC) activity and function. Normal SC performs asymmetric division when activated, while dystrophic SC fails to complete myogenic lineage commitment. Cell polarity regulator Mark2 is repressed in dystrophic SCs, resulting in the absence of Pard3 protein in the apical position. Carm1 in dystrophic SCs is inactivated by p38γ, leading to Pax7 methylation deficiency and subsequent inhibition of Myf5 expression. Wild-type myogenic cells fuse with existing muscle fibers or differentiate to form new muscle fibers, whereas dystrophic satellite cells lose their differentiation capacity.