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Review
. 2023 Jun 26:14:1183101.
doi: 10.3389/fphys.2023.1183101. eCollection 2023.

Duchenne muscular dystrophy: disease mechanism and therapeutic strategies

Addeli Bez Batti Angulski  1 , Nora Hosny  1 , Houda Cohen  1 , Ashley A Martin  1 , Dongwoo Hahn  1 , Jack Bauer  1 , Joseph M Metzger  1
Affiliations
Review

Duchenne muscular dystrophy: disease mechanism and therapeutic strategies

Addeli Bez Batti Angulski et al. Front Physiol. .

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials.

Keywords: Duchenne muscular dystrophy; dystrophin; muscle disease; pathophysiology; skeletal muscle; therapeutic strategies.

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Conflict of interest statement

JM is on the scientific advisory board of and holds shares in Phrixus Pharmaceuticals Inc., a company developing novel therapeutics for heart failure. The terms of this arrangement have been reviewed and approved by the University of Minnesota in accordance with its conflict-of-interest policies.

Figures

FIGURE 1
FIGURE 1
Full-length dystrophin and representative truncated dystrophins currently in use in clinical trials. (A) Full-length dystrophin versus (B) the truncated dystrophin constructs: i) mini-dystrophin Δ3990, ii) microdystrophin ΔR4-23/ΔCT (µDysH2) and iii) microdystrophin μDys-5R. Domains are identified as the N-terminal actin-binding domain, 1–24 spectrin-like repeats, four hinges (H1–H4), a cysteine-rich domain, and a C-terminal domain (CTD). The nNOS-binding domain is shown by the red numbers (repeats 16 and 17).
FIGURE 2
FIGURE 2
Overview of current and proposed experimental therapies for Duchenne muscular dystrophy (DMD). (A) AAV-mediated gene therapy employs viral vectors to deliver micro- or mini-dystrophin genes. Clinical trials using different adeno-associated virus (AAV) serotypes have shown promise for the treatment of patients with DMD. (B) Exon-skipping strategies seek to mask exons adjacent to others that have been deleted. This results in the restoration of the reading frame and permits the translation of a slightly smaller dystrophin product. (C) Stop codon read-through is a small molecule therapy aimed at reducing ribosomal sensitivity to mRNA stop codons, thus promoting ongoing dystrophin translation in those patients with nonsense mutations. (PTC: premature termination codon). (D) Genome editing, employing a CRISPR/Cas9 platform, has the potential to target specific pathogenic variants in the DMD gene but carries a risk of off-target effects.
FIGURE 3
FIGURE 3
Copolymer-based muscle membrane stabilization of dystrophic muscle. Representation of copolymer-based stabilization of the damaged membrane via the interface of its hydrophobic PPO block (red) with stabilization by PEO blocks (blue) to prevent the entry of extracellular Ca2+ into the cell.
See this image and copyright information in PMC

References

    1. Aartsma-Rus A., Ferlini A., Goemans N., Pasmooij A. M., Wells D. J., Bushby K., et al. (2014). Translational and regulatory challenges for exon skipping therapies. Hum. Gene Ther. 25, 885–892. 10.1089/hum.2014.086 - DOI - PubMed
    1. Aartsma-Rus A., Fokkema I., Verschuuren J., Ginjaar I., van Deutekom J., van Ommen G. J., et al. (2009). Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum. Mutat. 30, 293–299. 10.1002/humu.20918 - DOI - PubMed
    1. Aartsma-Rus A., van Putten M. (2020). The use of genetically humanized animal models for personalized medicine approaches. Dis. Model Mech. 13, dmm041673. 10.1242/dmm.041673 - DOI - PMC - PubMed
    1. Aartsma‐Rus A., Van Deutekom J. C. T., Fokkema I. F., Van Ommen G. B., Den Dunnen J. T. (2006). Entries in the leiden duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading‐frame rule. Muscle and Nerve Official J. Am. Assoc. Electrodiagn. Med. 34, 135–144. 10.1002/mus.20586 - DOI - PubMed
    1. Abmayr S., Chamberlain J. (2006). The structure and function of dystrophin. Molecular mechanisms of muscular dystrophies. Georget. Landes Biosci., 14–34.

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