Key Points
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Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular disease. It is caused by mutations in the DMD gene that lead to abnormalities of dystrophin protein expression in muscle. DMD is fatal and currently incurable.
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Well-characterized animal models for DMD exist, as do well-characterized and sensitive anatomical, biochemical and physiological methods for evaluating a therapeutic intervention in animal models of DMD.
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Gene therapy approaches (using both vector and vectorless strategies), as well as cell-based therapies (using myoblasts and stem cells) have met with some success in pre-clinical studies. They currently face a number of technical challenges.
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Pharmacological strategies can circumvent many of the hurdles that currently hamper gene- and cell-based therapies.
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This review covers a number of promising pharmacological strategies such as steroids, maintaining calcium homeostasis, decreasing inflammation, increasing muscle strength, suppressing stop codons, upregulation of utrophin, and increasing muscle mass via modulation of growth/developmental factors.
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Strategies associated with utrophin upregulation and increasing muscle mass via modulation of growth/developmental factors are covered in some detail.
Abstract
Duchenne muscular dystrophy (DMD) is a fatal, genetic disorder whose relentless progression underscores the urgency for developing a cure. Although Duchenne initiated clinical trials roughly 150 years ago, therapies for DMD remain supportive rather than curative. A paradigm shift towards developing rational therapeutic strategies occurred with identification of the DMD gene. Gene- and cell-based therapies designed to replace the missing gene and/or dystrophin protein have achieved varying degrees of success. However, pharmacological strategies not designed to replace dystrophin per se appear promising, and can circumvent many hurdles hampering gene- and cell-based therapy. Here, we will review present pharmacological strategies, in particular those dealing with functional substitution of dystrophin by utrophin and enhancing muscle progenitor commitment by myostatin blockade, with a view toward facilitating drug discovery for DMD.
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Acknowledgements
We dedicate this article to the memory of our colleague K. Arahata, whose tireless efforts and scholarship serve as an inspiration in the quest for a cure. We are indebted to the patients, families and organizations who have donated the samples and provided the funding that makes our research possible. Supported by grants from The Medical Research Council (UK), The Muscular Dystrophy Group (UK), Association Contre les Myopathies (France), Duchenne Parents Project (The Netherlands), The Muscular Dystrophy Association (USA) and the National Institutes of Health (USA). We are grateful to S. Bogdanovich, T. Krag and K. Perkins for contributing illustrations and tables. We thank them, as well as numerous other colleagues, for insightful suggestions.
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Online Mendelian Inheritance in Man
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Encyclopedia of Life Sciences
Glossary
- DUCHENNE MUSCULAR DYSTROPHY
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(DMD) A common, genetic neuromuscular disease associated with progressive deterioration of muscle function. In about a third of cases DMD is also associated with impairment of cognitive ability.
- DYSTROPHIN-RELATED PROTEINS
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A family of proteins that are structurally and functionally related to dystrophin, consisting of utrophin or DRP, DRP2 and dystrobrevin. Utrophin seems capable of functionally substituting for the missing dystrophin and improving muscle pathology when experimentally overexpressed.
- SARCOLEMMA
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A thin membrane enclosing a striated muscle fibre.
- REGENERATION
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Muscle has limited ability to regenerate and repair itself when damaged. Cells contained within mature muscle known as satellite cells (sometimes referred to as committed stem cells), proliferate in response to damage and attempt to repair it.
- NECROSIS
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The death of a cell due to external damage or the action of toxic substances. Distinct from programmed cell death (apoptosis), which is a normal part of the developmental process.
- ECCENTRIC CONTRACTION
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Skeletal muscle usually contracts when stimulated. Lengthening of muscle during an active contraction is known as an eccentric contraction (ECC). Dystrophic muscle is particularly susceptible to damage during ECC.
- PROMOTER
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A region of a gene that controls expression of that gene. Its activity is controlled by transcription factors that in turn are activated or repressed by a number of extra- and intracellular mechanisms.
- MYOGENIC
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Originating in or produced by muscle cells.
- MYOBLAST
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An undifferentiated cell in the mesoderm of the vertebrate embryo that is a precursor of a muscle cell.
- CALCIUM HOMEOSTASIS
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The ability of a cell to maintain the requisite intracellular calcium concentration. The body and individual cells have homeostatic mechanisms that can compensate or buffer the lowering or excess levels of intracellular calcium to some degree.
- SARCOPLASMIC RETICULUM
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A meshwork of internal membranes in muscle cells or fibres.
- MYOTUBE
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A muscle fibre precursor formed by the fusion of myoblasts.
- LUCIFERASE
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The enzyme that catalyses the oxidation of luciferin, a reaction that produces bioluminescence.
- INCREASING MUSCLE MASS
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Muscle mass can increase in response to a variety of physiological and pathological stimuli. Growth/developmental factors regulate muscle mass by complex mechanisms including regulation of the proliferation and differentiation of muscle precursor cells.
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Khurana, T., Davies, K. Pharmacological strategies for muscular dystrophy. Nat Rev Drug Discov 2, 379–390 (2003). https://doi.org/10.1038/nrd1085
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DOI: https://doi.org/10.1038/nrd1085
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