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Gene Therapy Sep 2020Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle-wasting disorders affecting young boys caused by mutations in the DMD gene. Exon skipping has... (Review)
Review
Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle-wasting disorders affecting young boys caused by mutations in the DMD gene. Exon skipping has emerged as a promising therapy for DMD. Antisense oligonucleotides (AONs) are designed to induce the skipping of exon(s), in order to restore the reading frame, and therefore, allow for dystrophin expression. Eteplirsen and golodirsen, AONs for DMD exons 51 and 53 skipping, have been recently approved by the FDA. Viltolarsen, an AON for DMD exon 53 skipping, was approved in Japan earlier this year. Although promising, the efficacy of eteplirsen and AON sequence employed remain controversial. In addition, exon skipping faces challenges including the applicability and delivery. This article reviews and discusses exon skipping and the current advances being made in the field, on drugs, multi-exon skipping, sequence design, and applicability. We also discuss challenges and future directions that will facilitate the development of exon skipping therapy.
Topics: Dystrophin; Exons; Humans; Male; Muscular Dystrophy, Duchenne; Oligonucleotides
PubMed: 32483212
DOI: 10.1038/s41434-020-0156-6 -
Medicine and Science in Sports and... Jan 2022The ability of skeletal muscle to adapt to eccentric (ECC) contraction-induced injury is known as the repeated bout effect (RBE). Despite the RBE being a...
PURPOSE
The ability of skeletal muscle to adapt to eccentric (ECC) contraction-induced injury is known as the repeated bout effect (RBE). Despite the RBE being a well-established phenomenon observed in skeletal muscle, cellular and molecular events particularly those at the membranes that contribute to the adaptive potential of muscle have yet to be established. Therefore, the purpose of this study was to examine how membrane-associated proteins respond to the RBE.
METHODS
Anterior crural muscles of C57BL/6 female mice (3-5 months) were subjected to repeated bouts of in vivo ECCs, with isometric torque being measured immediately before and after injury. A total of six bouts were completed with 7 d between each bout. Protein content of dystrophin, β-sarcoglycan, and junctophilin were then assessed via immunoblotting in injured and uninjured muscles.
RESULTS
When expressed relative to preinjury isometric torque of bout 1, deficits in postinjury isometric torque during bout 2 (38%) did not differ from bout 1 (36%; P = 0.646) and were attenuated during bouts 3 through 6 (range, 24%-15%; P ≤ 0.014). Contents of dystrophin, β-sarcoglycan, and junctophilin did not change immediately after a single bout of 50 maximal ECCs (P ≥ 0.155); however, as a result of repeated bouts, contents of dystrophin, β-sarcoglycan, and junctophilin all increased compared with muscles that completed one or no bouts of ECC contractions (P ≤ 0.003).
CONCLUSIONS
The RBE represents a physiological measure of skeletal muscle plasticity. Here, we demonstrate that repeated bouts of ECC contractions increase contents of dystrophin, β-sarcoglycan, and junctophilin and attenuate postinjury torque deficits. Given our results, accumulation of membrane-associated proteins likely contributes to strength adaptations observed after repeated bouts of ECC contractions.
Topics: Adaptation, Physiological; Animals; Dystrophin; Female; Membrane Proteins; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Skeletal; Sarcoglycans; Up-Regulation
PubMed: 34334717
DOI: 10.1249/MSS.0000000000002762 -
Human Molecular Genetics Jul 2023Duchene muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are genetic neuromuscular disorders that affect skeletal and cardiac muscle resulting from mutations...
Duchene muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are genetic neuromuscular disorders that affect skeletal and cardiac muscle resulting from mutations in the dystrophin gene (DMD), coding for dystrophin protein. Read-through therapies hold great promise for the treatment of genetic diseases harboring nonsense mutations, such as DMD/BMD, as they enable a complete translation of the affected mRNA. However, to date, most read-through drugs have not achieved a cure for patients. One possible explanation for the limitation of these therapies for DMD/BMD is that they rely on the presence of mutant dystrophin mRNAs. However, the mutant mRNAs containing premature termination codons are identified by the cellular surveillance mechanism, the nonsense-mediated mRNA decay (NMD) process, and are degraded. Here, we show that the combination of read-through drugs together with known NMD inhibitors have a synergistic effect on the levels of nonsense-containing mRNAs, among them the mutant dystrophin mRNA. This synergistic effect may enhance read-through therapies' efficacy and improve the current treatment for patients.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Codon, Terminator; Nonsense Mediated mRNA Decay; Mutation
PubMed: 37145099
DOI: 10.1093/hmg/ddad072 -
Proceedings of the National Academy of... Jul 2023Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the gene, leading to complete absence of dystrophin and progressive degeneration of...
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of exon 52 (Δ52), expression of an internally shortened dystrophin can be achieved by skipping of exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated Δ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). Δ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in Δ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of Δ51-52 pigs and its absence in Δ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in Δ52 vs. wild-type (WT) samples, was normalized in Δ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in Δ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in Δ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of exon 51 in Δ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of Δ51-52 pigs will show if they develop symptoms of the milder BMD.
Topics: Animals; Swine; Muscular Dystrophy, Duchenne; Dystrophin; Proteome; Stroke Volume; Ventricular Function, Left; Muscle, Skeletal; Exons
PubMed: 37428903
DOI: 10.1073/pnas.2301250120 -
Journal of Biosciences 2023Duchenne muscular dystrophy (DMD) is an X-linked genetic disease primarily affecting boys causing loss of the dystrophin protein, ultimately leading to muscle wastage... (Review)
Review
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease primarily affecting boys causing loss of the dystrophin protein, ultimately leading to muscle wastage and death by cardiac or respiratory failure. The genetic mutation involved can be overcome with antisense oligonucleotides which bind to a pre-mRNA and results in reading frame restoration by exon skipping. Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense agents with a neutral backbone derived from RNA which can induce effective exon skipping. In this review, the evolution of PMOs in exon skipping therapy for the last two decades has been detailed with the gradual structural and functional advancements. Even though the success rate of PMObased therapy has been high with four FDA approved drugs, several key challenges are yet to overcome, one being the dystrophin restoration in cardiac muscle. The current scenario in further improvement of PMOs has been discussed along with the future perspectives that have the potential to revolutionize the therapeutic benefits in DMD.
Topics: Male; Humans; Morpholinos; Dystrophin; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; Exons
PubMed: 37846020
DOI: No ID Found -
International Journal of Biological... Apr 2024Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive and severe muscle weakening and degeneration. Among the various... (Review)
Review
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive and severe muscle weakening and degeneration. Among the various forms of muscular dystrophy, it stands out as one of the most common and impactful, predominantly affecting boys. The condition arises due to mutations in the dystrophin gene, a key player in maintaining the structure and function of muscle fibers. The manuscript explores the structural features of dystrophin protein and their pivotal roles in DMD. We present an in-depth analysis of promising therapeutic approaches targeting dystrophin and their implications for the therapeutic management of DMD. Several therapies aiming to restore dystrophin protein or address secondary pathology have obtained regulatory approval, and many others are ongoing clinical development. Notably, recent advancements in genetic approaches have demonstrated the potential to restore partially functional dystrophin forms. The review also provides a comprehensive overview of the status of clinical trials for major therapeutic genetic approaches for DMD. In addition, we have summarized the ongoing therapeutic approaches and advanced mechanisms of action for dystrophin restoration and the challenges associated with DMD therapeutics.
Topics: Male; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Muscle Fibers, Skeletal; Genetic Diseases, X-Linked
PubMed: 38428778
DOI: 10.1016/j.ijbiomac.2024.130544 -
International Journal of Molecular... Oct 2018Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by... (Review)
Review
Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. The current understanding of the pathomechanisms in the dystrophic heart is limited, but there is growing evidence that dysfunctional voltage-dependent ion channels in dystrophin-deficient cardiomyocytes play a significant role. Herein, we summarize the current knowledge about abnormalities in voltage-dependent sarcolemmal ion channel properties in the dystrophic heart, and discuss the potentially underlying mechanisms, as well as their pathophysiological relevance.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathies; Dystrophin; Humans; Ion Channels; Potassium Channels; Sarcolemma; Sodium Channels
PubMed: 30360568
DOI: 10.3390/ijms19113296 -
The Journal of Clinical Investigation Jun 2020Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical... (Review)
Review
Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.
Topics: Animals; CRISPR-Cas Systems; Dystrophin; Gene Editing; Humans; Muscular Dystrophy, Duchenne; Mutation
PubMed: 32478678
DOI: 10.1172/JCI136873 -
Cardiovascular Research Jun 2022Alterations in the DMD gene, which codes for the protein dystrophin, cause forms of dystrophinopathies such as Duchenne muscular dystrophy, an X-linked disease.... (Review)
Review
Alterations in the DMD gene, which codes for the protein dystrophin, cause forms of dystrophinopathies such as Duchenne muscular dystrophy, an X-linked disease. Cardiomyopathy linked to DMD mutations is becoming the leading cause of death in patients with dystrophinopathy. Since phenotypic pathophysiological mechanisms are not fully understood, the improvement and development of new disease models, considering their relative advantages and disadvantages, is essential. The application of genetic engineering approaches on induced pluripotent stem cells, such as gene-editing technology, enables the development of physiologically relevant human cell models for in vitro dystrophinopathy studies. The combination of induced pluripotent stem cells-derived cardiovascular cell types and 3D bioprinting technologies hold great promise for the study of dystrophin-linked cardiomyopathy. This combined approach enables the assessment of responses to physical or chemical stimuli, and the influence of pharmaceutical approaches. The critical objective of in vitro microphysiological systems is to more accurately reproduce the microenvironment observed in vivo. Ground-breaking methodology involving the connection of multiple microphysiological systems comprised of different tissues would represent a move toward precision body-on-chip disease modelling could lead to a critical expansion in what is known about inter-organ responses to disease and novel therapies that have the potential to replace animal models. In this review, we will focus on the generation, development, and application of current cellular, animal, and potential for bio-printed models, in the study of the pathophysiological mechanisms underlying dystrophin-linked cardiomyopathy in the direction of personalized medicine.
Topics: Animals; Cardiomyopathies; Dystrophin; Heart; Induced Pluripotent Stem Cells; Muscular Dystrophy, Duchenne
PubMed: 34254111
DOI: 10.1093/cvr/cvab232 -
Journal of Biomolecular Screening Dec 2015Duchenne muscular dystrophy (DMD) is a genetic, lethal, muscle disorder caused by the loss of the muscle protein, dystrophin, leading to progressive loss of muscle... (Review)
Review
Duchenne muscular dystrophy (DMD) is a genetic, lethal, muscle disorder caused by the loss of the muscle protein, dystrophin, leading to progressive loss of muscle fibers and muscle weakness. Drug discovery efforts targeting DMD have used two main approaches: (1) the restoration of dystrophin expression or the expression of a compensatory protein, and (2) the mitigation of downstream pathological mechanisms, including dysregulated calcium homeostasis, oxidative stress, inflammation, fibrosis, and muscle ischemia. The aim of this review is to introduce the disease, its pathophysiology, and the available research tools to a drug discovery audience. This review will also detail the most promising therapies that are currently being tested in clinical trials or in advanced preclinical models.
Topics: Animals; Antioxidants; Benzoxazoles; Calcium; Disease Models, Animal; Drug Discovery; Dystrophin; Gene Expression; Humans; Muscular Dystrophy, Duchenne; Oxadiazoles
PubMed: 25975656
DOI: 10.1177/1087057115586535