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Expert Review of Neurotherapeutics 2023Duchenne muscular dystrophy (DMD) is a progressive genetic disease leading to muscular weakness. DMD is caused by mutations of the dystrophin gene on the X chromosome... (Review)
Review
INTRODUCTION
Duchenne muscular dystrophy (DMD) is a progressive genetic disease leading to muscular weakness. DMD is caused by mutations of the dystrophin gene on the X chromosome that is responsible for production of dystrophin protein. Dystrophin contributes to structural support in muscle cells and mutations result in dystrophin protein deficiency which causes muscle damage and the associated clinical presentation. Exon skipping medications, including the exon 53 targeting viltolarsen, are the first agents with the ability to partially restore dystrophin protein.
AREAS COVERED
Herein, the authors profile viltolarsen for the DMD patients who are amenable to exon 53 skipping therapy and provide their expert perspectives on this subject.
EXPERT OPINION
Current findings suggest that viltolarsen could play a role in the current and possible future treatment of DMD. Viltolarsen seems to be safe and restores dystrophin protein to around 6% of the normal level. Due to orphan drug status, after the completion of the phase 2 clinical trial, viltolarsen was granted accelerated approval in Japan and in the US. A phase 3 trial is currently in progress and needs to earn full approval. Although a multidisciplinary approach continues to be critical, the addition of exon skipping agents like viltolarsen may improve the quality of patients' lives. However, data on the long-term safety and efficacy of this medication are not yet available due to its recent accelerated approval.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Oligonucleotides, Antisense; Exons
PubMed: 37572081
DOI: 10.1080/14737175.2023.2246658 -
Hellenic Journal of Cardiology : HJC =... 2023Duchenne muscular dystrophy is a fatal X-linked recessive disease affecting approximately 1 in 3500 births. It is characterized by a genetic lack of dystrophin, which is... (Review)
Review
Duchenne muscular dystrophy is a fatal X-linked recessive disease affecting approximately 1 in 3500 births. It is characterized by a genetic lack of dystrophin, which is an essential protein for maintaining muscle integrity. The lack of dystrophin plays a pathophysiological role in the development of dilated cardiomyopathy in Duchenne muscular dystrophy. Currently, no consensus exists on specific pharmacological therapy guidelines for these patients; however, it centers around the guidelines for heart failure management. This systematic review investigated 12 randomized control trials dating back to 2005 in the pharmacotherapy of patients with dilated cardiomyopathy Duchenne muscular dystrophy. This review specifically included angiotensin-converting enzyme inhibitors, aldosterone receptor blockers, angiotensin receptor/neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Despite their limitations, these studies have shown promising effects in improving the overall heart function and prognosis in patients with this condition. However, to attain higher statistical significance, future studies should investigate larger populations and for longer periods.
Topics: Humans; Cardiomyopathy, Dilated; Muscular Dystrophy, Duchenne; Dystrophin; Angiotensin-Converting Enzyme Inhibitors; Adrenergic beta-Antagonists
PubMed: 37406964
DOI: 10.1016/j.hjc.2023.06.007 -
Neuromuscular Disorders : NMD Oct 2023We aimed to investigate the clinical, pathological, and genetic characteristics of Chinese female dystrophinopathy and to identify possible correlations among them. One...
We aimed to investigate the clinical, pathological, and genetic characteristics of Chinese female dystrophinopathy and to identify possible correlations among them. One hundred forty genetically and/or pathologically confirmed female DMD variant carriers were enrolled, including 104 asymptomatic carriers and 36 symptomatic carriers. Twenty of 36 symptomatic and 16 of 104 asymptomatic carriers were sporadic with no family history. Muscle pathological analysis was performed in 53 carriers and X chromosome inactivation (XCI) analysis in 19 carriers. In asymptomatic carriers, the median age was 35.0 (range 2.0-58.0) years, and the serum creatine kinase (CK) level was 131 (range 60-15,745) IU/L. The median age, age of onset, and CK level of symptomatic carriers were 15.5 (range 1.8-62.0) years, 6.3 (range 1.0-54.0) years, and 6,659 (range 337-58,340) IU/L, respectively. Four female carriers with X-autosome translocation presented with a Duchenne muscular dystrophy (DMD) phenotype. Skewed XCI was present in 70.0% of symptomatic carriers. Compared to Becker muscular dystrophy (BMD)-like carriers, DMD-like carriers were more likely to have an early onset age, rapidly progressive muscle weakness, delayed walking, elevated CK levels, severe reduction of dystrophin, and skewed XCI. Our study reports the largest series of symptomatic female DMD carriers and suggests that delayed walking, elevated CK levels, severe reduction of dystrophin, X-autosome translocation, and skewed XCI pattern are associated with a severe phenotype in female dystrophinopathy.
Topics: Humans; Female; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Infant; Dystrophin; East Asian People; Heterozygote; Mutation; Muscular Dystrophy, Duchenne
PubMed: 37716855
DOI: 10.1016/j.nmd.2023.08.008 -
Annals of Internal Medicine Sep 2023The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of... (Review)
Review
The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of a study of 12 boys. After a contentious review process and a high-profile meeting of an external advisory committee, FDA leaders concluded that very small increases in treated patients' levels of dystrophin, a muscle protein, were reasonably likely to predict clinical benefit. The eteplirsen approval, which was followed by approvals of other drugs in the same class via the same pathway, has been controversial because of the questionable evidence underlying these decisions, delays in mandated postapproval testing, and high U.S. prices. Questions remain about the effectiveness and long-term safety of these products. Although the FDA initially set a November 2020 deadline for eteplirsen's manufacturer to complete a clinical trial determining whether the drug has clinical benefit, the company will not complete the trial until 2024 or later. The relationship between levels of truncated dystrophin, the muscle protein studied in eteplirsen's pivotal trial, and clinical outcomes remains uncertain. Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.
Topics: United States; Male; Humans; Dystrophin; Muscular Dystrophies; Muscle Proteins; Advisory Committees; Patient Safety
PubMed: 37603868
DOI: 10.7326/M23-1073 -
Endokrynologia Polska 2021It is well established that thyroid hormones significantly affect skeletal muscle function, causing symptoms like myalgia and muscle weakness. Hypothyroid patients...
INTRODUCTION
It is well established that thyroid hormones significantly affect skeletal muscle function, causing symptoms like myalgia and muscle weakness. Hypothyroid patients present increased levels of creatine kinase (CK), indicating muscle destruction. Lately, we proposed new serum markers of muscle disturbances in thyroid disorders: titin (TTN) and dystrophin (DMD). The aim of this study is to determine the association between thyroid status, muscle metabolism, and serum levels of TTN and DMD in patients affected by hypoand hyperthyroidism, before and after the treatment.
MATERIAL AND METHODS
In the study 56 subjects were enrolled. The studied group consisted of 16 patients with newly diagnosed overt hypothyroidism and 20 patients with hyperthyroidism. Twenty healthy controls were also included in the study. Body composition, thyroid hormones, and biochemical markers of muscle deterioration levels were evaluated before and after restoration of euthyroidism.
RESULTS
Dystrophin and TTN levels were noticeably lower in the hypothyroid group and hyperthyroid group in comparison with controls, at the border of statistical significance. Along with the thyroid hormones and CK normalisation, DMD levels increased in the hypothyroid group, with no significant lowering of TTN levels. However, TTN concentrations and the fT3/fT4 ratio became significantly lower than in controls. Hyperthyroid patients experienced no significant changes in TTN and DMD.
CONCLUSIONS
The presented data indicate that TTN and DMD are potential new markers of musculoskeletal deterioration in thyroid disorders. In addition, the shift in TTN and DMD serum concentrations after the treatment of hypothyroidism accompanied by decreased fT3/fT4 ratio suggest the influence of the chosen therapeutic approach on muscle metabolism.
Topics: Adult; Case-Control Studies; Connectin; Dystrophin; Female; Humans; Hyperthyroidism; Male; Middle Aged; Poland; Thyroid Diseases; Thyroid Gland; Thyroid Hormones
PubMed: 33295636
DOI: 10.5603/EP.a2020.0083 -
Journal of Neuromuscular Diseases 2021Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for...
Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for Duchenne Muscular Dystrophy (DMD). However, these treatments have only demonstrated variable and largely sub-therapeutic levels of restored dystrophin protein in DMD patients, limiting their clinical impact. To better understand variable protein expression and the behavior of truncated dystrophin protein in vivo, we assessed turnover dynamics of restored dystrophin and dystrophin glycoprotein complex (DGC) proteins in mdx mice after exon skipping therapy, compared to those dynamics in wild type mice, using a targeted, highly-reproducible and sensitive, in vivo stable isotope labeling mass spectrometry approach in multiple muscle tissues. Through statistical modeling, we found that restored dystrophin protein exhibited altered stability and slower turnover in treated mdx muscle compared with that in wild type muscle (∼44 d vs. ∼24 d, respectively). Assessment of mRNA transcript stability (quantitative real-time PCR, droplet digital PCR) and dystrophin protein expression (capillary gel electrophoresis, immunofluorescence) support our dystrophin protein turnover measurements and modeling. Further, we assessed pathology-induced muscle fiber turnover through bromodeoxyuridine (BrdU) labeling to model dystrophin and DGC protein turnover in the context of persistent fiber degeneration. Our findings reveal sequestration of restored dystrophin protein after exon skipping therapy in mdx muscle leading to a significant extension of its half-life compared to the dynamics of full-length dystrophin in normal muscle. In contrast, DGC proteins show constant turnover attributable to myofiber degeneration and dysregulation of the extracellular matrix (ECM) in dystrophic muscle. Based on our results, we demonstrate the use of targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of disease and propose its use to optimize alternative gene correction strategies in development for DMD.
Topics: Animals; Dystroglycans; Dystrophin; Exons; Genetic Therapy; Mice; Mice, Inbred mdx; Muscle Fibers, Skeletal; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense
PubMed: 34569969
DOI: 10.3233/JND-210696 -
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 -
Progress in Molecular Biology and... 2021Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by loss of dystrophin protein, encoded by the DMD gene. DMD manifests early in childhood as... (Review)
Review
Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by loss of dystrophin protein, encoded by the DMD gene. DMD manifests early in childhood as difficulty walking, progresses to loss of ambulation by the teens, and leads to death in early adulthood. Adeno-associated virus-vectorized gene therapies to restore dystrophin protein expression using gene replacement or antisense oligonucleotide-mediated pre-mRNA splicing modulation have emerged, making great strides in uncovering barriers to gene therapies for DMD and other genetic diseases. While this first-generation of DMD therapies are being evaluated in ongoing clinical trials, uncertainties regarding durability and therapeutic efficacy prompted the development of new experimental therapies for DMD that take advantage of somatic cell gene editing. These experimental therapies continue to advance toward clinic trials, but questions remain unanswered regarding safety and translatable efficacy. Here we review the advancements toward treatment of DMD using gene editing and modulation therapies, with an emphasis on those nearest to clinical applications.
Topics: Adolescent; Adult; Dystrophin; Exons; Gene Editing; Humans; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense
PubMed: 34175043
DOI: 10.1016/bs.pmbts.2021.01.029 -
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