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Journal of Neurology Aug 2023Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disease, characterized by progressive deterioration of skeletal muscle that causes rapid loss... (Review)
Review
Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disease, characterized by progressive deterioration of skeletal muscle that causes rapid loss of mobility. The failure in respiratory and cardiac muscles is the underlying cause of premature death in most patients with DMD. Mutations in the gene encoding dystrophin result in dystrophin deficiency, which is the underlying pathogenesis of DMD. Dystrophin-deficient myocytes are dysfunctional and vulnerable to injury, triggering a series of subsequent pathological changes. In this review, we detail the molecular mechanism of DMD, dystrophin deficiency-induced muscle cell damage (oxidative stress injury, dysregulated calcium homeostasis, and sarcolemma instability) and other cell damage and dysfunction (neuromuscular junction impairment and abnormal differentiation of muscle satellite). We also describe aberrant function of other cells and impaired muscle regeneration due to deterioration of the muscle microenvironment, and dystrophin deficiency-induced multiple organ dysfunction, while summarizing the recent advances in the treatment of DMD.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Muscle, Skeletal; Mutation; Neuromuscular Junction
PubMed: 37258941
DOI: 10.1007/s00415-023-11796-x -
Drugs Sep 2023Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene... (Review)
Review
Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138 kDa) version of the dystrophin protein expressed in normal muscle cells (427 kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 10 vector genomes per kg of body weight or 10 mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the DMD gene.
Topics: Humans; Child; Dystrophin; Muscular Dystrophy, Duchenne; Genetic Therapy; Mutation; Muscles; Muscle, Skeletal
PubMed: 37566211
DOI: 10.1007/s40265-023-01929-x -
Nature Reviews. Drug Discovery Nov 2023Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most... (Review)
Review
Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.
Topics: Child; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Codon, Terminator; Oligonucleotides, Antisense; Mutation
PubMed: 37652974
DOI: 10.1038/s41573-023-00775-6 -
Current Opinion in Neurology Oct 2023The purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular dystrophy (BMD).
RECENT FINDINGS
As several treatment concepts have claimed to convert patients with Duchenne muscular dystrophy (DMD) into a BMD phenotype, BMD itself has moved into the focus of clinical research. Natural history studies have helped to better characterize patients with BMD and the disease is now a target for interventional trials. In parallel, there have been advances in diagnostics and in the development of preclinical models.
SUMMARY
Despite increased collaborative efforts to improve trial readiness amongst patients with BMD, there is still a lack of long-term natural history data, and the broad spectrum of disease severity remains a challenge for well designed clinical trials.
Topics: Humans; Muscular Dystrophy, Duchenne; Phenotype; Research Design
PubMed: 37591308
DOI: 10.1097/WCO.0000000000001191 -
Journal of Neurology Oct 2023Becker muscular dystrophy (BMD) is one of the most frequent among neuromuscular diseases, affecting approximately 1 in 18,000 male births. It is linked to a genetic... (Review)
Review
Becker muscular dystrophy (BMD) is one of the most frequent among neuromuscular diseases, affecting approximately 1 in 18,000 male births. It is linked to a genetic mutation on the X chromosome. In contrast to Duchenne muscular dystrophy, for which improved care and management have changed the prognosis and life expectancy of patients, few guidelines have been published for management of BMD. Many clinicians are inexperienced in managing the complications of this disease. In France, a committee of experts from a wide range of disciplines met in 2019 to establish recommendations, with the goal of improving care of patients with BMD. Here, we present the tools to provide diagnosis of BMD as quickly as possible and for differential diagnoses. Then, we describe the multidisciplinary approach essential for optimum management of BMD. We give recommendations for the initial assessment and follow-up of the neurological, respiratory, cardiac, and orthopedic consequences of males who present with BMD. Finally, we describe the optimal therapeutic management of these complications. We also provide guidance on cardiac management for female carriers.
Topics: Humans; Male; Female; Muscular Dystrophy, Duchenne; Heterozygote; Prognosis; Diagnosis, Differential; Mutation
PubMed: 37422773
DOI: 10.1007/s00415-023-11837-5 -
Biomolecules Aug 2023Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the gene, including Duchenne and Becker muscular dystrophy, and dilated... (Review)
Review
Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.
Topics: Humans; Dystrophin; Muscular Dystrophy, Duchenne; Cardiomyopathy, Dilated; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Oligonucleotides, Antisense
PubMed: 37759719
DOI: 10.3390/biom13091319 -
Drugs Jan 2024Vamorolone (AGAMREE) is an oral, selective, dissociative corticosteroid developed by ReveraGen BioPharma and Santhera Pharmaceuticals for the treatment of patients with... (Review)
Review
Vamorolone (AGAMREE) is an oral, selective, dissociative corticosteroid developed by ReveraGen BioPharma and Santhera Pharmaceuticals for the treatment of patients with muscular dystrophy. Vamorolone was approved in October 2023 for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older in the USA and received a positive opinion in the EU in October 2023 for the treatment of DMD in patients 4 years of age and older. This article summarizes the milestones in the development of vamorolone leading to this first approval for DMD.
Topics: Humans; Pregnadienediols; Adrenal Cortex Hormones; Muscular Dystrophy, Duchenne
PubMed: 38103149
DOI: 10.1007/s40265-023-01986-2 -
The New England Journal of Medicine Sep 2023We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dCas9 (i.e., "dead" Cas9,...
We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dCas9 (i.e., "dead" Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×10 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).
Topics: Adult; Humans; Antibodies; Dystrophin; Genetic Therapy; Muscular Dystrophy, Duchenne; Respiratory Distress Syndrome; Transgenes; Fatal Outcome; Immunity, Innate
PubMed: 37754285
DOI: 10.1056/NEJMoa2307798 -
JACC. Heart Failure Feb 2024Gene therapy is defined by the introduction of new genes or the genetic modification of existing genes and/or their regulatory portions via gene replacement and gene... (Review)
Review
Gene therapy is defined by the introduction of new genes or the genetic modification of existing genes and/or their regulatory portions via gene replacement and gene editing strategies, respectively. The genetic material is usually delivered though cardiotropic vectors such as adeno-associated virus 9 or engineered capsids. The enthusiasm for gene therapy has been hampered somewhat by adverse events observed in clinical trials, including dose-dependent immunologic reactions such as hepatotoxicity, acquired hemolytic uremic syndrome and myocarditis. Notably, gene therapy for Duchenne muscular dystrophy has recently been approved and pivotal clinical trials are testing gene therapy approaches in rare myocardial conditions such as Danon disease and Fabry disease. Furthermore, promising results have been shown in animal models of gene therapy in hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. This review summarizes the gene therapy techniques, the toxicity risk associated with adeno-associated virus delivery, the ongoing clinical trials, and future targets.
Topics: Animals; Humans; Heart Failure; Cardiomyopathies; Muscular Dystrophy, Duchenne; Genetic Therapy; Cardiomyopathy, Hypertrophic; Genetic Vectors
PubMed: 37966402
DOI: 10.1016/j.jchf.2023.09.015 -
Expert Review of Neurotherapeutics 2023Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year.... (Review)
Review
INTRODUCTION
Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year. The disease caused by mutations (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) in the DMD gene, progressively leads to muscle wasting and loss of ambulation. This situation is painful for both patients and their families, calling for an emergent need for effective treatments.
AREAS COVERED
In this review, the authors describe the state of the gene therapy approach in clinical trials for DMD. This therapeutics included gene replacement, gene substitution, RNA-based therapeutics, readthrough mutation, and the CRISPR approach.
EXPERT OPINION
Only a few drug candidates have yet been granted conditional approval for the treatment of DMD. Most of these therapies have only a modest capability to restore the dystrophin or improve muscle function, suggesting an important unmet need in the development of DMD therapeutics. Complementary genes and cellular therapeutics need to be explored to both restore dystrophin, improve muscle function, and efficiently reconstitute the muscle fibers in the advanced stage of the disease.
Topics: Infant, Newborn; Humans; Male; Muscular Dystrophy, Duchenne; Dystrophin; Mutation; Exons; Genetic Therapy
PubMed: 37602688
DOI: 10.1080/14737175.2023.2249607