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Science Translational Medicine Jan 2023Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the gene....
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10 vector genomes per kilogram (vg/kg), 1 × 10 vg/kg, and 2 × 10 vg/kg; = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.
Topics: Animals; Dogs; Humans; Infant, Newborn; Mice; Dystrophin; Genetic Therapy; Heart; Muscle, Skeletal; Muscles; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne
PubMed: 36599002
DOI: 10.1126/scitranslmed.abo1815 -
Glia Mar 2022In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However,...
In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis. Together, our DMD model provides evidence for altered astrocyte function in DMD suggesting that defective astrocyte responses may contribute to neural impairment and might provide additional potential therapeutic targets.
Topics: Astrocytes; Cell Differentiation; Dystrophin; Humans; Induced Pluripotent Stem Cells; Muscular Dystrophy, Duchenne
PubMed: 34773297
DOI: 10.1002/glia.24116 -
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 -
Neurotherapeutics : the Journal of the... Oct 2018Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in... (Review)
Review
Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety.
Topics: Animals; Dystrophin; Humans; Muscular Dystrophy, Duchenne
PubMed: 30414046
DOI: 10.1007/s13311-018-00687-z -
Trends in Molecular Medicine Jun 2016Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to... (Review)
Review
Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD.
Topics: Animals; Cell Polarity; Cell Proliferation; Dystrophin; Genetic Therapy; Humans; Mice; Mice, Inbred mdx; Muscle Development; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Satellite Cells, Skeletal Muscle
PubMed: 27161598
DOI: 10.1016/j.molmed.2016.04.002 -
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 -
Molecular Therapy : the Journal of the... May 2017Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation... (Review)
Review
Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups.
Topics: Animals; Dependovirus; Dogs; Dystrophin; Genetic Therapy; Genetic Vectors; History, 20th Century; History, 21st Century; Humans; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Mutation; Protein Domains
PubMed: 28416280
DOI: 10.1016/j.ymthe.2017.02.019 -
Trends in Molecular Medicine Jul 2015Targeted dystrophin exon removal is a promising therapy for Duchenne muscular dystrophy (DMD); however, dystrophin expression in some reports is not supported by the... (Review)
Review
Targeted dystrophin exon removal is a promising therapy for Duchenne muscular dystrophy (DMD); however, dystrophin expression in some reports is not supported by the associated data. As in the account of 'The Emperor's New Clothes', the validity of such claims must be questioned, with critical re-evaluation of available data. Is it appropriate to report clinical benefit and induction of dystrophin as dose dependent when the baseline is unclear? The inability to induce meaningful levels of dystrophin does not mean that dystrophin expression as an end point is irrelevant, nor that induced exon skipping as a strategy is flawed, but demands that drug safety and efficacy, and study parameters be addressed, rather than questioning the strategy or the validity of dystrophin as a biomarker.
Topics: Animals; Dystrophin; Exons; Humans; Muscular Dystrophy, Duchenne
PubMed: 26051381
DOI: 10.1016/j.molmed.2015.04.006 -
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