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Advances in Therapy Apr 2024Duchenne muscular dystrophy (DMD) is one of the most prevalent X-linked inherited neuromuscular disorders, with an estimated incidence between 1 in 3500 and 5000 live... (Review)
Review
Duchenne muscular dystrophy (DMD) is one of the most prevalent X-linked inherited neuromuscular disorders, with an estimated incidence between 1 in 3500 and 5000 live male births. The median life expectancy at birth is around 30 years due to a rapid and severe disease progression. Currently, there is no cure for DMD, and the standard of care is mainly palliative therapy and glucocorticoids to mitigate symptoms and improve quality of life. Recent advances in phosphorodiamidate morpholino antisense oligonucleotide (PMO) technology has proven optimistic in providing a disease-modifying therapy rather than a palliative treatment option through correcting the primary genetic defect of DMD by exon skipping. However, as a result of the high variance in mutations of the dystrophin gene causing DMD, it has been challenging to tailor an effective therapy in most patients. Viltolarsen is effective in 8% of patients and accurately skips exon 53, reestablishing the reading frame and producing a functional form of dystrophin and milder disease phenotype. Results of recently concluded preclinical and clinical trials show significantly increased dystrophin protein expression, no severe adverse effects, and stabilization of motor function. In summary, viltolarsen has provided hope for those working toward giving patients a safe and viable treatment option for managing DMD. This review summarizes an overview of the presentation, pathophysiology, genetics, and current treatment guidelines of DMD, pharmacological profile of viltolarsen, and a summary of the safety and efficacy with additional insights using recent clinical trial data.
Topics: Infant, Newborn; Humans; Male; Muscular Dystrophy, Duchenne; Dystrophin; Quality of Life; Oligonucleotides
PubMed: 38376743
DOI: 10.1007/s12325-024-02801-4 -
Neuromuscular Disorders : NMD Mar 2024Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by the absence of functional dystrophin. There are multiple ongoing clinical trials for DMD that...
Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by the absence of functional dystrophin. There are multiple ongoing clinical trials for DMD that are testing gene therapy treatments consisting of adeno-associated viral (AAV) vectors carrying miniaturized versions of dystrophin optimized for function, termed micro-dystrophins (μDys). Utrophin, the fetal homolog of dystrophin, has repeatedly been reported to be upregulated in human DMD muscle as a compensatory mechanism, but whether µDys displaces full-length utrophin is unknown. In this study, dystrophin/utrophin-deficient mice with transgenic overexpression of full-length utrophin in skeletal muscles were systemically administered low doses of either AAV6-CK8e-Hinge3-µDys (μDysH3) or AAV6-CK8e-μDys5 (μDys5). We used immunofluorescence to qualitatively assess the localization of μDys with transgenic utrophin and neuronal nitric oxide synthase (nNOS) in quadriceps muscles. μDys protein resulting from both gene therapies co-localized at myofiber membranes with transgenic utrophin. We also confirmed the sarcolemmal co-localization of nNOS with μDys5, but not with transgenic utrophin expression or μDysH3. Transgenic utrophin expression and μDys proteins produced from both therapies stabilize the dystrophin-glycoprotein complex as observed by sarcolemmal localization of β-dystroglycan. This study suggests that µDys gene therapy will likely not inhibit any endogenous compensation by utrophin in DMD muscle.
Topics: Animals; Humans; Mice; Dystrophin; Utrophin; Muscle Fibers, Skeletal; Muscle, Skeletal; Genetic Therapy
PubMed: 38301403
DOI: 10.1016/j.nmd.2024.01.004 -
No To Hattatsu = Brain and Development Jul 2016Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder, which is characterized by progressive muscle wasting, ultimately resulting in the death... (Review)
Review
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder, which is characterized by progressive muscle wasting, ultimately resulting in the death of patients in their twenties or thirties. In DMD the dystrophin gene is mutated, which results in a deficiency of the muscle dystrophin. Although expression of dystrophin is a fundamental treatment for DMD, no effective treatment for DMD is available until now. Promising molecular therapies which are mutation-specific have been developed. Antisense oligonucleotide-mediated exon skipping that convert out-of-frame mRNA into in-frame mRNA, thereby enabling semifunctional dystrophin production, is recognized as the most promising treatment for DMD. We demonstrated that the intravenous administration of the antisense oligonucleotide against the splicing enhancer sequence induced exon skipping and produced the dystrophin protein in DMD case for the first time. After extensive studies, antisense oligonucleotides comprising different monomers have undergone clinical trials and provided favorable results, enabling improvements in ambulation of DMD patients Induction of the read-through of nonsense mutations is expected to produce dystrophin in DMD patients with nonsense mutations. The clinical effectiveness of gentamicxin and PTC124 has been reported. We have demonstrated the effectiveness of arbekacin-mediated read-through in vitro. We have already begun an investigator initiated clinical trial of nonsense mutation read-through therapy using arbekacin. Some of these drug candidates are planned to undergo submission for approval to regulatory agencies in the US and EU. We hope that these molecular therapies will contribute towards DMD treatment.
Topics: Animals; Dystrophin; Exons; Humans; Muscular Dystrophy, Duchenne; Mutation; Small Molecule Libraries
PubMed: 30010301
DOI: No ID Found -
International Journal of Molecular... Mar 2023Several clinical trials are working on drug development for Duchenne and Becker muscular dystrophy (DMD and BMD) treatment, and, since the expected increase in...
Several clinical trials are working on drug development for Duchenne and Becker muscular dystrophy (DMD and BMD) treatment, and, since the expected increase in dystrophin is relatively subtle, high-sensitivity quantification methods are necessary. There is also a need to quantify dystrophin to reach a definitive diagnosis in individuals with mild BMD, and in female carriers. We developed a method for the quantification of dystrophin in DMD and BMD patients using spectral confocal microscopy. It offers the possibility to capture the whole emission spectrum for any antibody, ensuring the selection of the emission peak and allowing the detection of fluorescent emissions of very low intensities. Fluorescence was evaluated first on manually selected regions of interest (ROIs), proving the usefulness of the methodology. Later, ROI selection was automated to make it operator-independent. The proposed methodology correctly classified patients according to their diagnosis, detected even minimal traces of dystrophin, and the results obtained automatically were statistically comparable to the manual ones. Thus, spectral imaging could be implemented to measure dystrophin expression and it could pave the way for detailed analysis of how its expression relates to the clinical course. Studies could be further expanded to better understand the expression of dystrophin-associated protein complexes (DAPCs).
Topics: Humans; Female; Dystrophin; Muscular Dystrophy, Duchenne
PubMed: 37047330
DOI: 10.3390/ijms24076358 -
Methods in Molecular Biology (Clifton,... 2018Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated... (Review)
Review
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.
Topics: Codon, Terminator; Databases, Genetic; Dystrophin; Exons; Humans; Morpholinos; Muscle Cells; Muscular Dystrophy, Duchenne; Mutation; Oxadiazoles
PubMed: 29067652
DOI: 10.1007/978-1-4939-7374-3_1 -
Pediatric Neurology Apr 2024Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four...
BACKGROUND
Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein.
METHODS
Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment.
RESULTS
Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated.
CONCLUSIONS
Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Troponin I; Adrenal Cortex Hormones; Genetic Therapy; Muscle, Skeletal
PubMed: 38306745
DOI: 10.1016/j.pediatrneurol.2024.01.003 -
ACS Nano Dec 2018Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited...
Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited disease. Dystrophin, localized within a cytoplasmic lattice termed costameres, connects the intracellular cytoskeleton of a myofiber through the cell membrane (sarcolemma) to the surrounding extracellular matrix. In spite of its mechanical regulation roles in stabilizing the sarcolemma during muscle contraction, the underlying molecular mechanism is still elusive. Here, we systematically investigated the mechanical stability and kinetics of the force-bearing central domain of human dystrophin that contains 24 spectrin repeats using magnetic tweezers. We show that the stochastic unfolding and refolding of central domain of dystrophin is able to keep the forces below 25 pN over a significant length change up to ∼800 nm in physiological level of pulling speeds. These results suggest that dystrophin may serve as a molecular shock absorber that defines the physiological level of force in the dystrophin-mediated force-transmission pathway during muscle contraction/stretch, thereby stabilizing the sarcolemma.
Topics: Absorption, Physicochemical; Dystrophin; Humans; Kinetics; Protein Folding
PubMed: 30457830
DOI: 10.1021/acsnano.8b05721 -
Human Molecular Genetics Sep 2016Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemma is essential for dystrophin to protect...
Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemma is essential for dystrophin to protect muscle from contraction-induced injury. It has long been thought that membrane binding of dystrophin depends on its cysteine-rich (CR) domain. Here, we provide in vivo evidence suggesting that dystrophin contains three additional membrane-binding domains including spectrin-like repeats (R)1-3, R10-12 and C-terminus (CT). To systematically study dystrophin membrane binding, we split full-length dystrophin into ten fragments and examined subcellular localizations of each fragment by adeno-associated virus-mediated gene transfer. In skeletal muscle, R1-3, CR domain and CT were exclusively localized at the sarcolemma. R10-12 showed both cytosolic and sarcolemmal localization. Importantly, the CR-independent membrane binding was conserved in murine and canine muscles. A critical function of the CR-mediated membrane interaction is the assembly of the dystrophin-associated glycoprotein complex (DGC). While R1-3 and R10-12 did not restore the DGC, surprisingly, CT alone was sufficient to establish the DGC at the sarcolemma. Additional studies suggest that R1-3 and CT also bind to the sarcolemma in the heart, though relatively weak. Taken together, our study provides the first conclusive in vivo evidence that dystrophin contains multiple independent membrane-binding domains. These structurally and functionally distinctive membrane-binding domains provide a molecular framework for dystrophin to function as a shock absorber and signaling hub. Our results not only shed critical light on dystrophin biology and DMD pathogenesis, but also provide a foundation for rationally engineering minimized dystrophins for DMD gene therapy.
Topics: Animals; Binding Sites; Conserved Sequence; Cytosol; Dogs; Dystrophin; Glycoproteins; Humans; Mice; Mice, Inbred mdx; Muscular Dystrophy, Animal; Myocardium; Protein Domains; Sarcolemma
PubMed: 27378693
DOI: 10.1093/hmg/ddw210 -
Cells Sep 2022Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the gene and characterized by progressive muscle... (Review)
Review
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the gene and characterized by progressive muscle degeneration, respiratory insufficiency, cardiac failure, and premature death by the age of thirty. Albeit DMD is one of the most common types of fatal genetic diseases, there is no curative treatment for this devastating disorder. In recent years, gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system has paved a new path toward correcting pathological mutations at the genetic source, thus enabling the permanent restoration of dystrophin expression and function throughout the musculature. To date, the therapeutic benefits of CRISPR genome-editing systems have been successfully demonstrated in human cells, rodents, canines, and piglets with diverse DMD mutations. Nevertheless, there remain some nonignorable challenges to be solved before the clinical application of CRISPR-based gene therapy. Herein, we provide an overview of therapeutic CRISPR genome-editing systems, summarize recent advancements in their applications in DMD contexts, and discuss several potential obstacles lying ahead of clinical translation.
Topics: Animals; CRISPR-Cas Systems; Dogs; Dystrophin; Gene Editing; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Swine
PubMed: 36230926
DOI: 10.3390/cells11192964 -
Handbook of Experimental Pharmacology 2020Drug development and pharmacotherapy of rare pediatric diseases have significantly expanded over the last decade, in part due to incentives and financial support... (Clinical Trial)
Clinical Trial
Drug development and pharmacotherapy of rare pediatric diseases have significantly expanded over the last decade, in part due to incentives and financial support provided by governments, regulators, and nonprofit foundations. Duchenne muscular dystrophy (DMD) is among the most common rare pediatric disorders, and clinical trials of therapeutic approaches have seen dramatic expansion. Pharmacotherapeutic standard of care has been limited to off-label prescription of high-dose, daily corticosteroids (prednisone, deflazacort). Deflazacort received FDA approval for DMD in 2016, although the price increases associated with formal FDA approval and the severe side effects associated with corticosteroid use have limited patient/physician uptake and insurance coverage in the USA. In Europe, EMA has given conditional marketing authorization for prescription of Translarna (a stop codon read-through drug prescribed to ~10% of DMD patients), although there is not yet evidence of clinical efficacy. The FDA awarded conditional approval to etiplirsen, an exon-skipping oligonucleotide drug, based on accelerated pathways (increased dystrophin production in patient muscle). Evidence of clinical efficacy remains the focus of post-marketing studies. There are many innovative pharmacotherapies under clinical development for DMD (Phase I, II, and III clinical trials). All are "disease modifying" in the sense that none seek to replace the full-length, normal DMD gene or dystrophin protein, but instead either seek to introduce an abnormal "Becker-like" version of the gene or protein or target pathophysiological pathways downstream of the primary defect. It is envisioned that the most significant benefit to DMD patients will be through multidrug approaches simultaneously aiming to introduce partially functional dystrophin in patient muscle while also targeting both chronic inflammation and the fibrofatty replacement of muscle.
Topics: Adrenal Cortex Hormones; Child; Dystrophin; Exons; Humans; Muscular Dystrophy, Duchenne
PubMed: 31375923
DOI: 10.1007/164_2019_256