scholarly journals Current Pharmacological Strategies for Duchenne Muscular Dystrophy

2021 ◽  
Vol 9 ◽  
Author(s):  
Shanshan Yao ◽  
Zihao Chen ◽  
Yuanyuan Yu ◽  
Ning Zhang ◽  
Hewen Jiang ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Meta Analysis ◽  
Symptom Relief ◽  
Standard Of Care ◽  
Neuromuscular Disorder ◽  
Therapeutic Strategies ◽  
Gene Profiling ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder caused by the absence of dystrophin protein, which is essential for muscle fiber integrity. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. There is still no cure for DMD so far and the standard of care is principally limited to symptom relief through glucocorticoids treatments. Current therapeutic strategies could be divided into two lines. Dystrophin-targeted therapeutic strategies that aim at restoring the expression and/or function of dystrophin, including gene-based, cell-based and protein replacement therapies. The other line of therapeutic strategies aims to improve muscle function and quality by targeting the downstream pathological changes, including inflammation, fibrosis, and muscle atrophy. This review introduces the important developments in these two lines of strategies, especially those that have entered the clinical phase and/or have great potential for clinical translation. The rationale and efficacy of each agent in pre-clinical or clinical studies are presented. Furthermore, a meta-analysis of gene profiling in DMD patients has been performed to understand the molecular mechanisms of DMD.

scholarly journals Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1366
Author(s):  
Ankita Tulangekar ◽  
Tamar E. Sztal
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Tissue Injury ◽  
Dystrophin Gene ◽  
Neuromuscular Disorder ◽  
Muscle Membrane ◽  
Dystrophin Protein ◽  
Pro Inflammatory Cytokines

Duchenne muscular dystrophy (DMD) is a severe and progressive, X-linked, neuromuscular disorder caused by mutations in the dystrophin gene. In DMD, the lack of functional dystrophin protein makes the muscle membrane fragile, leaving the muscle fibers prone to damage during contraction. Muscle degeneration in DMD patients is closely associated with a prolonged inflammatory response, and while this is important to stimulate regeneration, inflammation is also thought to exacerbate muscle damage. Neutrophils are one of the first immune cells to be recruited to the damaged muscle and are the first line of defense during tissue injury or infection. Neutrophils can promote inflammation by releasing pro-inflammatory cytokines and compounds, including myeloperoxidase (MPO) and neutrophil elastase (NE), that lead to oxidative stress and are thought to have a role in prolonging inflammation in DMD. In this review, we provide an overview of the roles of the innate immune response, with particular focus on mechanisms used by neutrophils to exacerbate muscle damage and impair regeneration in DMD.

scholarly journals The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Dominic Scaglioni ◽  
Francesco Catapano ◽  
Matthew Ellis ◽  
Silvia Torelli ◽  
Darren Chambers ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Antisense Oligonucleotide ◽  
De Novo ◽  
Exon Skipping ◽  
Significant Negative Correlation ◽  
Entire Cohort ◽  
Associated Proteins ◽  
Analysis Platform ◽  
Dystrophin Protein

AbstractDuring the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

2009 ◽  
Vol 20 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Michelle S. Steen ◽  
Marvin E. Adams ◽  
Yan Tesch ◽  
Stanley C. Froehner
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Mdx Mouse ◽  
Lysosomal Storage ◽  
Transgenic Expression ◽  
New Therapeutic Approaches ◽  
Human Disorders ◽  
Niemann Pick ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

scholarly journals The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 648
Author(s):  
Andrea L. Reid ◽  
Matthew S. Alexander
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Disease Onset ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Mitochondrial Morphology ◽  
Gene Therapies ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

scholarly journals Duchenne Muscular Dystrophy - Family in a Crisis

1970 ◽  
pp. 36-39
Author(s):  
M Robed Amin ◽  
Chowdhury Chironjib Borua ◽  
Kaji Shafiqul Alam ◽  
Fazle Rabbi Chowdhury ◽  
Rabiul Jahan Sarkar ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Case Series ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Motor Neuron Diseases ◽  
Muscle Diseases ◽  
Progressive Muscle Weakness ◽  
Recessive Disorders ◽  
Dystrophin Protein

Progressive muscular weakness with deformity leading to crippled states develop due to musculoskeletal and neurological disorders. Sometimes it is difficult to differentiate between primary muscle disease and neurological disease. But there is some classical presentation of muscle diseases which have its own entity and thus can be clinically differentiated from neurological disorder especially spinal cord and motor neuron diseases. Muscular dystrophy is one of those disorder with distinct clinical features. Muscular dystrophy refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness. Most types of MD are multi-system disorders with manifestations in body systems including skeletal system, the heart, gastrointestinal and nervous systems, endocrine glands, skin, eyes and other organs. Duchenne muscular dystrophy (DMD), is inherited in an X-linked recessive pattern, meaning that the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes, and is thus considered sex-linked. Males are therefore affected by X-linked recessive disorders much more often than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Duchenne muscular dystrophy and Backers muscular dystrophy are caused by mutations of the gene for the dystrophin protein and lead to an overabundance of the enzyme creatine kinase. The dystrophin gene is the largest gene in humans. In this case series a family with three brothers suffering from Duchenne muscular dystrophy is described and review with literature was done.   doi:10.3329/jom.v10i3.2015 J Medicine 2009; 10 (Supplement 1): 36-39

scholarly journals Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (21) ◽  
pp. e2270-e2282 ◽  
Author(s):  
Diane E. Frank ◽  
Frederick J. Schnell ◽  
Cody Akana ◽  
Saleh H. El-Husayni ◽  
Cody A. Desjardins ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Exon Skipping ◽  
Study Drug ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Dystrophin Protein ◽  
Muscle Biopsies

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

scholarly journals AYURVEDIC MANAGEMENT OF DUCHENNE MUSCULAR DYSTROPHY: A SHORT REVIEW

2019 ◽  
Vol 7 (1) ◽  
pp. 179-183
Author(s):  
Akshay A Patankar ◽  
Renu B Rathi
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Social Contact ◽  
Signs And Symptoms ◽  
Short Review ◽  
Receptive Language ◽  
Modern Medicine ◽  
Autism Spectrum ◽  
Neuromuscular Disorder ◽  
Significant Treatment

Duchenne muscular dystrophy is a neuromuscular disorder characterized by deficient dystrophin protein in the muscle. The main symptoms the patient presented were delay in expressive and receptive language development, visual discontent, hyperkinetic behaviour, and inability to initiate and maintain social contact with peers. The data obtained from the family, following clinical examination, laboratory investigation results and assessment of mental status were significant for the diagnosis of Autism Spectrum Disorder, hyperkinetic behaviour and Duchenne Muscular Dystrophy. In Ayurveda it has been classified under Medomamsa dusti further vitiates the Vata doshas occurs due to the Bheejabagahaavyava Dusti. In modern medicine there is no significant treatment available for this diseases while in Ayurvedic panchakrma therapy shows significant results in all signs and symptoms of this diseases.

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Cathleen E. Buckon ◽  
Susan E. Sienko ◽  
Eileen G. Fowler ◽  
Anita M. Bagley ◽  
Loretta A. Staudt ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Genetic Disorder ◽  
Knee Extensor ◽  
Standard Of Care ◽  
Rate Of Change ◽  
Isokinetic Dynamometry ◽  
Gross Motor

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7–13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. Objective: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. Methods: Eighty-four ambulatory boys with DMD (49–180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. Results: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. Conclusion: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

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