scholarly journals Muscular dystrophy: the route to a cure: Genetic and cell therapies

2008 ◽  
Vol 30 (3) ◽  
pp. 18-21
Author(s):  
Taeyoung Koo ◽  
Takis Athanasopoulos ◽  
George Dickson
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Wasting ◽  
Therapeutic Approaches ◽  
Childhood Diseases ◽  
Cell Therapies ◽  
New Therapies ◽  
Clinical Evaluations ◽  
Dystrophin Protein ◽  
The Way

Duchenne muscular dystrophy (DMD) is one of the most common Xlinked and lifethreatening childhood diseases and affects about 1 in 3000 newborn boys. Lack of dystrophin protein causes severe progressive muscle wasting and death in the second/third decade of life, due to breathing and circulatory complications. Currently, there are no effective medications for DMD, but many differ ent therapeutic approaches are under active development. In the case of genetic and cell therapies, preclinical and clinical evaluations of safety and validity are paving the way towards effective new therapies which could be available routinely for DMD patients in the next 5 years.

scholarly journals Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

2021 ◽  
Vol 10 (4) ◽  
pp. 820
Author(s):  
Fernanda Fortunato ◽  
Rachele Rossi ◽  
Maria Sofia Falzarano ◽  
Alessandra Ferlini
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dystrophin Gene ◽  
Orphan Drugs ◽  
Therapeutic Approaches ◽  
Anchoring Protein ◽  
Cardiac Muscles ◽  
Dystrophin Protein ◽  
The Brain

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

scholarly journals From diagnosis to therapy in Duchenne muscular dystrophy

2020 ◽  
Vol 48 (3) ◽  
pp. 813-821 ◽  
Author(s):  
Arran Babbs ◽  
Maria Chatzopoulou ◽  
Ben Edwards ◽  
Sarah E. Squire ◽  
Isabel V.L. Wilkinson ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Wasting ◽  
Exon Skipping ◽  
Short Review ◽  
Current Status ◽  
Muscle Membrane ◽  
Therapeutic Approaches ◽  
Wasting Disease ◽  
Muscle Wasting Disease

Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421 kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.

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 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.

Muscle wasting and carbohydrate homeostasis in Duchenne muscular dystrophy

Neurology ◽  
1978 ◽  
Vol 28 (12) ◽  
pp. 1224-1224 ◽  
Author(s):  
M. W. Haymond ◽  
K. E. Strobel ◽  
D. C. DeVivo
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Wasting ◽  
Carbohydrate Homeostasis

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.

Abstract 19370: Myocardial Extracellular Volume is Elevated in Human Duchenne Muscular Dystrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jonathan H Soslow ◽  
Stephen M Damon ◽  
Bruce M Damon ◽  
David A Parra ◽  
W B Burnette ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Age Of Onset ◽  
Extracellular Volume ◽  
Lv Function ◽  
Therapeutic Approaches ◽  
Matrix Expansion ◽  
The Mean ◽  
Normal Lvef ◽  
Extracellular Matrix Expansion

Introduction: Duchenne muscular dystrophy (DMD) leads to cardiomyopathy (CM) with variable severity and age of onset. Predicting early CM would alter therapeutic approaches and improve morbidity and mortality. Extracellular volume (ECV) calculated with cardiac MRI (CMR) quantifies extracellular matrix expansion, including myocardial fibrosis, and has never been reported in human DMD. We hypothesized that subjects with DMD would have abnormal ECV and that these values would correlate with other markers of LV function. Methods: 27 DMD subjects were prospectively studied. CMR included LVEF, late gadolinium enhancement (LGE), circumferential strain (ε cc ), and modified Look-Locker (MOLLI) sequences to calculate ECV maps (in-house software using Matlab). ECV calculated for each segment in the short axis at mid-ventricle and compared with LVEF and ε cc using linear regression. Normal values taken from unmatched cohort of healthy male adults with mean ECV of 0.25 ± 0.015 (range 0.23-0.28). Results: Imaging was adequate to calculate ECV maps in 20 DMD subjects. Mean age in years was 14. Mean LVEF was 52% and mean global ε cc was -14.6%; 11 subjects had LVEF < 55% and 6 had negative LGE. Mean ECV was 0.33 ± 0.05 (0.25-0.45); there was significant intersubject and intersegment variability (Figure 1). When compared with highest mean control ECV (0.28), only one subject had a normal ECV in every segment. In subjects with LVEF ≥ 55%, the mean ECV was 0.32 ± 0.07 (0.25-0.45). In subjects with negative LGE, the mean ECV was 0.28 ± 0.04 (0.25-0.36). The ECV of the inferolateral and anterolateral segments correlated with LVEF (p=0.025 and p<0.001) and the inferolateral ECV correlated with mean ε cc (p=0.025). Conclusions: In this cohort, 19/20 DMD subjects have elevated segmental ECV, even with normal LVEF and negative LGE. Segmental ECV correlates with both LVEF and mean ε cc . ECV may be a more subtle biomarker of early myocardial disease than standard measures such as LVEF and LGE in human DMD.

scholarly journals Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 837 ◽  
Author(s):  
Chengmei Sun ◽  
Luoan Shen ◽  
Zheng Zhang ◽  
Xin Xie
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Disorders ◽  
Dystrophin Gene ◽  
Current Status ◽  
Muscle Stem Cells ◽  
Cell Based Therapy ◽  
Dystrophin Protein

Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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