Making sense in Duchenne muscular dystrophy: Slowing the natural progression of muscle wasting

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

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Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12414 ◽

2019 ◽

Vol 10 (3) ◽

pp. 557-573 ◽

Cited By ~ 4

Author(s):

Peng Zhang ◽

Jian He ◽

Fei Wang ◽

Jing Gong ◽

Lu Wang ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Wasting ◽

Age Related

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Special Issue: Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System

Biomedicines ◽

10.3390/biomedicines9121911 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1911

Author(s):

Andrea Farini

Keyword(s):

Immune System ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Wasting ◽

Special Issue ◽

Wasting Disease ◽

Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood [...]

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

The Biochemist ◽

10.1042/bio03003018 ◽

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.

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The Failed Clinical Story of Myostatin Inhibitors Against Duchenne Muscular Dystrophy: Exploring the Biology Behind the Battle

10.20944/preprints202010.0234.v1 ◽

2020 ◽

Author(s):

Emma Rybalka ◽

Cara Timpani ◽

Danielle Debruin ◽

Ryan Bagaric ◽

Dean Campelj ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Clinical Data ◽

Muscle Wasting ◽

Disease Course ◽

Biological Mechanisms ◽

Outcomes Measures ◽

Myostatin Inhibition ◽

Secondary Outcomes ◽

Deficient Mice

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcomes measures selected: the myostatin inhibition story thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models has failed to translate into clinical benefit to patients has been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

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Metabogenic and Nutriceutical Approaches to Address Energy Dysregulation and Skeletal Muscle Wasting in Duchenne Muscular Dystrophy

Nutrients ◽

10.3390/nu7125498 ◽

2015 ◽

Vol 7 (12) ◽

pp. 9734-9767 ◽

Cited By ~ 12

Author(s):

Emma Rybalka ◽

Cara Timpani ◽

Christos Stathis ◽

Alan Hayes ◽

Matthew Cooke

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Wasting ◽

Skeletal Muscle Wasting

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From diagnosis to therapy in Duchenne muscular dystrophy

Biochemical Society Transactions ◽

10.1042/bst20190282 ◽

2020 ◽

Vol 48 (3) ◽

pp. 813-821 ◽

Cited By ~ 3

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.

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Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Frontiers in Physiology ◽

10.3389/fphys.2021.647010 ◽

2021 ◽

Vol 12 ◽

Author(s):

Satvik Mareedu ◽

Emily D. Million ◽

Dongsheng Duan ◽

Gopal J. Babu

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Therapeutic Strategy ◽

Muscle Wasting ◽

Premature Death ◽

Calcium Handling ◽

Muscle Degeneration ◽

Wasting Disease ◽

Fatty Replacement ◽

Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

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