Dimethyl fumarate modulates the dystrophic disease program following short-term treatment

JCI Insight, Journal Year: 2023, Volume and Issue: 8(21)

Published: Sept. 26, 2023

New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in treatment of multiple sclerosis and psoriasis that could be effective for DMD rapidly translatable. Here, we tested weeks daily 100 mg/kg DMF versus 5 standard-care prednisone (PRED) juvenile mdx mice early symptomatic DMD. Both drugs modulated seed genes driving program improved force production fast-twitch muscle. However, only showed pro-mitochondrial effects, protected contracting muscles from fatigue, histopathology, augmented clinically compatible muscle function tests. may more selective modulator than PRED, warranting follow-up longitudinal studies evaluate disease-modifying impact.

Language: Английский

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Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract In Duchenne muscular dystrophy (DMD), corticosteroids significantly slow disease progression and have been used as a standard of care tool for more than 30 years. However, also impart side effects severe enough to preclude use in some patients. There remains an unmet need new therapeutics that target the flow-on pathogenic mechanisms DMD with favourable side-effect profile. We previously demonstrated short-term treatment dual-purpose anti-inflammatory, anti-oxidative dimethyl fumarate (DMF), drug indication established safety data Multiple Sclerosis, selectively modulates ( mdx ) immunology frequently corticosteroid, prednisone (PRED). Here, we assess effect moderate-term DMF over 5 weeks typically mild mouse model aggravated using exercise. show like PRED, maintains anti-inflammatory action but additional anti-fibrotic anti-lipogenic on muscle use. This study supports our previous work highlighting possible repurposing candidate DMD, especially patients who cannot tolerate chronic corticosteroid treatment.

Language: Английский

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Diagnosis of ADSSL1 Mutation-Induced Myopathy Through Electrophysiology and Genetic Tools

Journal of Electrodiagnosis and Neuromuscular Diseases, Journal Year: 2024, Volume and Issue: 26(2), P. 35 - 39

Published: Aug. 29, 2024

Mutations in the adenylosuccinate synthase 1 (ADSSL1) gene, resulting deficiency, are a rare genetic anomaly characterized by muscular weakness, elevated serum creatine kinase levels, and pathological muscle findings. However, these clinical symptoms similar to those observed many other myopathies, increasing risk of misdiagnosis. In an era rapidly expanding knowledge, authors sought verify diagnostic utility electromyography for disorders. Through combined electrophysiological studies, patient initially thought have Becker’s dystrophy was conclusively diagnosed with ADSSL1 mutagenic myopathy. This case underscores importance re-evaluating diseases that do not follow typical progression traditional especially light recent advancements.

Language: Английский

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Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics

Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Abstract Heart failure (HF) is a complex syndrome and leading cause of mortality worldwide. While current medical treatment based on known pathophysiology effective for many patients, the underlying cellular mechanisms are poorly understood. Energy deficiency characteristic HF, marked by alterations in metabolism. Within tricarboxylic acid cycle, anaplerosis emerges as an essential metabolic process responsible replenishing lost intermediates, thereby playing crucial role sustaining energy metabolism consequently cardiac function. Alterations commonly observed demonstrating potential therapeutic intervention. This review discusses recent advances understanding anaplerotic adaptations that occur HF. We also explore therapeutics can directly modulate or likely to confer cardioprotective effects through anaplerosis, which could potentially be implemented rescue failing heart.

Language: Английский

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Adenylosuccinic Acid Is a Non-Toxic Small Molecule In Vitro and In Vivo

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(10), P. 1458 - 1458

Published: Oct. 13, 2023

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabolism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, although 10-year trial on Duchenne muscular dystrophy patients suggests it chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and its acute systemic mice. non-toxic with an LD

Language: Английский

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Adenylosuccinic Acid Is a Non-Toxic Small Molecule In Vitro and In Vivo

Published: Sept. 7, 2023

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year trial in Duchenne muscular dystrophy patients suggests chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts vitro and acute systemic mice. non-toxic with an LD50> 5000mg/kg. Some background necrotic foci liver, kidney gastrointestinal tract were shown likely incidental but warrant follow-up sub-/chronic oral exposure studies.

Language: Английский

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