Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies

Angelini, Giuseppe; Mura, Giada; Messina, Graziella

doi:10.1016/j.yexcr.2021.112968

Cited by 15 publications

(11 citation statements)

References 160 publications

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“…AAV-micro-dystrophin also successfully transduces cardiac muscle and improves function in a DMD heart failure mouse model ( Gregorevic et al, 2004 ; Howard et al, 2021a ). However, genetic therapies will not restore normal levels of full-length dystrophin, leaving at least residual inflammation that must be targeted to prevent exacerbation of disease pathology ( Angelini et al, 2022 ).…”

Section: Introduction: Duchenne Muscular Dystrophy and Chronic Inflam...mentioning

confidence: 99%

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

et al. 2022

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Duchenne muscular dystrophy (DMD) is a striated muscle degenerative disease due to loss of functional dystrophin protein. Loss of dystrophin results in susceptibility of muscle membranes to damage, leading to muscle degeneration and continuous inflammation and fibrosis that further exacerbate pathology. Long-term glucocorticoid receptor (GR) agonist treatment, the current standard-of-care for DMD, modestly improves prognosis but has serious side effects. The mineralocorticoid receptor (MR), a ligand-activated transcription factor present in many cell types, has been implicated as a therapeutic target for DMD. MR antagonists (MRAs) have fewer side effects than GR agonists and are used clinically for heart failure. MRA efficacy has recently been demonstrated for DMD cardiomyopathy and in preclinical studies, MRAs also alleviate dystrophic skeletal muscle pathology. MRAs lead to improvements in muscle force and membrane stability and reductions in degeneration, inflammation, and fibrosis in dystrophic muscles. Myofiber-specific MR knockout leads to most of these improvements, supporting an MR-dependent mechanism of action, but MRAs additionally stabilize myofiber membranes in an MR-independent manner. Immune cell MR signaling in dystrophic and acutely injured normal muscle contributes to wound healing, and myeloid-specific MR knockout is detrimental. More research is needed to fully elucidate MR signaling in striated muscle microenvironments. Direct comparisons of genomic and non-genomic effects of glucocorticoids and MRAs on skeletal muscles and heart will contribute to optimal temporal use of these drugs, since they compete for binding conserved receptors. Despite the advent of genetic medicines, therapies targeting inflammation and fibrosis will be necessary to achieve optimal patient outcomes.

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Section: Introduction: Duchenne Muscular Dystrophy and Chronic Inflam...mentioning

confidence: 99%

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

et al. 2022

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“…Although various MPO inhibitors have been investigated in preclinical studies using mouse models of diseases such as multiple system atrophy (Stefanova et al., 2012), Parkinson's disease (Choi et al., 2005; Jucaite et al., 2015) and post‐myocardial infarction (Ali et al., 2016), the use of MPO inhibitors as a therapeutic treatment for DMD has not yet been investigated. The development of treatments for DMD which target reduced HOCl may also be important as a secondary treatment to currently available genetic treatments for DMD in instances where genetic treatments are not completely effective (Angelini et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

“…The limited effectiveness of DTT in recovering maximal force production may explain the limited success of clinical trials of antioxidants for DMD and supports the development of treatments that reduce oxidant levels by preventing production or scavenging ROS (e.g. resveratrol, epicatechin) rather than reversing oxidation (Angelini et al, 2022;Shakibaei et al, 2012;Shay et al, 2015).…”

Section: Effect Of Hocl Partially Reversible By the Antioxidant Dtt A...mentioning

confidence: 99%

Hypochlorous acid exposure impairs skeletal muscle function and Ca²⁺ signalling: implications for Duchenne muscular dystrophy pathology

Lea,

Panizza,

Arthur

et al. 2023

The Journal of Physiology

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Duchenne muscular dystrophy (DMD) is a fatal X‐linked disease characterised by severe muscle wasting. The mechanisms underlying the DMD pathology likely involve the interaction between inflammation, oxidative stress and impaired Ca2+ signalling. Hypochlorous acid (HOCl) is a highly reactive oxidant produced endogenously via myeloperoxidase; an enzyme secreted by neutrophils that is significantly elevated in dystrophic muscle. Oxidation of Ca2+‐handling proteins by HOCl may impair Ca2+ signalling. This study aimed to determine the effects of HOCl on skeletal muscle function and its potential contribution to the dystrophic pathology. Extensor digitorum longus (EDL), soleus and interosseous muscles were surgically isolated from anaesthetised C57 (wild‐type) and mdx (dystrophic) mice for measurement of ex vivo force production and intracellular Ca2+ concentration. In whole EDL muscle, HOCl (200 μM) significantly decreased maximal force and increased resting muscle tension which was only partially reversible by dithiothreitol. The effects of HOCl (200 μM) on maximal force in slow‐twitch soleus were lower than found in the fast‐twitch EDL muscle. In single interosseous myofibres, HOCl (10 μM) significantly increased resting intracellular Ca2+ concentration and decreased Ca2+ transient amplitude. These effects of HOCl were reduced by the application of tetracaine, Gd3+ or streptomycin, implicating involvement of ryanodine receptors and transient receptor potential channels. These results demonstrate the potent effects of HOCl on skeletal muscle function potentially mediated by HOCl‐induced oxidation to Ca2+ signalling proteins. Hence, HOCl may provide a link between chronic inflammation, oxidative stress and impaired Ca2+ handling that is characteristic of DMD and presents a potential therapeutic target for DMD. imageKey points Duchenne muscular dystrophy is a fatal genetic disease with pathological mechanisms which involve the complex interaction of chronic inflammation, increased reactive oxygen species production and increased cytosolic Ca2+ concentrations. Hypochlorous acid can be endogenously produced by neutrophils via the enzyme myeloperoxidase. Both neutrophil and myeloperoxidase activity are increased in dystrophic mice. This study found that hypochlorous acid decreased muscle force production and increased cytosolic Ca2+ concentrations in isolated muscles from wild‐type and dystrophic mice at relatively low concentrations of hypochlorous acid. These results indicate that hypochlorous acid may be key in the Duchenne muscular dystrophy disease pathology and may provide a unifying link between the chronic inflammation, increased reactive oxygen species production and increased cytosolic Ca2+ concentrations observed in Duchenne muscular dystrophy. Hypochlorous acid production may be a potential target for therapeutic treatments of Duchenne muscular dystrophy.

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“…DMD begins around the age of two years, and affects first proximal muscles, then distal limb muscles, and later the heart and respiratory muscles. Until recently, individuals with DMD did not survive beyond their teen years, but with medical treatment, and cardiac and respiratory care, the life expectancy is increasing [ 114 , 115 ]. There are currently nine RNA-based drugs in clinical trials for the treatment of DMD, LGMD, and Pompe disease, including four approved drugs for DMD (see Table 1 ).…”

Section: Approved Rna Drugs For Neurological Diseasesmentioning

confidence: 99%

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Holm

Hansen²,

Klitgaard³

et al. 2022

RNA Biology

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RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. Abbreviations 2’-MOE: 2’- O -(2-methoxyethyl); 2’- O -Me: 2’- O -methyl; 2’-F: 2’-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin

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Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies

Cited by 15 publications

References 160 publications

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Hypochlorous acid exposure impairs skeletal muscle function and Ca²⁺ signalling: implications for Duchenne muscular dystrophy pathology

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

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Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies

Cited by 15 publications

References 160 publications

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Hypochlorous acid exposure impairs skeletal muscle function and Ca2+ signalling: implications for Duchenne muscular dystrophy pathology

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

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Product

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Hypochlorous acid exposure impairs skeletal muscle function and Ca²⁺ signalling: implications for Duchenne muscular dystrophy pathology