Therapeutic Approaches for Duchenne Muscular Dystrophy: Old and New

Mackenzie, Samuel J.; Nicolau, Stefan; Connolly, Anne M.; Mendell, Jerry R.

doi:10.1016/j.spen.2021.100877

Cited by 24 publications

(16 citation statements)

References 88 publications

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“…This therapeutic regimen maintains muscle strength and extends life expectancy, but corticosteroids long-term use could cause severe and very debilitating side effects (i.e., weight gain, glucose intolerance, hypertension, and depression) [ 41 , 42 ], thus making necessary the identification of an alternative and less toxic approach. Recently, the most intriguing therapeutical proposals are represented by stop-codon read-through therapy, gene replacement approaches, myoblast transfer therapy, and also drug-related inhibition of resident macrophages [ 43 , 44 , 45 ]. We suggest CB2 receptor agonism as an alternative, effective, and safe anti-inflammatory target for the therapy of DMD.…”

Section: Introductionmentioning

confidence: 99%

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

Argenziano

Pota

Paola

et al. 2023

IJMS

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Duchenne Muscular Dystrophy (DMD) is a very severe X-linked dystrophinopathy. It is due to a mutation in the DMD gene and causes muscular degeneration in conjunction with several secondary co-morbidities, such cardiomyopathy and respiratory failure. DMD is characterized by a chronic inflammatory state, and corticosteroids represent the main therapy for these patients. To contradict drug-related side effects, there is need for novel and more safe therapeutic strategies. Macrophages are immune cells stringently involved in both physiological and pathological inflammatory processes. They express the CB2 receptor, one of the main elements of the endocannabinoid system, and have been proposed as an anti-inflammatory target in several inflammatory and immune diseases. We observed a lower expression of the CB2 receptor in DMD-associated macrophages, hypothesizing its involvement in the pathogenesis of this pathology. Therefore, we analyzed the effect of JWH-133, a CB2 receptor selective agonist, on DMD-associated primary macrophages. Our study describes the beneficial effect of JWH-133 in counteracting inflammation by inhibiting pro-inflammatory cytokines release and by directing macrophages’ phenotype toward the M2 anti-inflammatory one.

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Section: Introductionmentioning

confidence: 99%

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

Argenziano

Pota

Paola

et al. 2023

IJMS

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“…Dystrophin-replacement approaches via exon-skipping or micro-dystrophin gene therapies have been showing promising results in the prevention of muscle necrosis (recently reviewed by Sun et al [ 7 ]); however, they do not fully rescue all pathological outcomes [ 8 , 9 ]. Moreover, these exon-skipping therapies are effective only in patients with specific pathogenic DYSTORPHIN variants, and thus only a subset of DMD patients are amenable to these strategies [ 7 , 10 ]. A combinatorial approach to DMD treatment strategy is the most likely to succeed, and thus it is important to understand the driving pathological mechanisms at play in DMD.…”

Section: Introductionmentioning

confidence: 99%

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Reid

Alexander

2021

Life

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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.

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“…Encouraging results have also been shown for Duchenne muscular dystrophy by systemic delivery of AAV vectors expressing short forms of dystrophin in early-stage clinical trials ( 14 ). Systemic, intrathecal, and intraparenchymal administration of AAV vectors is under early clinical testing for several neurodegenerative diseases, both genetic early-onset (mucopolysaccharidoses (MPS), globoid leukodystrophy (GLD), Fabry disease, Canavan disease) and non-genetic adult-onset diseases [e.g., Parkinson disease (PD), Alzheimer Disease (AD)] ( 15 ).…”

Section: Commercial and Clinical Stage Productsmentioning

confidence: 99%

In vivo Gene Therapy to the Liver and Nervous System: Promises and Challenges

et al. 2022

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In vivo genetic engineering has recently shown remarkable potential as a novel effective treatment for an ever-growing number of diseases, as also witnessed by the recent marketing authorization of several in vivo gene therapy products. In vivo genetic engineering comprises both viral vector-mediated gene transfer and the more recently developed genome/epigenome editing strategies, as long as they are directly administered to patients. Here we first review the most advanced in vivo gene therapies that are commercially available or in clinical development. We then highlight the major challenges to be overcome to fully and broadly exploit in vivo gene therapies as novel medicines, discussing some of the approaches that are being taken to address them, with a focus on the nervous system and liver taken as paradigmatic examples.

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Therapeutic Approaches for Duchenne Muscular Dystrophy: Old and New

Cited by 24 publications

References 88 publications

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

In vivo Gene Therapy to the Liver and Nervous System: Promises and Challenges

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