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International Journal of Molecular... Jan 2024Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular... (Review)
Review
Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases.
Topics: Humans; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Biomedical Research; Chromosome Mapping; Gastrointestinal Microbiome
PubMed: 38203802
DOI: 10.3390/ijms25010631 -
Cell Reports Sep 2023Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays...
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.
Topics: Humans; Amyotrophic Lateral Sclerosis; Gene Expression Regulation; Genes, Homeobox; Homeodomain Proteins; Muscle, Skeletal; Muscular Dystrophy, Facioscapulohumeral; Neurodegenerative Diseases; Nuclear Matrix-Associated Proteins; RNA-Binding Proteins
PubMed: 37703175
DOI: 10.1016/j.celrep.2023.113120 -
Circulation. Genomic and Precision... Oct 2023
Topics: Humans; Cardiomyopathy, Dilated; Muscular Dystrophy, Duchenne; Phenotype; Genotype
PubMed: 37753649
DOI: 10.1161/CIRCGEN.123.004384 -
Annals of Clinical and Translational... Dec 2023We explored various prognostic factors of motor outcomes in corticosteroid-naive boys with Duchenne Muscular Dystrophy (DMD).
OBJECTIVE
We explored various prognostic factors of motor outcomes in corticosteroid-naive boys with Duchenne Muscular Dystrophy (DMD).
METHODS
The associations between parent-reported neurodevelopmental concerns (speech delay, speech and language difficulties (SLD), and learning difficulties), DMD mutation location, and motor outcomes (6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA) total score, 10-meter walk/run velocity, and rise from floor velocity) were studied in 196 corticosteroid-naive boys from ages 4 to less than 8 years.
RESULTS
Participants with SLD walked 25.8 fewer meters in 6 minutes than those without SLD (p = 0.005) but did not demonstrate statistical differences in NSAA total score, 10-meter walk/run velocity, and rise from floor velocity. Participants with distal DMD mutations with learning difficulties walked 51.8 fewer meters in 6 minutes than those without learning difficulties (p = 0.0007). Participants with distal DMD mutations were slower on 10-meter walk/run velocity, and rise from floor velocity (p = 0.02) than those with proximal DMD mutations. Participants with distal DMD mutations, who reported speech delay or learning difficulties, were slower on rise from floor velocity (p = 0.04, p = 0.01) than those with proximal DMD mutations. The mean NSAA total score was lower in participants with learning difficulties than in those without (p = 0.004).
INTERPRETATION
Corticosteroid-naive boys with DMD with distal DMD mutations may perform worse on some timed function tests, and that those with learning difficulties may perform worse on the NSAA. Pending confirmatory studies, our data underscore the importance of considering co-existing neurodevelopmental symptoms on motor outcome measures.
Topics: Male; Humans; Muscular Dystrophy, Duchenne; Walking; Adrenal Cortex Hormones; Outcome Assessment, Health Care; Language Development Disorders
PubMed: 37804000
DOI: 10.1002/acn3.51914 -
Science Advances Aug 2023Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular...
Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 () or CypD () in a δ-sarcoglycan () gene-deleted mouse model of MD, revealing that dystrophic mice lacking were partially protected from cell death and MD pathology. Dystrophic mice lacking both and together were almost completely protected from necrotic cell death and MD disease. This study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell death, suggesting a previously unrecognized therapeutic approach in MD and other necrotic diseases.
Topics: Animals; Mice; Muscular Dystrophies; Necrosis; Cell Death; Peptidyl-Prolyl Isomerase F; Disease Models, Animal
PubMed: 37624892
DOI: 10.1126/sciadv.adi2767 -
Muscle & Nerve Oct 2023As promising therapeutic interventions are tested among patients with facioscapulohumeral muscular dystrophy (FSHD), there is a clear need for valid and reliable outcome...
INTRODUCTION/AIMS
As promising therapeutic interventions are tested among patients with facioscapulohumeral muscular dystrophy (FSHD), there is a clear need for valid and reliable outcome tools to track disease progression and therapeutic gain in clinical trials and for clinical monitoring. Our aim was to develop and validate the Facioscapulohumeral Muscular Dystrophy-Health Index (FSHD-HI) as a multifaceted patient-reported outcome measure (PRO) designed to measure disease burden in adults with FSHD.
METHODS
Through initial interviews with 20 individuals and a national cross-sectional study with 328 individuals with FSHD, we identified the most prevalent and impactful symptoms in FSHD. The most relevant symptoms were included in the FSHD-HI. We used patient interviews, test-retest reliability evaluation, known groups validity testing, and factor analysis to evaluate and optimize the FSHD-HI.
RESULTS
The FSHD-HI contains 14 subscales that measure FSHD disease burden from the patient's perspective. Fourteen adults with FSHD participated in semistructured beta interviews and found the FSHD-HI to be clear, usable, and relevant to them. Thirty-two adults with FSHD participated in test-retest reliability assessments, which demonstrated the high reliability of the FSHD-HI total score (intraclass correlation coefficient = 0.924). The final FSHD-HI and its subscales also demonstrated a high internal consistency (Cronbach α = 0.988).
DISCUSSION
The FSHD-HI provides researchers and clinicians with a reliable and valid mechanism to measure multifaceted disease burden in patients with FSHD. The FSHD-HI may facilitate quantification of therapeutic effectiveness, as demonstrated by its use as a secondary and exploratory measure in several clinical trials.
Topics: Adult; Humans; Cross-Sectional Studies; Muscular Dystrophy, Facioscapulohumeral; Reproducibility of Results; Cost of Illness; Disease Progression
PubMed: 37610084
DOI: 10.1002/mus.27951 -
BioDrugs : Clinical Immunotherapeutics,... Jan 2024Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic... (Comparative Study)
Comparative Study Review
Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.
Topics: Humans; Dystrophin; Genetic Therapy; Muscular Dystrophy, Duchenne; Utrophin
PubMed: 37917377
DOI: 10.1007/s40259-023-00632-3 -
Expert Opinion on Investigational Drugs Mar 2024Current therapies are unable to cure Duchenne muscular dystrophy (DMD), a severe and common form of muscular dystrophy, and instead aim to delay disease progression.... (Review)
Review
INTRODUCTION
Current therapies are unable to cure Duchenne muscular dystrophy (DMD), a severe and common form of muscular dystrophy, and instead aim to delay disease progression. Several treatments currently in phase I trials could increase the number of therapeutic options available to patients.
AREAS COVERED
This review aims to provide an overview of current treatments undergoing or having recently undergone early-stage trials. Several exon-skipping and gene therapy approaches are currently being investigated at the clinical stage to address an unmet need for DMD treatments. This article also covers Phase I trials from the last 5 years that involve inhibitors, small molecules, a purified synthetic flavanol, a cell-based therapy, and repurposed cardiac or tumor medications.
EXPERT OPINION
With antisense oligonucleotide (AON) treatments making up the majority of conditionally approved DMD therapies, most of the clinical trials occurring within the last 5 years have also evaluated exon-skipping AONs. The approval of Elevidys, a micro-dystrophin therapy, is reflected in a recent trend toward gene transfer therapies in phase I DMD clinical trials, but their safety and efficacy are being established in this phase of development. Other Phase I clinical-stage approaches are diverse, but have a range in efficacy, safety, and endpoint measures.
Topics: Humans; Genetic Therapy; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; RNA Splicing; Clinical Trials as Topic
PubMed: 38291016
DOI: 10.1080/13543784.2024.2313105 -
Biomolecules Nov 2023mice with a spontaneous mutation in exon 23 of the gene represent the most common model to investigate the pathophysiology of Duchenne muscular dystrophy (DMD). The...
mice with a spontaneous mutation in exon 23 of the gene represent the most common model to investigate the pathophysiology of Duchenne muscular dystrophy (DMD). The disease, caused by the lack of functional dystrophin, is characterized by irreversible impairment of muscle functions, with the diaphragm affected earlier and more severely than other skeletal muscles. We applied a label-free (LF) method and the more thorough tandem mass tag (TMT)-based method to analyze differentially expressed proteins in the diaphragm of 6-week-old mice. The comparison of both methods revealed 88 commonly changed proteins. A more in-depth analysis of the TMT-based method showed 953 significantly changed proteins, with 867 increased and 86 decreased in dystrophic animals (-value < 0.05, fold-change threshold: 1.5). Consequently, several dysregulated processes were demonstrated, including the immune response, fibrosis, translation, and programmed cell death. Interestingly, in the dystrophic diaphragm, we found a significant decrease in the expression of enzymes generating hydrogen sulfide (HS), suggesting that alterations in the metabolism of this gaseous mediator could modulate DMD progression, which could be a potential target for pharmacological intervention.
Topics: Animals; Mice; Mice, Inbred mdx; Diaphragm; Proteome; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Mice, Inbred C57BL
PubMed: 38002330
DOI: 10.3390/biom13111648 -
Neurotherapeutics : the Journal of the... Oct 2023Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. It is caused by mutations in the DMD gene, leading to reduced or absent... (Review)
Review
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. It is caused by mutations in the DMD gene, leading to reduced or absent expression of the dystrophin protein. Clinically, this results in loss of ambulation, cardiomyopathy, respiratory failure, and eventually death. In the past decades, the use of corticosteroids has slowed down the disease progression. More recently, the development of genetically mediated therapies has emerged as the most promising treatment for DMD. These strategies include exon skipping with antisense oligonucleotides, gene replacement therapy with adeno-associated virus, and gene editing with CRISPR (clustered regularly interspaced short palindromic repeats) technology. In this review, we highlight the most up-to-date therapeutic progresses in the field, with emphasis on past and recent experiences, as well as the latest clinical results of DMD micro-dystrophin gene therapy. Additionally, we discuss the lessons learned along the way and the challenges encountered, all of which have helped advance the field, with the potential to finally alleviate such a devastating disease.
Topics: Humans; Child; Muscular Dystrophy, Duchenne; Dystrophin; Gene Editing; Exons; Genetic Therapy
PubMed: 37673849
DOI: 10.1007/s13311-023-01423-y