keyword
https://read.qxmd.com/read/38301403/gene-therapy-delivered-micro-dystrophins-co-localize-with-transgenic-utrophin-in-dystrophic-skeletal-muscle-fibers
#1
JOURNAL ARTICLE
Swathy Krishna, Arden B Piepho, Dana M Lake, Laurel R Cumby, Kaelyn K Lortz, Jeovanna Lowe, Jeffrey S Chamberlain, Jill A Rafael-Fortney
Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by the absence of functional dystrophin. There are multiple ongoing clinical trials for DMD that are testing gene therapy treatments consisting of adeno-associated viral (AAV) vectors carrying miniaturized versions of dystrophin optimized for function, termed micro-dystrophins (μDys). Utrophin, the fetal homolog of dystrophin, has repeatedly been reported to be upregulated in human DMD muscle as a compensatory mechanism, but whether µDys displaces full-length utrophin is unknown...
March 2024: Neuromuscular Disorders: NMD
https://read.qxmd.com/read/37725998/mimicking-sarcolemmal-damage-in-vitro-a-contractile-3d-model-of-skeletal-muscle-for-drug-testing-in-duchenne-muscular-dystrophy
#2
JOURNAL ARTICLE
Ainoa Tejedera-Villafranca, Marisol Montolio, Javier Ramón-Azcón, Juan M Fernández-Costa
Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disease diagnosed in childhood. It is a progressive and wasting disease, characterized by a degeneration of skeletal and cardiac muscles caused by the lack of dystrophin protein. The absence of this crucial structural protein leads to sarcolemmal fragility, resulting in muscle fiber damage during contraction. Despite ongoing efforts, there is no cure available for DMD patients. One of the primary challenges is the limited efficacy of current preclinical tools, which fail in modeling the biological complexity of the disease...
September 19, 2023: Biofabrication
https://read.qxmd.com/read/37060897/utrophin-correlates-with-disease-severity-in-duchenne-muscular-dystrophy
#3
JOURNAL ARTICLE
Simon Guiraud, Kay Davies
This month in Med, the description of an unusually severely affected DMD patient suffering from a large deletion in the dystrophin gene confirms that absence of utrophin worsens the dystrophy and supports the concept that utrophin upregulation ameliorates the pathology. This study may guide the development of dystrophin-based gene therapies.
April 14, 2023: Med
https://read.qxmd.com/read/36905929/unusually-severe-muscular-dystrophy-upon-in-frame-deletion-of-the-dystrophin-rod-domain-and-lack-of-compensation-by-membrane-localized-utrophin
#4
JOURNAL ARTICLE
Svetlana Gorokhova, Joachim Schessl, Yaqun Zou, Michele L Yang, Peter T Heydemann, Robert L Sufit, Katherine Meilleur, Sandra Donkervoort, Livija Medne, Richard S Finkel, Carsten G Bönnemann
BACKGROUND: Utrophin, a dystrophin homolog, is consistently upregulated in muscles of patients with Duchenne muscular dystrophy (DMD) and is believed to partially compensate for the lack of dystrophin in dystrophic muscle. Even though several animal studies support the idea that utrophin can modulate DMD disease severity, human clinical data are scarce. METHODS: We describe a patient with the largest reported in-frame deletion in the DMD gene, including exons 10-60 and thus encompassing the entire rod domain...
March 7, 2023: Med
https://read.qxmd.com/read/36609344/multi-omics-analysis-of-sarcospan-overexpression-in-mdx-skeletal-muscle-reveals-compensatory-remodeling-of-cytoskeleton-matrix-interactions-that-promote-mechanotransduction-pathways
#5
JOURNAL ARTICLE
Jackie L McCourt, Kristen M Stearns-Reider, Hafsa Mamsa, Pranav Kannan, Mohammad Hossein Afsharinia, Cynthia Shu, Elizabeth M Gibbs, Kara M Shin, Yerbol Z Kurmangaliyev, Lauren R Schmitt, Kirk C Hansen, Rachelle H Crosbie
BACKGROUND: The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury...
January 6, 2023: Skeletal Muscle
https://read.qxmd.com/read/36409820/biological-and-genetic-therapies-for-the-treatment-of-duchenne-muscular-dystrophy
#6
JOURNAL ARTICLE
Harry Wilton-Clark, Toshifumi Yokota
INTRODUCTION: Duchenne muscular dystrophy is a lethal genetic disease which currently has no cure, and poor standard treatment options largely focused on symptom relief. The development of multiple biological and genetic therapies is underway across various stages of clinical progress which could markedly affect how DMD patients are treated in the future. AREAS COVERED: The purpose of this review is to provide an introduction to the different therapeutic modalities currently being studied, as well as a brief description of their progress to date and relative advantages and disadvantages for the treatment of DMD...
December 1, 2022: Expert Opinion on Biological Therapy
https://read.qxmd.com/read/36401046/identifying-fda-approved-drugs-that-upregulate-utrophin-a-as-a-therapeutic-strategy-for-duchenne-muscular-dystrophy
#7
JOURNAL ARTICLE
Christine Péladeau, Bernard J Jasmin
Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations and deletions within the DMD gene, which result in a lack of dystrophin protein at the sarcolemma of skeletal muscle fibers. The absence of dystrophin fragilizes the sarcolemma and compromises its integrity during cycles of muscle contraction, which, progressively, leads to reductions in muscle mass and function. DMD is thus a progressive muscle-wasting disease that results in a loss of ambulation, cardiomyopathy , respiratory impairment, and death...
2023: Methods in Molecular Biology
https://read.qxmd.com/read/36401024/cardiac-and-skeletal-muscle-pathology-in-the-d2-mdx-mouse-model-and-caveats-associated-with-the-quantification-of-utrophin
#8
JOURNAL ARTICLE
Tahnee L Kennedy, Hannah F Dugdale
Duchenne muscular dystrophy (DMD) (the most common form of muscular dystrophy) is caused by a lack of dystrophin protein. Currently, although many therapeutic strategies are under investigation, there is no cure for DMD and unfortunately, patients succumb to respiratory and/or cardiac failure in their second or third decade of life. Preclinical work has focused on the mouse model C57BL/10ScSn-Dmdmdx /J (BL10/mdx), which does not exhibit a robust pathophenotype. More recently, the D2.B10-Dmdmdx /J (D2/mdx) mouse has been utilized, which presents a more severe pathology and therefore more closely mimics the human pathophenotype, particularly in the heart...
2023: Methods in Molecular Biology
https://read.qxmd.com/read/35772287/structure-activity-relationships-of-2-pyrimidinecarbohydrazides-as-utrophin-modulators-for-the-potential-treatment-of-duchenne-muscular-dystrophy
#9
JOURNAL ARTICLE
Maria Chatzopoulou, Daniel Conole, Enrico Emer, Jessica A Rowley, Nicky J Willis, Sarah E Squire, Becky Gill, Steve Brough, Francis X Wilson, Graham M Wynne, Stephen G Davies, Kay E Davies, Angela J Russell
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid...
May 18, 2022: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/35557546/matricellular-protein-ccn5-gene-transfer-ameliorates-cardiac-and-skeletal-dysfunction-in-mdx-utrn-%C3%A2-haploinsufficient-mice-by-reducing-fibrosis-and-upregulating-utrophin-expression
#10
JOURNAL ARTICLE
Min Ho Song, Jimeen Yoo, Jae Gyun Oh, Hyun Kook, Woo Jin Park, Dongtak Jeong
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to dystrophin gene mutations. Patients with DMD initially experience muscle weakness in their limbs during adolescence. With age, patients develop fatal respiratory and cardiac dysfunctions. During the later stages of the disease, severe cardiac fibrosis occurs, compromising cardiac function. Previously, our research showed that the matricellular protein CCN5 has antifibrotic properties. Therefore, we hypothesized that CCN5 gene transfer would ameliorate cardiac fibrosis and thus improve cardiac function in DMD-induced cardiomyopathy...
2022: Frontiers in Cardiovascular Medicine
https://read.qxmd.com/read/34904931/poly-c-binding-protein-2-dependent-nuclear-retention-of-the-utrophin-a-mrna-in-c2c12-cells
#11
JOURNAL ARTICLE
Gargi Ghosh, Satyabrata Samui, Santanu Das, Vandana Singh, Doel Pal, Subhanwita Das, Jishu Naskar, Soumya Sinha Roy, Utpal Basu
Upregulation of utrophin, the autosomal homologue of dystrophin, can compensate dystrophin deficiency in Duchenne Muscular Dystrophy (DMD) although the therapeutic success is yet to be achieved. The present study has identified Poly (C) binding protein 2 (PCBP2) as a post-transcriptional suppresser for the expression of utrophin-A, the muscle-specific utrophin isoform. This study confirms nuclear retention of utrophin-A mRNA in C2C12 cells, which is mediated by PCBP2. Further investigation demonstrates PCBP2-dependent nuclear retention of follistatin mRNA as well...
December 14, 2021: RNA Biology
https://read.qxmd.com/read/34790118/lessons-learned-from-discontinued-clinical-developments-in-duchenne-muscular-dystrophy
#12
JOURNAL ARTICLE
Theodora Markati, Liesbeth De Waele, Urlike Schara-Schmidt, Laurent Servais
Duchenne muscular dystrophy (DMD) is an X-linked condition caused by a deficiency of functional dystrophin protein. Patients experience progressive muscle weakness, cardiomyopathy and have a decreased life expectancy. Standards of care, including treatment with steroids, and multidisciplinary approaches have extended the life expectancy and improved the quality of life of patients. In the last 30 years, several compounds have been assessed in preclinical and clinical studies for their ability to restore functional dystrophin levels or to modify pathways involved in DMD pathophysiology...
2021: Frontiers in Pharmacology
https://read.qxmd.com/read/34581784/sarcospan-increases-laminin-binding-capacity-of-%C3%AE-dystroglycan-to-ameliorate-dmd-independent-of-galgt2
#13
JOURNAL ARTICLE
Hafsa Mamsa, Rachelle L Stark, Kara M Shin, Aaron M Beedle, Rachelle H Crosbie
In Duchenne muscular dystrophy (DMD), mutations in dystrophin result in a loss of the dystrophin-glycoprotein complex at the myofiber membrane, which functions to connect the extracellular matrix with the intracellular actin cytoskeleton. The dystroglycan subcomplex interacts with dystrophin and spans the sarcolemma where its extensive carbohydrates (matriglycan and CT2 glycan) directly interact with the extracellular matrix. In the current manuscript, we show that sarcospan overexpression enhances the laminin-binding capacity of dystroglycan in DMD muscle by increasing matriglycan glycosylation of α-dystroglycan...
September 28, 2021: Human Molecular Genetics
https://read.qxmd.com/read/34521928/duchenne-muscular-dystrophy-cell-culture-models-created-by-crispr-cas9-gene-editing-and-their-application-in-drug-screening
#14
JOURNAL ARTICLE
Patricia Soblechero-Martín, Edurne Albiasu-Arteta, Aina Anton-Martinez, Laura de la Puente-Ovejero, Iker Garcia-Jimenez, Gabriela González-Iglesias, Irene Larrañaga-Aiestaran, Andrea López-Martínez, Javier Poyatos-García, Estíbaliz Ruiz-Del-Yerro, Federico Gonzalez, Virginia Arechavala-Gomeza
Gene editing methods are an attractive therapeutic option for Duchenne muscular dystrophy, and they have an immediate application in the generation of research models. To generate myoblast cultures that could be useful in in vitro drug screening, we have optimised a CRISPR/Cas9 gene edition protocol. We have successfully used it in wild type immortalised myoblasts to delete exon 52 of the dystrophin gene, modelling a common Duchenne muscular dystrophy mutation; and in patient's immortalised cultures we have deleted an inhibitory microRNA target region of the utrophin UTR, leading to utrophin upregulation...
September 14, 2021: Scientific Reports
https://read.qxmd.com/read/34377959/early-administration-of-l-arginine-in-mdx-neonatal-mice-delays-the-onset-of-muscular-dystrophy-in-tibialis-anterior-ta-muscle
#15
JOURNAL ARTICLE
Roy W R Dudley, Alain S Comtois, David H St-Pierre, Gawiyou Danialou
Duchenne muscular dystrophy (DMD) is a genetic disorder that results in the absence of dystrophin, a cytoskeletal protein. Individuals with this disease experience progressive muscle destruction, which leads to muscle weakness. Studies have been conducted to find solutions for the relief of individuals with this disease, several of which have shown that utrophin, a protein closely related to dystrophin, when overexpressed in mdx neonatal mice (the murine model of DMD), is able to prevent the progressive muscle destruction observed in the absence of dystrophin...
August 2021: FASEB BioAdvances
https://read.qxmd.com/read/34017265/cardioprotective-effect-of-whole-body-periodic-acceleration-in-dystrophic-phenotype-mdx-rodent
#16
JOURNAL ARTICLE
Arkady Uryash, Alfredo Mijares, Eric Esteve, Jose A Adams, Jose R Lopez
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and the development of a dilated cardiomyopathy (DCM), which is the leading cause of death in DMD patients. Despite knowing the cause of DMD, there are currently no therapies which can prevent or reverse its inevitable progression. We have used whole body periodic acceleration (WBPA) as a novel tool to enhance intracellular constitutive nitric oxide (NO) production. WBPA adds small pulses to the circulation to increase pulsatile shear stress, thereby upregulating endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) and subsequently elevating the production of NO...
2021: Frontiers in Physiology
https://read.qxmd.com/read/33963617/stars-overexpression-in-the-mdx-mouse-enhances-muscle-functional-capacity-and-regulates-the-actin-cytoskeleton-and-oxidative-phosphorylation-pathways
#17
JOURNAL ARTICLE
Kate J Sadler, Paul A Della Gatta, Timur Naim, Marita A Wallace, Albert Lee, Thiri Zaw, Angus Lindsay, Roger S Chung, Luca Bello, Elena Pegoraro, Séverine Lamon, Gordon S Lynch, Aaron P Russell
NEW FINDINGS: What is the central question of this study? Striated Muscle activator of Rho signalling (STARS) is an actin-binding protein that regulates transcriptional pathways controlling muscle function, growth and myogenesis; processes impaired in dystrophic muscle. Regulation of the STARS pathway in Duchenne muscular dystrophy (DMD is unknown. What is the main finding and its importance? Members of the STARS signalling pathway are reduced in the quadriceps of patients with DMD and in mouse models of muscular dystrophy...
May 7, 2021: Experimental Physiology
https://read.qxmd.com/read/33915371/discovery-and-mechanism-of-action-studies-of-4-6-diphenylpyrimidine-2-carbohydrazides-as-utrophin-modulators-for-the-treatment-of-duchenne-muscular-dystrophy
#18
JOURNAL ARTICLE
Aini Vuorinen, Isabel V L Wilkinson, Maria Chatzopoulou, Ben Edwards, Sarah E Squire, Rebecca J Fairclough, Noelia Araujo Bazan, Josh A Milner, Daniel Conole, James R Donald, Nandini Shah, Nicky J Willis, R Fernando Martínez, Francis X Wilson, Graham M Wynne, Stephen G Davies, Kay E Davies, Angela J Russell
Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter...
April 20, 2021: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/33432327/loss-of-sarcospan-exacerbates-pathology-in-mdx-mice-but-does-not-affect-utrophin-amelioration-of-disease
#19
JOURNAL ARTICLE
Elizabeth M Gibbs, Jackie L McCourt, Kara M Shin, Katherine G Hammond, Jamie L Marshall, Rachelle H Crosbie
The dystrophin-glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte's internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin, an autosomal homologue of dystrophin, is upregulated in dystrophic muscle and partially compensates for loss of dystrophin in muscle from patients with DMD...
January 11, 2021: Human Molecular Genetics
https://read.qxmd.com/read/33335663/decreasing-hepg2-cytotoxicity-by-lowering-the-lipophilicity-of-benzo-d-oxazolephosphinate-ester-utrophin-modulators
#20
JOURNAL ARTICLE
Maria Chatzopoulou, Enrico Emer, Cristina Lecci, Jessica A Rowley, Anne-Sophie Casagrande, Lee Moir, Sarah E Squire, Stephen G Davies, Shawn Harriman, Graham M Wynne, Francis X Wilson, Kay E Davies, Angela J Russell
Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties...
December 10, 2020: ACS Medicinal Chemistry Letters
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