Articles de revues : « Duchenne, animal models, DMD »

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Lim, Kenji Rowel Q., Quynh Nguyen, Kasia Dzierlega, Yiqing Huang et Toshifumi Yokota. « CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy ». Genes 11, n^o 3 (24 mars 2020) : 342. http://dx.doi.org/10.3390/genes11030342.

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Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

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Nakamura, Akinori, et Shin'ichi Takeda. « Mammalian Models of Duchenne Muscular Dystrophy : Pathological Characteristics and Therapeutic Applications ». Journal of Biomedicine and Biotechnology 2011 (2011) : 1–8. http://dx.doi.org/10.1155/2011/184393.

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Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disorder characterized by muscle wasting which is caused by mutations in theDMDgene. TheDMDgene encodes the sarcolemmal protein dystrophin, and loss of dystrophin causes muscle degeneration and necrosis. Thus far, therapies for this disorder are unavailable. However, various therapeutic trials based on gene therapy, exon skipping, cell therapy, read through therapy, or pharmaceutical agents have been conducted extensively. In the development of therapy as well as elucidation of pathogenesis in DMD, appropriate animal models are needed. Various animal models of DMD have been identified, and mammalian (murine, canine, and feline) models are indispensable for the examination of the mechanisms of pathogenesis and the development of therapies. Here, we review the pathological features of DMD and therapeutic applications, especially of exon skipping using antisense oligonucleotides and gene therapies using viral vectors in murine and canine models of DMD.

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Donandt, Tina, Stefan Hintze, Sabine Krause, Eckhard Wolf, Benedikt Schoser, Maggie C. Walter et Peter Meinke. « Isolation and Characterization of Primary DMD Pig Muscle Cells as an In Vitro Model for Preclinical Research on Duchenne Muscular Dystrophy ». Life 12, n^o 10 (21 octobre 2022) : 1668. http://dx.doi.org/10.3390/life12101668.

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Duchenne muscular dystrophy (DMD) is the most frequent genetic myopathy in childhood and leads to progressive muscle atrophy, weakness, and premature death. So far, there is no curative treatment available. Therapeutic development from bench to bedside takes time, and promising therapies need to be tested in suitable preclinical animal models prior to clinical trials in DMD patients. Existing mouse and dog models are limited with regard to the comparability of the clinical phenotype and the underlying mutation. Therefore, our group established a tailored large animal model of DMD, the DMD pig, mirroring the human size, anatomy, and physiology. For testing novel approaches, we developed a corresponding in vitro model, facilitating preclinical testing for toxicity, dosing, and efficacy, which we describe here. We first extracted primary muscle cells from wild-type and DMD pigs of different age groups and characterized those cells, then improved their differentiation process for identification of dystrophin and utrophin in myotubes. Our porcine in vitro model represents an important step for the development of novel therapeutic approaches, which should be validated further to minimize the need for living animals for bioassays, and thereby support the ‘3R’ (replace, reduce, refine) principle, as fewer animals have to be raised and treated for preclinical trials.

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Wilson, Kristin, Crystal Faelan, Janet C. Patterson-Kane, Daniel G. Rudmann, Steven A. Moore, Diane Frank, Jay Charleston, Jon Tinsley, G. David Young et Anthony J. Milici. « Duchenne and Becker Muscular Dystrophies : A Review of Animal Models, Clinical End Points, and Biomarker Quantification ». Toxicologic Pathology 45, n^o 7 (octobre 2017) : 961–76. http://dx.doi.org/10.1177/0192623317734823.

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Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are neuromuscular disorders that primarily affect boys due to an X-linked mutation in the DMD gene, resulting in reduced to near absence of dystrophin or expression of truncated forms of dystrophin. Some newer therapeutic interventions aim to increase sarcolemmal dystrophin expression, and accurate dystrophin quantification is critical for demonstrating pharmacodynamic relationships in preclinical studies and clinical trials. Current challenges with measuring dystrophin include the variation in protein expression within individual muscle fibers and across whole muscle samples, the presence of preexisting dystrophin-positive revertant fibers, and trace amounts of residual dystrophin. Immunofluorescence quantification of dystrophin can overcome many of these challenges, but manual quantification of protein expression may be complicated by variations in the collection of images, reproducible scoring of fluorescent intensity, and bias introduced by manual scoring of typically only a few high-power fields. This review highlights the pathology of DMD and BMD, discusses animal models of DMD and BMD, and describes dystrophin biomarker quantitation in DMD and BMD, with several image analysis approaches, including a new automated method that evaluates protein expression of individual muscle fibers.

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Sayers, Stephen P. « The Role of Exercise as a Therapy for Children with Duchenne Muscular Dystrophy ». Pediatric Exercise Science 12, n^o 1 (février 2000) : 23–33. http://dx.doi.org/10.1123/pes.12.1.23.

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Duchenne muscular dystrophy (DMD) is a disease affecting muscle fiber integrity in boys that leads to progressive weakness in skeletal muscle and premature death. Currently, there is no known cure for the disease. Different interventions have been explored to delay the progression of the disease and improve the quality of life for the DMD patient. Physical activity is one treatment that has generated controversy due to the increased mechanical stress placed on the muscle during contraction. This review explores the literature in animal models and human DMD patients and evaluates the known theoretical risks and benefits of increased physical activity in DMD patients.

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English, Katherine G., Andrea L. Reid, Adrienne Samani, Gerald J. F. Coulis, S. Armando Villalta, Christopher J. Walker, Sharon Tamir et Matthew S. Alexander. « Next-Generation SINE Compound KPT−8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD ». Biomedicines 10, n^o 10 (26 septembre 2022) : 2400. http://dx.doi.org/10.3390/biomedicines10102400.

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Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT−8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT−8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT−8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT−8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT−8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT−8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes.

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Wong, Tatianna Wai Ying, Abdalla Ahmed, Grace Yang, Eleonora Maino, Sydney Steiman, Elzbieta Hyatt, Parry Chan et al. « A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy ». Disease Models & ; Mechanisms 13, n^o 9 (1 septembre 2020) : dmm045369. http://dx.doi.org/10.1242/dmm.045369.

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ABSTRACTDuchenne muscular dystrophy (DMD) is a life-threatening neuromuscular disease caused by the lack of dystrophin, resulting in progressive muscle wasting and locomotor dysfunctions. By adulthood, almost all patients also develop cardiomyopathy, which is the primary cause of death in DMD. Although there has been extensive effort in creating animal models to study treatment strategies for DMD, most fail to recapitulate the complete skeletal and cardiac disease manifestations that are presented in affected patients. Here, we generated a mouse model mirroring a patient deletion mutation of exons 52-54 (Dmd Δ52-54). The Dmd Δ52-54 mutation led to the absence of dystrophin, resulting in progressive muscle deterioration with weakened muscle strength. Moreover, Dmd Δ52-54 mice present with early-onset hypertrophic cardiomyopathy, which is absent in current pre-clinical dystrophin-deficient mouse models. Therefore, Dmd Δ52-54 presents itself as an excellent pre-clinical model to evaluate the impact on skeletal and cardiac muscles for both mutation-dependent and -independent approaches.

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Wells, Dominic J. « Tracking progress : an update on animal models for Duchenne muscular dystrophy ». Disease Models & ; Mechanisms 11, n^o 6 (1 juin 2018) : dmm035774. http://dx.doi.org/10.1242/dmm.035774.

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Echigoya, Yusuke, Nhu Trieu, William Duddy, Hong M. Moulton, HaiFang Yin, Terence A. Partridge, Eric P. Hoffman et al. « A Dystrophin Exon-52 Deleted Miniature Pig Model of Duchenne Muscular Dystrophy and Evaluation of Exon Skipping ». International Journal of Molecular Sciences 22, n^o 23 (2 décembre 2021) : 13065. http://dx.doi.org/10.3390/ijms222313065.

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Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the DMD gene and the subsequent lack of dystrophin protein. Recently, phosphorodiamidate morpholino oligomer (PMO)-antisense oligonucleotides (ASOs) targeting exon 51 or 53 to reestablish the DMD reading frame have received regulatory approval as commercially available drugs. However, their applicability and efficacy remain limited to particular patients. Large animal models and exon skipping evaluation are essential to facilitate ASO development together with a deeper understanding of dystrophinopathies. Using recombinant adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer, we generated a Yucatan miniature pig model of DMD with an exon 52 deletion mutation equivalent to one of the most common mutations seen in patients. Exon 52-deleted mRNA expression and dystrophin deficiency were confirmed in the skeletal and cardiac muscles of DMD pigs. Accordingly, dystrophin-associated proteins failed to be recruited to the sarcolemma. The DMD pigs manifested early disease onset with severe bodywide skeletal muscle degeneration and with poor growth accompanied by a physical abnormality, but with no obvious cardiac phenotype. We also demonstrated that in primary DMD pig skeletal muscle cells, the genetically engineered exon-52 deleted pig DMD gene enables the evaluation of exon 51 or 53 skipping with PMO and its advanced technology, peptide-conjugated PMO. The results show that the DMD pigs developed here can be an appropriate large animal model for evaluating in vivo exon skipping efficacy.

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Hughes, K. J., A. Rodriguez, K. M. Flatt, S. Ray, A. Schuler, B. Rodemoyer, V. Veerappan et al. « Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy ». Proceedings of the National Academy of Sciences 116, n^o 9 (12 février 2019) : 3508–17. http://dx.doi.org/10.1073/pnas.1811379116.

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Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and death. Current animal models have been challenged by their inability to model the early onset and severity of the disease. It remains unresolved whether increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle’s disrupted contractile machinery. This knowledge has important implications for patients, as potential physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. Recently we showed how burrowing dystrophic (dys-1) C. elegans recapitulate many salient phenotypes of DMD, including loss of mobility and muscle necrosis. Here, we report that dys-1 worms display early pathogenesis, including dysregulated sarcoplasmic calcium and increased lethality. Sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes (e.g., mitochondrial, and contractile machinery damage) and can be mitigated by reducing calmodulin expression. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring high intensity or high frequency of muscle exertion during locomotion. We find that several muscular parameters (e.g., size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion, regardless of effort duration. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insight into the pathology of the disease as well as the initial assessment of potential treatment strategies.

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Zhang, Yu, Hui Li, Yi-Li Min, Efrain Sanchez-Ortiz, Jian Huang, Alex A. Mireault, John M. Shelton et al. « Enhanced CRISPR-Cas9 correction of Duchenne muscular dystrophy in mice by a self-complementary AAV delivery system ». Science Advances 6, n^o 8 (février 2020) : eaay6812. http://dx.doi.org/10.1126/sciadv.aay6812.

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Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the dystrophin gene (DMD). Previously, we applied CRISPR-Cas9–mediated “single-cut” genome editing to correct diverse genetic mutations in animal models of DMD. However, high doses of adeno-associated virus (AAV) are required for efficient in vivo genome editing, posing challenges for clinical application. In this study, we packaged Cas9 nuclease in single-stranded AAV (ssAAV) and CRISPR single guide RNAs in self-complementary AAV (scAAV) and delivered this dual AAV system into a mouse model of DMD. The dose of scAAV required for efficient genome editing were at least 20-fold lower than with ssAAV. Mice receiving systemic treatment showed restoration of dystrophin expression and improved muscle contractility. These findings show that the efficiency of CRISPR-Cas9–mediated genome editing can be substantially improved by using the scAAV system. This represents an important advancement toward therapeutic translation of genome editing for DMD.

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Riddell, Dominique O., John C. W. Hildyard, Rachel C. M. Harron, Dominic J. Wells et Richard J. Piercy. « Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy ». Wellcome Open Research 6 (17 août 2022) : 354. http://dx.doi.org/10.12688/wellcomeopenres.17398.2.

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Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying within the hotspot for human patients, making it especially valuable. Prior to conducting therapeutic trials using this novel animal model, it is essential to establish a panel of viable biomarkers. Methods: We evaluated a panel of blood-borne biomarkers of musculoskeletal disease in the DE50-MD dog. Venous blood samples were obtained monthly throughout an 18-month study period in DE50-MD (N=18) and wild-type (WT) control (N=14) dogs. A panel of potential plasma/serum biomarkers of DMD was measured and their theoretical utility in future clinical trials determined using sample size calculations. Results: Compared to WT dogs, DE50-MD dogs had substantially higher circulating creatine kinase (CK) activities, myomesin-3 (MYOM3), and the dystromiRs miR-1, miR-133a and miR-206, but significantly lower serum myostatin concentrations. An age-associated pattern, similar to that observed in DMD patients, was seen for CK and MYOM3. Sample size calculations suggested that low cohort sizes (N≤3) could be used to detect up to a 50% improvement in DE50-MD results towards WT levels for each biomarker or a combination thereof (via principal component analysis); as few as N=3 animals should enable detection of a 25% improvement using a combined biomarker approach (alpha 0.05, power 0.8). Conclusions: We have established a panel of blood-borne biomarkers that could be used to monitor musculoskeletal disease or response to a therapeutic intervention in the DE50-MD dog using low numbers of animals. The blood biomarker profile closely mimics that of DMD patients, supporting the hypothesis that this DMD model would be suitable for use in pre-clinical trials.

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Riddell, Dominique O., John C. W. Hildyard, Rachel C. M. Harron, Dominic J. Wells et Richard J. Piercy. « Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy ». Wellcome Open Research 6 (20 décembre 2021) : 354. http://dx.doi.org/10.12688/wellcomeopenres.17398.1.

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Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying within the hotspot for human patients, making it especially valuable. Prior to conducting therapeutic trials using this novel animal model, it is essential to establish a panel of viable biomarkers. Methods: We evaluated a panel of blood-borne biomarkers of musculoskeletal disease in the DE50-MD dog. Venous blood samples were obtained monthly throughout an 18-month study period in DE50-MD (N=18) and wild-type (WT) control (N=14) dogs. A panel of potential plasma/serum biomarkers of DMD was measured and their theoretical utility in future clinical trials determined using sample size calculations. Results: Compared to WT dogs, DE50-MD dogs had substantially higher circulating creatine kinase (CK) activities, myomesin-3 (MYOM3), and the dystromiRs miR-1, miR-133a and miR-206, but significantly lower serum myostatin concentrations. An age-associated pattern, similar to that observed in DMD patients, was seen for CK and MYOM3. Sample size calculations suggested that low cohort sizes (N≤3) could be used to detect up to a 50% improvement in DE50-MD results towards WT levels for each biomarker or a combination thereof (via principal component analysis); as few as N=3 animals should enable detection of a 25% improvement using a combined biomarker approach (alpha 0.05, power 0.8). Conclusions: We have established a panel of blood-borne biomarkers that could be used to monitor musculoskeletal disease or response to a therapeutic intervention in the DE50-MD dog using low numbers of animals. The blood biomarker profile closely mimics that of DMD patients, supporting the hypothesis that this DMD model would be suitable for use in pre-clinical trials.

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Klymiuk, N., C. Thirion, K. Burkhardt, A. Wuensch, S. Krause, A. Richter, B. Kessler et al. « 238 TAILORED PIG MODEL OF DUCHENNE MUSCULAR DYSTROPHY ». Reproduction, Fertility and Development 24, n^o 1 (2012) : 231. http://dx.doi.org/10.1071/rdv24n1ab238.

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Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases in humans, affecting 1 in 3500 boys. It is characterised by progressive muscle weakness and wasting due to mutations in the dystrophin (DMD) gene resulting in absence of dystrophin protein in skeletal muscle. Although curative treatments are currently not available, genetic and pharmacological approaches are under investigation including early-phase clinical trials. Existing animal models in different species (e.g. mdx mouse, GRMD dog) have been instrumental to understand the pathophysiology of DMD, but have several limitations. Importantly, the causative point mutations (mdx mouse: nonsense mutation; GRMD dog: splice mutation) are different from the most common human mutations (out-of-frame deletion of one or several exons of the DMD gene). We used gene targeting in somatic cells and nuclear transfer to generate a genetically tailored pig model of DMD. A bacterial artificial chromosome (BAC) from the porcine DMD gene was modified by recombineering to replace exon 52, resulting in a frame shift in the transcript. Modified BAC were transfected into male neonatal kidney cells, which were screened by quantitative polymerase chain reaction for replacement of exon 52 in the X-linked DMD gene. Eight of 436 cell clones were successfully targeted and 2 of them were used for nuclear transfer. For each of the cell clones, a pregnancy was established by transfer of cloned embryos into recipient gilts. Four piglets of the first litter were live born and killed within 48 h and tissue samples were processed for histological characterisation. Two piglets of the second litter died during birth due to obstetric complications, whereas the other 2 piglets were delivered by Caesarean section and raised in an artificial feeding system. Their serum creatine kinase (CK) levels were grossly elevated. Although both piglets showed reduced mobility compared with age-matched controls, they were able to move and feed on their own. Immunofluorescence staining of dystrophin was negative in muscle fibres of DMD mutant piglets and the complete absence of dystrophin protein was confirmed by immunoblot analysis. Histological examination of biceps femoris muscle from DMD mutant pigs showed a degenerative myopathy with fibre size variation, rounded fibres, central nuclei, fibrosis and fatty replacement of muscle tissue mimicking the hallmarks of the human disease. In conclusion, we generated the first pig model for a genetic muscle disease. The DMD mutant pig appears to be a bona fide model of the human dystrophy as ascertained by absence of the dystrophin protein, elevated serum CK levels and early degenerative changes on muscle histology. Because deletion of exon 52 is one of the most frequent mutations found in human DMD, the exon 52 mutated DMD pig represents an excellent model for testing targeted genetic treatments. This study was supported by the Bayerische Forschungsstiftung.

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McGreevy, J. W., C. H. Hakim, M. A. McIntosh et D. Duan. « Animal models of Duchenne muscular dystrophy : from basic mechanisms to gene therapy ». Disease Models & ; Mechanisms 8, n^o 3 (1 mars 2015) : 195–213. http://dx.doi.org/10.1242/dmm.018424.

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Herbelet, Sandrine, Arthur Rodenbach, Boel De Paepe et Jan L. De Bleecker. « Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy : Exploration of Steroid-Sparing Agents ». International Journal of Molecular Sciences 21, n^o 13 (28 juin 2020) : 4596. http://dx.doi.org/10.3390/ijms21134596.

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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

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Rybalka, Emma, Cara Timpani, Danielle Debruin, Ryan Bagaric, Dean Campelj et Alan Hayes. « The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy : Exploring the Biology behind the Battle ». Cells 9, n^o 12 (10 décembre 2020) : 2657. http://dx.doi.org/10.3390/cells9122657.

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Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

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Maruyama, Rika, et Toshifumi Yokota. « Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases ». Journal of Personalized Medicine 10, n^o 3 (16 septembre 2020) : 129. http://dx.doi.org/10.3390/jpm10030129.

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With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy. However, several new personalized therapies, including antisense oligonucleotides eteplirsen for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the start of a therapeutic revolution in neuromuscular diseases. However, the studies also made clear that these therapies are still far from a cure. Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue “Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases” highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era.

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Morroni, Jacopo, Leonardo Schirone, Daniele Vecchio, Carmine Nicoletti, Luca D’Ambrosio, Valentina Valenti, Sebastiano Sciarretta, Biliana Lozanoska-Ochser et Marina Bouchè. « Accelerating the Mdx Heart Histo-Pathology through Physical Exercise ». Life 11, n^o 7 (17 juillet 2021) : 706. http://dx.doi.org/10.3390/life11070706.

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Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel therapies for the treatment of dystrophic heart problems depends on the availability of animal models that closely mirror the human pathology. The widely used DMD animal model, the mdx mouse, presents a milder cardiac pathology compared to humans, with a late onset, which precludes large-scale and reliable studies. In this study, we used an exercise protocol to accelerate and worsen the cardiac pathology in mdx mice. The mice were subjected to a 1 h-long running session on a treadmill, at moderate speed, twice a week for 8 weeks. We demonstrate that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increases necrosis and inflammation, and reduces heart function compared to controls. We believe that our exercised mdx model represents an easily reproducible and useful tool to study the molecular and cellular networks involved in dystrophic heart alterations, as well as to evaluate novel therapeutic strategies aimed at ameliorating dystrophic heart pathology.

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Mordechay, Sharon, Shaun Smullen, Paul Evans, Olga Genin, Mark Pines et Orna Halevy. « Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy ». International Journal of Molecular Sciences 22, n^o 13 (30 juin 2021) : 7063. http://dx.doi.org/10.3390/ijms22137063.

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Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(−)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form’s effect. No effect was observed for (−)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (−)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (−)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy.

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Dubuisson, Nicolas, Romain Versele, Chloé Planchon, Camille M. Selvais, Laurence Noel, Michel Abou-Samra et María A. Davis-López de Carrizosa. « Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy ». International Journal of Molecular Sciences 23, n^o 24 (16 décembre 2022) : 16080. http://dx.doi.org/10.3390/ijms232416080.

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Duchenne muscular dystrophy (DMD) is a progressive disease caused by the loss of function of the protein dystrophin. This protein contributes to the stabilisation of striated cells during contraction, as it anchors the cytoskeleton with components of the extracellular matrix through the dystrophin-associated protein complex (DAPC). Moreover, absence of the functional protein affects the expression and function of proteins within the DAPC, leading to molecular events responsible for myofibre damage, muscle weakening, disability and, eventually, premature death. Presently, there is no cure for DMD, but different treatments help manage some of the symptoms. Advances in genetic and exon-skipping therapies are the most promising intervention, the safety and efficiency of which are tested in animal models. In addition to in vivo functional tests, ex vivo molecular evaluation aids assess to what extent the therapy has contributed to the regenerative process. In this regard, the later advances in microscopy and image acquisition systems and the current expansion of antibodies for immunohistological evaluation together with the development of different spectrum fluorescent dyes have made histology a crucial tool. Nevertheless, the complexity of the molecular events that take place in dystrophic muscles, together with the rise of a multitude of markers for each of the phases of the process, makes the histological assessment a challenging task. Therefore, here, we summarise and explain the rationale behind different histological techniques used in the literature to assess degeneration and regeneration in the field of dystrophinopathies, focusing especially on those related to DMD.

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Hildyard, John C. W., Dominique O. Riddell, Rachel C. M. Harron, Faye Rawson, Emma M. A. Foster, Claire Massey, Frances Taylor-Brown, Dominic J. Wells et Richard J. Piercy. « The skeletal muscle phenotype of the DE50-MD dog model of Duchenne muscular dystrophy ». Wellcome Open Research 7 (23 septembre 2022) : 238. http://dx.doi.org/10.12688/wellcomeopenres.18251.1.

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Background: Animal models of Duchenne muscular dystrophy (DMD) are essential to study disease progression and assess efficacy of therapeutic intervention, however dystrophic mice fail to display a clinically relevant phenotype, limiting translational utility. Dystrophin-deficient dogs exhibit disease similar to humans, making them increasingly important for late-stage preclinical evaluation of candidate therapeutics. The DE50-MD canine model of DMD carries a mutation within a human ‘hotspot’ region of the dystrophin gene, amenable to exon-skipping and gene editing strategies. As part of a large natural history study of disease progression, we have characterised the DE50-MD skeletal muscle phenotype to identify parameters that could serve as efficacy biomarkers in future preclinical trials. Methods: Vastus lateralis muscles were biopsied from a large cohort of DE50-MD dogs and healthy male littermates at 3-monthly intervals (3-18 months) for longitudinal analysis, with multiple muscles collected post-mortem to evaluate body-wide changes. Pathology was characterised quantitatively using histology and measurement of gene expression to determine statistical power and sample sizes appropriate for future work. Results: DE50-MD skeletal muscle exhibits widespread degeneration/regeneration, fibrosis, atrophy and inflammation. Degenerative/inflammatory changes peak during the first year of life, while fibrotic remodelling appears more gradual. Pathology is similar in most skeletal muscles, but in the diaphragm, fibrosis is more prominent, associated with fibre splitting and pathological hypertrophy. Picrosirius red and acid phosphatase staining represent useful quantitative histological biomarkers for fibrosis and inflammation respectively, while qPCR can be used to measure regeneration (MYH3, MYH8), fibrosis (COL1A1), inflammation (SPP1), and stability of DE50-MD dp427 transcripts. Conclusion: The DE50-MD dog is a valuable model of DMD, with pathological features similar to young, ambulant human patients. Sample size and power calculations show that our panel of muscle biomarkers are of strong pre-clinical value, able to detect therapeutic improvements of even 25%, using trials with only six animals per group.

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Campbell, Katherine, Louise Rodino-Klapac, Zarife Sahenk, Chris Shilling, Sarah Lewis, Dawn Bowles, Steven Gray et al. « Revertant muscle fibers expressing dystrophin do not tolerize the immune system in Duchenne muscular dystrophy : lessons learned from a Phase I clinical trial (96.9) ». Journal of Immunology 184, n^o 1_Supplement (1 avril 2010) : 96.9. http://dx.doi.org/10.4049/jimmunol.184.supp.96.9.

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Abstract Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness due to mutation of the dystrophin gene. Muscle inflammation is an unexplained feature of DMD. T lymphocytes dominate the inflammatory infiltrate but antigen(s) they target have not been identified. Here we evaluated T cell immunity to dystrophin in 6 humans with DMD before and after delivery of a gene therapy vector to skeletal muscle. The vector transgene encoded a miniaturized version of human dystrophin that restores muscle function in animal models of DMD. Sustained transgene expression was not observed in any of the subjects. Non-self epitopes encoded by the vector transgene, but deleted from the defective dystrophin gene, provoked CD4+ and CD8+ T cell responses in a subset of the subjects. Dystrophin-specific T cell immunity was unexpectedly detected in two subjects before gene therapy. Epitopes were mapped to revertant dystrophin protein spontaneously expressed in rare muscle fibers when alternative splicing restores the correct open reading frame. Delivery of the minidystrophin gene to skeletal muscle of one subject provoked a very rapid increase in the frequency of these self-reactive T cells. T cell priming by idiosyncratic expression of revertant dystrophin could explain muscle inflammation and contribute to the pathogenesis of DMD. Recall of auto-reactive T cells also has important clinical significance in the design and monitoring of experimental therapies for this disease.

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Moorwood, Catherine, Neha Soni, Gopal Patel, Steve D. Wilton et Tejvir S. Khurana. « A Cell-Based High-Throughput Screening Assay for Posttranscriptional Utrophin Upregulation ». Journal of Biomolecular Screening 18, n^o 4 (30 octobre 2012) : 400–406. http://dx.doi.org/10.1177/1087057112465648.

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Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease caused by mutations in the dystrophin gene. Utrophin is a homologue of dystrophin that can compensate for its absence when overexpressed in DMD animal models. Utrophin upregulation is therefore a promising therapeutic approach for DMD. Utrophin is regulated at both transcriptional and posttranscriptional levels. Transcriptional regulation has been studied extensively, and assays have been described for the identification of utrophin promoter-targeting molecules. However, despite the profound impact that posttranscriptional regulation has on utrophin expression, screening assays have not yet been described that could be used to discover pharmaceuticals targeting this key phase of regulation. We describe the development and validation of a muscle cell line–based assay in which a stably expressed luciferase coding sequence is flanked by the utrophin 5′- and 3′-untranslated regions (UTRs). The assay was validated using the posttranscriptional regulation of utrophin by miR-206. The assay has a Z′ of 0.7, indicating robust performance in high-throughput format. This assay can be used to study utrophin regulatory mechanisms or to screen chemical libraries for compounds that upregulate utrophin posttranscriptionally via its UTRs. Compounds identified via this assay, used alone or in a synergistic combination with utrophin promoter-targeting molecules, would be predicted to have therapeutic potential for DMD.

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Andre, Alexander B., Liqiang Zhang, Jalen D. Nix, Nora Elmadbouly, Alexandra R. Lucas, Jeanne Wilson-Rawls et Alan Rawls. « Myxomavirus Serp-1 Protein Ameliorates Inflammation in a Mouse Model of Duchenne Muscular Dystrophy ». Biomedicines 10, n^o 5 (17 mai 2022) : 1154. http://dx.doi.org/10.3390/biomedicines10051154.

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Duchenne muscular dystrophy is an X-linked disease afflicting 1 in 3500 males that is characterized by muscle weakness and wasting during early childhood, and loss of ambulation and death by early adulthood. Chronic inflammation due to myofiber instability leads to fibrosis, which is a primary cause of loss of ambulation and cardiorespiratory insufficiency. Current standard of care focuses on reducing inflammation with corticosteroids, which have serious adverse effects. It is imperative to identify alternate immunosuppressants as treatments to reduce fibrosis and mortality. Serp-1, a Myxoma virus-derived 55 kDa secreted glycoprotein, has proven efficacy in a range of animal models of acute inflammation, and its safety and efficacy has been shown in a clinical trial. In this initial study, we examined whether pegylated Serp-1 (PEGSerp-1) treatment would ameliorate chronic inflammation in a mouse model for Duchenne muscular dystrophy. Our data revealed a significant reduction in diaphragm fibrosis and increased myofiber diameter, and significantly decreased pro-inflammatory M1 macrophage infiltration. The M2a macrophage and overall T cell populations showed no change. These data demonstrate that treatment with this new class of poxvirus-derived immune-modulating serpin has potential as a therapeutic approach designed to ameliorate DMD pathology and facilitate muscle regeneration.

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Bremner, Samantha B., Christian J. Mandrycky, Andrea Leonard, Ruby M. Padgett, Alan R. Levinson, Ethan S. Rehn, J. Manuel Pioner, Nathan J. Sniadecki et David L. Mack. « Full-length dystrophin deficiency leads to contractile and calcium transient defects in human engineered heart tissues ». Journal of Tissue Engineering 13 (janvier 2022) : 204173142211196. http://dx.doi.org/10.1177/20417314221119628.

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Cardiomyopathy is currently the leading cause of death for patients with Duchenne muscular dystrophy (DMD), a severe neuromuscular disorder affecting young boys. Animal models have provided insight into the mechanisms by which dystrophin protein deficiency causes cardiomyopathy, but there remains a need to develop human models of DMD to validate pathogenic mechanisms and identify therapeutic targets. Here, we have developed human engineered heart tissues (EHTs) from CRISPR-edited, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing a truncated dystrophin protein lacking part of the actin-binding domain. The 3D EHT platform enables direct measurement of contractile force, simultaneous monitoring of Ca2+ transients, and assessment of myofibril structure. Dystrophin-mutant EHTs produced less contractile force as well as delayed kinetics of force generation and relaxation, as compared to isogenic controls. Contractile dysfunction was accompanied by reduced sarcomere length, increased resting cytosolic Ca2+ levels, delayed Ca2+ release and reuptake, and increased beat rate irregularity. Transcriptomic analysis revealed clear differences between dystrophin-deficient and control EHTs, including downregulation of genes related to Ca2+ homeostasis and extracellular matrix organization, and upregulation of genes related to regulation of membrane potential, cardiac muscle development, and heart contraction. These findings indicate that the EHT platform provides the cues necessary to expose the clinically-relevant, functional phenotype of force production as well as mechanistic insights into the role of Ca2+ handling and transcriptomic dysregulation in dystrophic cardiac function, ultimately providing a powerful platform for further studies in disease modeling and drug discovery.

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Mázala, Davi A. G., Robert W. Grange et Eva R. Chin. « The role of proteases in excitation-contraction coupling failure in muscular dystrophy ». American Journal of Physiology-Cell Physiology 308, n^o 1 (1 janvier 2015) : C33—C40. http://dx.doi.org/10.1152/ajpcell.00267.2013.

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Duchenne muscular dystrophy (DMD) is one of the most frequent types of muscular dystrophy. Alterations in intracellular calcium (Ca2+) handling are thought to contribute to the disease severity in DMD, possibly due to the activation of Ca2+-activated proteases. The purpose of this study was twofold: 1) to determine whether prolonged excitation-contraction (E-C) coupling disruption following repeated contractions is greater in animals lacking both dystrophin and utrophin ( mdx/Utr−/−) compared with mice lacking only dystrophin ( mdx); and 2) to assess whether protease inhibition can prevent E-C coupling failure following repeated tetani in these dystrophic mouse models. Excitation-contraction coupling was assessed using Fura-2 ratio, as an index of intracellular free Ca2+ concentration, in response to electrical stimulation of single muscle fibers from the flexor digitorum brevis muscle. Resting Fura-2 ratio was higher in dystrophic compared with control (Con) fibers, but peak Fura-2 ratios during stimulation were similar in dystrophic and Con fibers. One hour after a series of repeated tetani, peak Fura-2 ratios were reduced by 30 ± 5.6%, 23 ± 2%, and 36 ± 3.1% in mdx, mdx/Utr+/−, and mdx/Utr−/−, respectively, with the greatest reduction in mdx/Utr−/− fibers ( P < 0.05). Protease inhibition attenuated this decrease in peak Fura-2 ratio. These data indicate that E-C coupling impairment after repeated contractions is greatest in fibers lacking both dystrophin and utrophin and that prevention of protease activation can mitigate the prolonged E-C coupling impairment. These data further suggest that acute protease inhibition may be useful in reducing muscle weakness in DMD.

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Fiorillo, Alyson A., Christopher B. Tully, Jesse M. Damsker, Kanneboyina Nagaraju, Eric P. Hoffman et Christopher R. Heier. « Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone ». Physiological Genomics 50, n^o 9 (1 septembre 2018) : 735–45. http://dx.doi.org/10.1152/physiolgenomics.00134.2017.

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Corticosteroids are highly prescribed and effective anti-inflammatory drugs but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use is an important goal for treatment of chronic inflammatory diseases such as Duchenne muscular dystrophy (DMD). We have developed vamorolone (VBP15), a first-in-class dissociative glucocorticoid receptor (GR) ligand that shows the anti-inflammatory efficacy of corticosteroids without key steroid side effects in animal models. miRNAs are increasingly recognized as key regulators of inflammatory responses. To define effects of prednisolone and vamorolone on the muscle miRNAome, we performed a preclinical discovery study in the mdx mouse model of DMD. miRNAs associated with inflammation were highly elevated in mdx muscle. Both vamorolone and prednisolone returned these toward wild-type levels (miR-142-5p, miR-142-3p, miR-146a, miR-301a, miR-324-3p, miR-455-5p, miR-455-3p, miR-497, miR-652). Effects of vamorolone were largely limited to reduction of proinflammatory miRNAs. In contrast, prednisolone activated a separate group of miRNAs associated with steroid side effects and a noncoding RNA cluster homologous to human chromosome 14q32. Effects were validated for inflammatory miRNAs in a second, independent preclinical study. For the anti-inflammatory miRNA signature, bioinformatic analyses showed all of these miRNAs are directly regulated by, or in turn activate, the inflammatory transcription factor NF-κB. Moving forward miR-146a and miR-142 are of particular interest as biomarkers or novel drug targets. These data validate NF-κB signaling as a target of dissociative GR-ligand efficacy in vivo and provide new insight into miRNA signaling in chronic inflammation.

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Martins, Isabela M., Lygia M. M. Malvestio, Jair R. Engracia-Filho, Gustavo S. Claudiano, Flávio R. Moraes et Julieta R. E. Moraes. « Mast cells in the pathophysiology of Duchenne muscular dystrophy in Golden Retriever dogs ». Pesquisa Veterinária Brasileira 40, n^o 10 (octobre 2020) : 791–97. http://dx.doi.org/10.1590/1678-5150-pvb-6340.

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ABSTRACT: The Golden Retriever muscular dystrophy (GRMD) is one of the best models of Duchenne muscular dystrophy (DMD), with similar genotypic and phenotypic manifestations. Progressive proliferation of connective tissue in the endomysium of the muscle fibers occurs in parallel with the clinical course of the disease in GRMD animals. Previous studies suggest a relationship between mast cells and the deposition of fibrous tissue due to the release of mediators that recruit fibroblasts. The aim of this study was to evaluate the presence of mast cells and their relationship with muscle injury and fibrosis in GRMD dogs of different ages. Samples of muscle groups from six GRMD and four control dogs, aged 2 to 8 months, were collected and analyzed. The samples were processed and stained with HE, toluidine blue, and Azan trichrome. Our results showed that there was a significant increase in infiltration of mast cells in all muscle groups of GRMD dogs compared to the control group. The average number of mast cells, as well as the deposition of fibrous tissue, decreased with age in GRMD dogs. In the control group, all muscle types showed a significant increase in the amount of collagenous tissue. This suggests increased mast cell degranulation occurred in younger GRMD dogs, resulting in increased interstitial space and fibrous tissue in muscle, which then gradually decreased over time as the dogs aged. However, further studies are needed to clarify the role of mast cells in the pathogenesis of fibrosis.

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Martins, D. S., N. Z. Saraiva, J. M. Garcia, C. E. Ambrósio, M. Zatz et M. A. Miglino. « 201 CHARACTERIZATION OF CANINE EMBRYONIC GERM CELLS : AN EXPERIMENTAL MODEL FOR CELL THERAPY ». Reproduction, Fertility and Development 18, n^o 2 (2006) : 209. http://dx.doi.org/10.1071/rdv18n2ab201.

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Dogs represent excellent models to test different approaches before use for human therapy. Studies with animal models have suggested that the transplant of stem cells may have success in the treatment of degenerative diseases such as Parkinson's disease, diabetes, Duchenne muscular dystrophy (DMD), and acquired lesions. Embryonic stem cells are pluripotent and therefore have the potential to form all tissues. Our research aims to contribute to the treatment of DMD through the isolation and identification of embryonic germ cells and the development of the methodology of cellular differentiation for future transplantation into dystrophic dogs. Mongrel female dogs were ovariehysterectomized between 25 and 30 days of pregnancy. For recovery of embryos, the excised uterine horns were flushed with heparinized PBS. Samples collected from somites near the mesonephros area of four embryos recovered at 22 to 24 days of pregnancy and designated as A1 through A4 were dissociated and placed in culture. Isolated embryonic cells were allowed to plate onto monolayers of canine fibroblast cells. Flow cytometry was used to identify CD34+ markers. Isolated compact colonies of embryonic germ cells were seen growing around tissue fragments at 7 days of culture and remained in the undifferentiated stage until approximately 21 days in culture. At 14 days of explant, cell colonies were analyzed by flow cytometry. Cells from the A2 embryos contained the highest number of CD34+ cells, whereas no cells from A4 embryos showed specificity for the marker. A small proportion (2.12%) of cells from embryos A1 and A3 showed specificity for the CD34 marker. A quantity of A2 embryo cells that had maintained stem cell characteristics were frozen for future studies. Our results suggest that although spontaneous differentiation occurred, a small population of cells maintain the characteristics of stem cells. We are currently trying to improve the methodology to maintain cells undifferentiated for longer periods and to better control the specific differentiation process.

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Buscara, Laurine, David-Alexandre Gross et Nathalie Daniele. « Of rAAV and Men : From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back ». Journal of Personalized Medicine 10, n^o 4 (28 novembre 2020) : 258. http://dx.doi.org/10.3390/jpm10040258.

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Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed.

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Peres, M. A., M. Nichi, A. M. Rocha, C. M. Mendes, P. B. Cavalcanti, J. S. A. Gonçalves, J. A. Visintin et M. E. O. A. Assumpção. « 230 COMPARISON OF SEMEN SAMPLES FROM NORMAL AND MUSCULAR DYSTROPHY AFFECTED ANIMAL MODELS BY THIOBARBITURIC ACID REACTIVE SUBSTANCES TEST AND FLUORESCENCE-ACTIVATED CELL SORTING ANALYSIS ». Reproduction, Fertility and Development 21, n^o 1 (2009) : 213. http://dx.doi.org/10.1071/rdv21n1ab230.

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Duchenne’s muscular dystrophy (DMD) is the most common human muscular affliction with high frequency in male individuals. The condition is characterized by progressive muscle degeneration, weakness, and loss of motion capacity. These individuals exhibit longer lifespans resulting from improvements in technical patient care and now raise new questions ranging from ethical to physiological issues never observed before, such as the possibility of reproduction. Thus, this study used Golden Retriever muscular dystrophy (GRMD)-affected dogs, a natural experimental model of DMD, to evaluate semen quality and oxidative stress by thiobarbituric acid reactive substances (TBARS) test. Thirty-seven ejaculates from 4 non-affected Golden Retriever and 5 GRMD-affected dogs (from 1.5 to 4.5 years old) were collected monthly and evaluated as 5 different replicates. Semen samples were processed, and initial analysis comprised of sperm concentration, percent of straightforward motility and morphology. Samples were then diluted to a final concentration of 106 spermatozoa mL–1 of prior incubation with each fluorescent probe. Acrosome integrity assessment was conducted with PSAFITC (100 g mL–1), and mitochondrial activity was assessed by JC1 (50 g mL–1). Fluorescence-activated cell sorting was performed in 103 spermatozoa, from a pre-selected gate that contained only these cells. Seminal plasma was submitted to TBARS quantification by spectrophotometer under normal and oxidative conditions (stress). Parametric data were compared by Student’s t-test. There were no significant differences in ejaculate volume, sperm concentration, acrosomal integrity, mithocondrial activity, and ejaculate TBARS tests between GRMD and normal dogs. Data are summarized in the table. GRMD does not affect the production and quality of semen of dogs. This animal model suggests that ejaculates from DMD men can be obtained by the proper stimulation and that conventional in vitro fertilization techniques combined with preimplantation genetic diagnosis for single gene disorders may be able to satisfy the desire of paternity of DMD patients with the birth of non-affected children. Table 1.Sperm analysis and TBARS tests of ejaculates from GRMD and normal dogs FAPESP for the financial support (06/50272-3); Surgery Department and Reproduction Department of FMVZ-USP; Canil GRMD Brazil.

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Alves, Flávio R., Matheus L. T. Feitosa, André Gatti, Leandro Fadel, Silvana M. Unruh, Carlos E. Ambrósio, Franklin A. Sterman, Ana C. B. C. F. Pinto et Maria A. Miglino. « Imagem radiográfica da cavidade torácica de cães Golden Retriever acometidos pela distrofia muscular ». Pesquisa Veterinária Brasileira 29, n^o 2 (février 2009) : 99–104. http://dx.doi.org/10.1590/s0100-736x2009000200002.

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A distrofia muscular de Duchenne (DMD) é uma doença de origem genética, cuja principal manifestação clínica é enfraquecimento e atrofia progressiva dos músculos. Os cães da raça Golden Retriever podem apresentar distrofia muscular, com características genotípicas e fenotípicas muito próximas à distrofia muscular humana, sendo considerado o modelo animal mais apropriado para o estudo da DMD. Foram realizadas radiografias torácicas látero-laterais e dorsoventrais de 10 cães Golden Retriever afetados pela distrofia muscular, com o objetivo de relatar as alterações radiográficas associadas a essa patologia. O exame radiográfico da cavidade torácica evidenciou: (a) padrão pulmonar intersticial e alveolar predominante, (b) um quadro de pneumonia e edema pulmonar em fase inicial, (c) a cardiomegalia como o principal achado de comprometimento circulatório na cavidade torácica, (d) O megaesôfago torácico foi observado deslocando a traquéia e silhueta cardíaca ventralmente e, (e) a cúpula diafragmática apresentou modificação morfológica, mostrando protrusão para o interior da cavidade torácica e hérnia hiatal, com deslocamento do estômago para o espaço mediastino caudal. Os achados de necropsia evidenciaram efusão pleural e enfisema pulmonar e lesões compatíveis com processos degenerativos e metaplásicos da musculatura diafragmática e intercostal. A avaliação radiográfica constituiu-se como um meio diagnóstico auxiliar essencial na identificação de doença cardíaca e respiratória em cães Golden Retriever acometidos pela Distrofia Muscular, capaz de identificar processos pneumônicos primários, permitindo o estabelecimento de terapêutica adequada de tratamento, com prognóstico reservado nos estágios mais avançados desta alteração.

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Abreu, Dilayla K., Carolina Costola-de-Souza, Dayane Alcântara, Elaine A. F. Rodrigues, Karla P. C. Araújo, Paulo C. Maiorka, Maria A. Miglino et Carlos E. Ambrósio. « Estudo morfofuncional dos rins de cães da raça Golden Retriever afetados pela distrofia muscular (GRMD) ». Pesquisa Veterinária Brasileira 32, n^o 10 (octobre 2012) : 1067–72. http://dx.doi.org/10.1590/s0100-736x2012001000022.

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A Distrofia Muscular de Duchenne (DMD) é uma miopatia severa de caráter recessivo ligada ao cromossomo X e o modelo animal de estudo mais relevante é o Golden Retriever Muscular Dystrophy (GRMD). Além das severas alterações que ocorrem na musculatura estriada, muitos estudos mostram que outras estruturas, inclusive viscerais, podem se mostrar alteradas nesta patologia. Desta forma, este trabalho objetivou análisar e comparar possíveis alterações estruturais e funcionais do rim em cães GRMD. Neste modelo de estudo, foi possível observar a presença das faces convexa e côncava, do hilo renal e dos pólos craniais e caudais dos rins. O órgão mostrou-se envolto por uma cápsula fibrosa. Em um corte sagital do órgão, notou-se a presença das regiões cortical e medular e da pelve renal. Na análise microscópica foi possível identificar a zona medular e cortical com suas estruturas: os corpúsculos renais formados pelo glomérulo e pela cápsula de Bowman, os túbulos contorcidos proximais e distais, os ductos coletores, vasos sanguíneos e os segmentos das Alças de Henle. As dosagens séricas de creatinina e uréia encontram-se dentro dos limites de normalidade. Desta forma, de acordo com os nossos resultados, podemos concluir que os animais afetados estudados, não apresentaram alterações estruturais ou funcionais dos rins, o que nos permitir sugerir que apesar da ingestão hídrica comprometida, a estrutura renal, mantem- se preservada nos animais GRMD.

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Mbakam, C. Happi, J. Rousseau, G. Tremblay et J. Tremblay. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S77—S78. http://dx.doi.org/10.1016/j.nmd.2021.07.119.

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Egorova, T., A. Polikarpova, I. Savchenko, S. Vassilieva, Y. Ivanova, V. Skopenkova, M. Dzhenkova et al. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S73. http://dx.doi.org/10.1016/j.nmd.2021.07.104.

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Dubuisson, N., M. Abou-Samra, M. Davis, L. Noel, C. Selvais et S. Brichard. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S76. http://dx.doi.org/10.1016/j.nmd.2021.07.113.

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Hong, A. Vu, N. Bourg-Alibert, P. Sanatine, J. Poupiot, K. Charton, E. Gicquel, M. Spinazzi, I. Richard et D. Israeli. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S77. http://dx.doi.org/10.1016/j.nmd.2021.07.118.

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Lambert, M., Y. Zhang, J. Spinazzola, J. Widrick, J. Conner et L. Kunkel. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S78. http://dx.doi.org/10.1016/j.nmd.2021.07.120.

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Abou-Samra, M., A. Marino, C. Selvais, N. Dubuisson, L. Noel, C. Beauloye, S. Horman et S. Brichard. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S76—S77. http://dx.doi.org/10.1016/j.nmd.2021.07.116.

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Yavas, A., M. van Putten, E. Niks et A. Aartsma-Rus. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S75—S76. http://dx.doi.org/10.1016/j.nmd.2021.07.112.

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Mantuano, P., B. Boccanegra, F. Sanarica, E. Conte, A. Mele, M. De Bellis, O. Cappellari et A. De Luca. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S73. http://dx.doi.org/10.1016/j.nmd.2021.07.105.

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Kreher, N., X. Li, M. Kheirabadi, K. Kamer, P. Dougherty, W. Lian, C. Waters et al. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S74. http://dx.doi.org/10.1016/j.nmd.2021.07.106.

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Engelbeen, S., C. Tanganyika-de Winter, D. Van De Vijver, M. Holierhoek, A. Yavas, S. Kooijman, A. Aartsma-Rus et M. van Putten. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S73. http://dx.doi.org/10.1016/j.nmd.2021.07.103.

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Schneider, A., S. Jirka, C. Tanganyika-de Winter, H. Mei, J. Boom et A. Aartsma-Rus. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S75. http://dx.doi.org/10.1016/j.nmd.2021.07.111.

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Creisméas, A., C. Gazaille, A. Bourdon, A. Lafoux, M. Allais, V. Le Razavet, M. Ledevin et al. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S76. http://dx.doi.org/10.1016/j.nmd.2021.07.114.

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van Putten, M., C. Tanganyika-de Winter, K. Putker, S. Engelbeen, D. Van de Vijver, M. Verhaeg, M. Overzier et A. Aartsma-Rus. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S74. http://dx.doi.org/10.1016/j.nmd.2021.07.107.

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Mantuano, P., B. Boccanegra, E. Bresciani, F. Sanarica, A. Mele, M. De Bellis, O. Cappellari et al. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S77. http://dx.doi.org/10.1016/j.nmd.2021.07.117.

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Morin, A., O. Petrova, M. Petkova, T. Tensorer, T. Manoliu, I. Richard, L. Garcia et al. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S72—S73. http://dx.doi.org/10.1016/j.nmd.2021.07.102.

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Kim, S., N. Buss, C. Qiao, H. Patel, L. Yang, K. Elliott, R. Qian, L. Ye, M. Fiscella et O. Danos. « DMD – ANIMAL MODELS ». Neuromuscular Disorders 31 (octobre 2021) : S76. http://dx.doi.org/10.1016/j.nmd.2021.07.115.

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