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Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening  [PDF]
Catherine Moorwood, Olga Lozynska, Neha Suri, Andrew D. Napper, Scott L. Diamond, Tejvir S. Khurana
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026169
Abstract: Background Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.
Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy
Dawn A Delfín, Ying Xu, Jennifer M Peterson, Denis C Guttridge, Jill A Rafael-Fortney, Paul ML Janssen
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-68
Abstract: To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko) mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice.At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice.We conclude that NBD can significantly improve cardiac contractile dysfunction in the dko mouse model of DMD and may thus provide a novel therapeutic treatment for heart failure.Duchenne muscular dystrophy (DMD) is a degenerating striated muscle disease caused by the absence of the dystrophin protein[1]. Although limb muscle weakness and the loss of ambulation are usually the initial clinical signs of the disease, patients with DMD die from respiratory failure or heart failure. Pertaining to the heart, ninety-five percent of DMD patients develop dilated cardiomyopathy, and over twenty-five percent die from heart failure [2]. These numbers are predicted to grow as prophylactic treatments targeted at maintaining respirat
Detection of mRNA expression of Utrophin in gastrocnemius muscle tissue of patients with pseudohypertrophy muscular dystrophy

- , 2017, DOI: 10.13705/j.issn.1671-6825.2017.04.021
Abstract: 目的:探讨抗肌萎缩蛋白相关蛋白(Utrophin)在Duchenne型肌营养不良症(DMD)与Becker型肌营养不良症(BMD)患儿腓肠肌组织中的表达水平及临床意义。方法:采用实时荧光定量PCR方法检测肌营养不良症组(n=31)[包括DMD组(n=24)与BMD组(n=7),DMD组又分为DMD1组(n=6)、DMD2组(n=12)、DMD3组(n=6)]与对照组(n=21)腓肠肌组织中抗肌萎缩蛋白相关蛋白(Utrophin)及抗肌萎缩蛋白(Dystrophin)mRNA的表达水平,分析肌营养不良症患儿腓肠肌组织中Utrophin mRNA表达水平与Hammersmith功能运动评分(HFMS)之间的相关性。结果:与对照组比较,肌营养不良症组腓肠肌组织中Utrophin mRNA的表达水平升高(P=0.002)。与BMD组比较,DMD组Utrophin mRNA的表达上调(P=0.003)。与DMD1组比较,Utrophin mRNA在DMD2组与DMD3组的表达水平上调,其中以DMD3组上调最为显著(P<0.05)。肌营养不良症患儿Utrophin mRNA的表达水平与HFMS呈正相关(rS=0.671,P=0.003)。结论:Utrophin在肌营养不良症患儿腓肠肌组织中表达上调, Utrophin可能替代成熟骨骼肌纤维中Dystrophin的部分功能,在阻遏DMD进展过程中起着重要作用。
Aim: To investigate the expression level of Utrophin in the gastrocnemius muscle tissue of patients with Duchenne and Becker muscular dystrophy(DMD and BMD).Methods: A total of 24 patients with DMD(DMD group)and 7 patients with BMD(BMD group)were chosen, and 21 healthy male children were chosen as control. The DMD group was further allocated into DMD1 group(n=6), DMD2 group(n=12), and DMD3 group(n=6). The expression levels of Utrophin and Dystrophin mRNA in the above groups were detected by real-time quantitative PCR. The relationship between Utrophin mRNA and Hammersmith functional motor score(HFMS)of the patients with muscular dystrophy was analyzed.Results: Compared with the control group, Utrophin mRNA significantly over-expressed in the muscular dystrophy group(P=0.002). The expression level of Utrophin mRNA in the gastrocnemius muscle in the DMD group was significantly higher compared with BMD group(P=0.003); compared with BMD1 group,the expression level of Utrophin mRNA in BMD2 group and BMD3 group was significantly higher,especially in DMD3 group(P<0.05). There was a positive correlation between Utrophin mRNA expression and HFMS in patients with DMD or BMD(rS=0.671,P=0.003).Conclusion: Utrophin expression level in gastrocnemius muscle tissue from the patients with muscular dystrophy rises. Utrophin could replace part of Dystrophin function in the mature skeletal muscle, which may play a role in delaying the progression of muscle weakness
Functional and Molecular Effects of Arginine Butyrate and Prednisone on Muscle and Heart in the mdx Mouse Model of Duchenne Muscular Dystrophy  [PDF]
Alfredo D. Guerron,Rashmi Rawat,Arpana Sali,Christopher F. Spurney,Emidio Pistilli,Hee-Jae Cha,Gouri S. Pandey,Ramkishore Gernapudi,Dwight Francia,Viken Farajian,Diana M. Escolar,Laura Bossi,Magali Becker,Patricia Zerr,Sabine de la Porte,Heather Gordish-Dressman,Terence Partridge,Eric P. Hoffman,Kanneboyina Nagaraju
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011220
Abstract: The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD) is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin.
Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse  [PDF]
Jonathon M. Tinsley,Rebecca J. Fairclough,Richard Storer,Fraser J. Wilkes,Allyson C. Potter,Sarah E. Squire,Dave S. Powell,Anna Cozzoli,Roberta F. Capogrosso,Adam Lambert,Francis X. Wilson,Stephen P. Wren,Annamaria De Luca,Kay E. Davies
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019189
Abstract: Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle. There is significant evidence demonstrating that increasing levels of the dystrophin-related protein, utrophin, in mouse models results in sarcolemmal bound utrophin and prevents the muscular dystrophy pathology. The aim of this work was to develop a small molecule which increases the levels of utrophin in muscle and thus has therapeutic potential.
Recent advances in Duchenne muscular dystrophy  [cached]
Perkins KJ,Davies KE
Degenerative Neurological and Neuromuscular Disease , 2012,
Abstract: Kelly J Perkins,1,2 Kay E Davies21Sir William Dunn School of Pathology, 2MRC Functional Genomics Unit, University of Oxford, Oxford, UKAbstract: Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.Keywords: dystrophy, animal models, pharmacological, exon skipping, gene therapy, utrophin
Ullrich Congenital Muscular Dystrophy  [cached]
Goknur Haliloglu,Haluk Topaloglu
Iranian Journal of Child Neurology , 2011,
Abstract: ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenital muscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in the Western world mostly seen with de novo dominant mutations in the collagen VI genes. Milder form of the condition is the Bethlem myopathy. There may be overlap forms in the clinic resembling the Ehler-Danlos syndrome. There has been some radical efforts for cure especially through the apoptosis cascades.
Translational Regulation of Utrophin by miRNAs  [PDF]
Utpal Basu, Olga Lozynska, Catherine Moorwood, Gopal Patel, Steve D. Wilton, Tejvir S. Khurana
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029376
Abstract: Background Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified. Methodology/Principal Findings Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ~99% in C2C12 cells and is mediated by both the 5′- and 3′-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR-206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells. Conclusions/Significance The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA-mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD.
Duchenne muscular dystrophy
Yiu Eppie,Kornberg Andrew
Neurology India , 2008,
Abstract: Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. Patients usually become wheelchair-bound by the age of 12 years, and die of cardiorespiratory complications in their late teens to early twenties. Advances in the management of DMD, including treatment with corticosteroids and the use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. The clinical features, investigations, and management of DMD are reviewed, as well as the latest in some of the novel therapies.
Evaluation of cases with congenital muscular dystrophy  [cached]
Ulu? Yi?,G?khan Uyan?k,Semra H?z Kurul,Handan ?akmak??
Turk Pediatri Ar?ivi , 2009,
Abstract: Aim: The aim of this study is to evaluate clinical and radiological features of our cases with congenital muscular dystrophy. Material and Method: The data of cases who were diagnosed with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine between July 2005 and July 2008 were analysed retrospectively. Results: A total of 13 cases were evaluated. Among the 13 cases, seven (53%) were boys and six (47%) were girls. Seven patients (53%) were in the alfa dystroglycanopathy group, five patients (38%) were in collagen VI related congenital muscular dystrophy group and one patient (9%) was in “rigid spine” group. The mean age of cases with alfa dystroglycanopathy and collagen VI related congenital muscular dystrophy were 3.57±2.92 (0.5-7) and 10.83±5.67 (1-16) years, respectively. In alfa dystroglycanopathy group, five cases (71%) had eye involvement and six cases (85%) had developmental malformations of the central nervous system. All cases had brainstem hypoplasia and six cases (85%) had cerebellar cysts. In collagen VI related congenital muscular dystrophy group, the main complaints were retardation in motor mile stones, contractures in proximal joints and hyperlaxicity in distal joints. The most important clinical features in the case diagnosed with “rigid spine” syndrome were severe scoliosis and muscle atrophy. Conclusions: The clinical features of congenital muscular dystrophies are heterogenous and increase in number of cases diagnosed as congenital muscular dystrophy should give an opportunity to determine the incidence of different types of congenital muscular dystrophies in our country.
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