Дисертації: "Duchenne Muscular Dystrophy (DMD)"

1

Cockburn, David James. "Analysis of DMD translocations." Thesis, University of Oxford, 1991. http://ora.ox.ac.uk/objects/uuid:ab53825b-b18e-4f60-954a-4ea9e0435126.

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Duchenne and Becker muscular dystrophies (DMD, BMD) are allelic X-linked diseases which affect approximately one in 3500 male newborns. They are caused by mutations in a gene positioned on the short arm of the X chromosome at Xp21. The first indication of the location of this gene was the description of rare females expressing DMD and who were found to have constitutional X;autosome translocations with an X chromosome breakpoint at this site. There are now 24 such females known worldwide. They express DMD as a consequence of preferential inactivation of the normal X chromosome. In order to contribute to the understanding of the aetiology of mutations causing DMD and the aetiology of constitutional translocations, two types of study have been performed here. Firstly, the detailed mapping of the X chromosome breakpoints of DMD-associated X;autosome translocations has been investigated. The results of this study have been compared with data on the physical distribution of mutations causing DMD in male patients. Secondly, one translocation, an X;l translocation with an autosomal breakpoint at Ip34, has been selected for more detailed investigation and the DNA sequence has been determined at the site of the rearrangement. Translocation breakpoint mapping studies were performed by somatic cell hybrid analysis. Hybrids were karyotyped and this information was used to construct a hybrid panel for the purpose of determining the autosomal localisations of anonymous DNA probes. The mapping of seven probes using this panel is described. The work described in this thesis revealed that the distribution of translocation breakpoints within the DMD gene appears to be random and may differ from the distribution of mutations in male patients. The X;l translocation whose breakpoints are cloned and sequenced was found to involve two expressed loci, one coding for dystrophin on the X chromosome and one for the leukocyte antigen related protein on chromosome 1. Sequence data revealed that a deletion of four to seven nucleotides from the X chromosome and a duplication of two to five nucleotides are associated with the translocation. The possible involvement of trinucleotides adjacent to the breakpoints, and of a LINE, a SINE and a stretch of potential Z-DNA within 1 kb of the X chromosome or the chromosome 1 breakpoint, is discussed.

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2

Woolf, Peter James. "Cardiac calcium handling in the mouse model of Duchenne Muscular Dystrophy." University of Southern Queensland, Faculty of Sciences, 2003. http://eprints.usq.edu.au/archive/00001525/.

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The dystrophinopathies are a group of disorders characterised by cellular absence of the membrane stabilising protein, dystrophin. Duchenne muscular dystrophy is the most severe disorder clinically. The deficiency of dystrophin, in the muscular dystrophy X-linked (mdx) mouse causes an elevation in intracellular calcium in cardiac myocytes. Potential mechanisms contributing to increased calcium include enhanced influx, sarcoplasmic reticular calcium release and\or reduced sequestration or sarcolemmal efflux. This dissertation examined the potential mechanisms that may contribute to an intracellular calcium overload in a murine model of muscular dystrophy. The general cardiomyopathy of the mdx myocardium was evident, with the left atria from mdx consistently producing less force than control atria. This was associated with delayed relaxation. The role of the L-type calcium channels mediating influx was initially investigated. Dihydropyridines had a lower potency in contracting left atria corresponding to a redued dihydropyridine receptor affinity in radioligand binding studies of mdx ventricular homogenates (P<0.05). This was associated with increased ventricular dihydropyridine receptor protein and mRNA levels (P<0.05). The function of the sarcoplasmic reticulum in terms of release and also sequestration of calcium via the sarco-endoplasmic reticulum ATPase were investigated. A lower force of contraction was evident in mdx left atria in response to a range of stimulation frequencies (P<0.05) and concentrations of extracellular calcium (P<0.05). However, in the presence of 1 nM Ryanodine to block sarcoplasmic reticular calcium release, increased stimulation frequency caused similar forces to those obtained in control mice suggesting enhanced calcium influx via L-type calcium channels in mdx. Rapid cooling contractures showed a reduced contracture in mdx compared to control in response to cooling. This suggests some dysfunction in SR storage, which may be associated with the delayed relaxation time. Concentration-response curves to inhibitors of the sarco-endoplasmic reticulum showed no difference in function of the enzyme responsible for calcium uptake into the sarcoplasmic reticulum. Although sarco-endoplasmic reticulum ATPase mRNA was upregulated, no functional benefit was evident. This study indicates that a deficiency of dystrophin leads to upregulation of L-type calcium channels that contribute to increased calcium influx, with no functional change in sarcoplasmic reticular sequestration. Upregulation of the influx pathway is a potential mechanism for the calcium overload observed in mdx cardiac muscle.

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3

Taylor, Peter John Medical Sciences Faculty of Medicine UNSW. "Molecular genetic analysis of a New South Wales muscular dystrophy cohort." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43309.

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Duchenne muscular dystrophy (DMD) is an X-linked lethal condition associated with high morbidity and mortality. There is currently no cure for this disease. Several gene-based therapeutic approaches for treating DMD are currently under development but all are dependent on the knowledge of the causative dystrophin gene mutation. A combined mutation detection approach consisting of a quantitative PCR based analysis and DNA sequencing of the dystrophin gene resulted in a mutation etection rate of 96% in the New South Wales (NSW) DMD cohort. The proportion of exon duplication mutations was twice that generally reported for similar patient opulations. The clinical utility of the combined mutation protocol for DMD carrier testing clarified the carrier status of an additional one-third (33%) of female relatives compared to a conventional approach of biochemical, pedigree and linkage studies. The generally accepted view that two-thirds of mothers of isolated cases of DMD are themselves mutation carriers is challenged. Although this assumption is valid for duplication and DNA sequence mutations, it is not valid for deletion mutations in the NSW cohort. The incidence of new cases of DMD in the New South Wales population was educed from approximately 1 in 3594 live male births to 1 in 6022 live male births over a 25 year period, indicative of a significant effect of the combination of genetic counselling and improved methods of carrier detection over that period. In a study of a cohort of boys with DMD, who had both psychological and mutational analysis, it was shown that mutations affecting the shorter, C-terminal isoforms of dystrophin are associated with decreased mean intellectual function. A hypothesis is presented that mutations within the long 5' untranslated region of the Dp140 isoform are unlikely to significantly affect expression of this brain-expressed isoform. During the course of studying the NSW DMD cohort a family was identified which exhibited X-linkage and a unique clinical presentation involving episodes of severe and prolonged muscle weakness. A novel variant in the pyruvate dehydrogenase E1 alpha subunit (PDHA 1) was identified. The phenotypic effect of this variant is not proven but a body of evidence implicates this as likely to be causative of the observed phenotype.

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4

Sharma, Dishant. "Development of tolerogenic plasmid vectors for gene therapy of Duchenne muscular dystrophy (DMD)." Thesis, University of Portsmouth, 2017. https://researchportal.port.ac.uk/portal/en/theses/development-of-tolerogenic-plasmid-vectors-for-gene-therapy-of-duchenne-muscular-dystrophy-dmd(55b88eaa-5f23-4ae6-83e7-baed45f82d00).html.

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This project focused on the development of an effective gene replacement therapy for the Duchenne muscular dystrophy (DMD) in its mouse models [(X-linked muscular dystrophy, mdx) and mdx-βgeo mice]. Earlier studies on the DMD replacement therapy (usually using mini-dystrophin) were largely not successful because dystrophin is being recognised as an antigen upon re-expression in dystrophic muscles and initiates the specific immune response. This leads to a short-lived or no expression of mini-dystrophin as was found in both human clinical trials and in animal models. It had been shown that the presence of pre-existing Tcells responding to dystrophin was responsible for this effect and immunosuppressive drug treatments in a canine model of DMD (cxmd) resulted in a stable expression of dystrophin for 2 years. This study investigated the potential of using immunomodulatory factors such as IDO (Indoleamine 2,3-dioxygenase) and TDO (tryptophan 2,3-dioxygenase) to prolong expression of newly synthesised antigenic products in dystrophic mice. IDO and TDO are the rate-limiting enzymes of the tryptophan catabolism pathway, which regulate the production of kynurenines. These enzymes are known to increase the survival of grafts in transplantation by targeting dendritic cells, which play an important role in the T-cell activation. The plasmid with the general CMV promoter was used for expression of these enzymes in cell lines (HEK 293 cells and SC5 dystrophic myoblasts) and in skeletal muscles in vivo. To achieve targeting of the immunomodulatory constructs specifically into dendritic cells, the CD11c minimal promoter has been used. The plasmid driven by the CMV promoter was used for expression of the mini-dystrophin (an intracellular, structural protein) or the E.coli b-galactosidase (cytoplasmic but also secreted, strongly antigenic protein) in cells in vitro and muscles in vivo. Another plasmid construct expressing the minidystrophin gene under the muscle- specific creatine kinase promoter and the myosin light chain 1/3 enhancer combination was also used for studies of the effects of muscle-specific expressions of the transgene. The cloning resulted in the generation of plasmids with the mini-dystrophin driven by MCK or CMV promoters and IDO transcripts under the control of CMV or CD11c minimal promoter (Chapter 3). The Western blotting analyses confirmed the ability of plasmids to drive specific transgenes' expression in HEK 293, mouse myoblasts and RAW 264.7 macrophage cell lines in vitro. The RT-PCR analyses confirmed the expression of specific plasmids (Chapter 4). The single plasmid expression experiment using the mini-dystrophin construct targeted into muscles was analysed by Western blotting, RT-PCR and immunohistochemistry. While RT-PCR confirmed its expression, the Western blotting results were ill-reproducible and immunohistochemistry did not confirm transgene expression. Moreover, there was no significant difference in the expression of mini-dystrophin driven by CMV or the muscle-specific MCK promoter/MLC enhancer combination (Chapter 5). The use of Pluronic SP1017-2 did not yield any significant improvement in the expression profile of plasmids as compared with normal saline. Hence, normal saline was used in subsequent experiments as a vehicle of choice. Moreover, to support the hypothesis, there was a requirement to analyse the fold increase of the target plasmid expression in the presence of immunomodulatory factors. This could not be achieved using the minidystrophin plasmids due to low expression and lack of reproducibility. Therefore, the expression profile of b-galactosidase used as a model transgene was analysed instead. This protein is immunogenic due to its E.coli origin and is a 120 KDa protein, which is very close to 125 KDa size of the mini-dystrophin. The timeline of b-galactosidase expression was established based on the presence of this protein at 7 and 14 days and its absence 21 days post-injection, as assessed by Western blotting. The expression profiles of IDO1 driven by CMV or CD11c were analysed and confirmed using RT-PCR; IDO1 did not show detectable expression in Western blotting. (Chapter 5). The effects of co-injection of β-galactosidase with IDO1 driven by CMV or CD11c were analysed by Western blotting, RT-PCR and qPCR. In the control samples, 25% of muscles expressed b-galactosidase two weeks after the injection. This increased to 42% (5 out of 12 muscles) in samples co-injected with CD11c-driven IDO1 and 69% (11 out of 16 muscles) in samples co-injected with IDO1 driven by the CMV promoter. This confirmed the hypothesis that the presence of IDO1 has a potential to sustain the expression of an immunogenic transgene and indicated that the more widespread rather than targeted expression of IDO1 in antigen-presenting cells was more effective in supporting such an expression (Chapter 5). The RT-PCR data showed IDO1 expression in most samples, also some that were not showing β-galactosidase in Western blots, and confirmed the plasmid-driven IDO1 expression. The qPCR data also confirmed significantly increased expression of b-galactosidase and IDO1 in co-injected samples compared to β-galactosidaseonly controls. This further supported the hypothesis that co-expression of immunomodulatory IDO1 increases the transgene expression (Chapter 5). The X-gal staining identified the expression of b-galactosidase in very few myofibres, which correlated with the Western blotting data and confirmed the low efficiency of the "naked" plasmid uptake by skeletal muscles. The presence of infiltrating immune cells surrounding these β-galactosidase positive myofibres was probed by immunohistochemical methods (Chapter 6). The qPCR analyses of a selection of the immune cell markers showed statistically significantly higher expression of CD4, CD8a, FoxP3 and COX2 in co-injected samples while expressions of IL-10 and IL-12 were statistically significantly lower in co-injected muscles. The levels of antibodies against beta-galactosidase were quantified by ELISA in control, b-galactosidase-only injected samples and IDO1 co-injected samples. The anti-β-galactosidase antibody levels were significantly lower in co-injected samples compared to the controls (Chapter 6). These results indicate that co-expression of genes encoding immunomodulatory enzymes of the kynurenine pathway can be a feasible strategy for preventing loss of expression of transgenes targeted into muscles with pre-existing inflammation. Hypothesis: "Co-expression of immunomodulatory factors (IDO/TDO) with minidystrophin or beta-galactosidase transgenes in skeletal muscles of the mdx mouse prolongs the expression of these transgenes." Aims:1-To prolong expression of immunogenic transgenes in dystrophic muscles withpre-existing inflammation.2-To prevent this loss of transgene by exploiting co-expression of genes encoding enzymes controlling kynurenine pathways instead of global immunosuppression. Objectives:1-To modify and validate expression profile of plasmids expressing target genes(mini-dystrophin and beta-galactosidase) and immunomodulatory genes(IDO1/IDO2/TDO/FoxO3) both in vitro and in vivo.2-To check the effects of immunomodulatory genes on the prolongation of target genes expression in vivo.3-To assess the occurrence of the tolerance induction.

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5

Heller, Kristin Noreen. "Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7)." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639.

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6

Laws, Nicola. "Characterisation and strategic treatment of dystrophic muscle." University of Southern Queensland, Faculty of Sciences, 2005. http://eprints.usq.edu.au/archive/00001457/.

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The mdx mouse is widely used as a model for Duchenne Muscular Dystrophy, a fatal X-linked disease caused by a deficiency of the sub-sarcolemmal protein, dystrophin. This dissertation reports characterisation of the features of dystrophy in the mdx mouse, including parameters such as electrophysiological and contractile properties of dystrophic cardiac tissue, quantitative evaluation of kyphosis throughout the mdx lifespan, and contractile properties of respiratory and paraspinal muscles. Following these characterisation studies, the efficacy of antisense oligonucleotides (AOs) to induce alternative mRNA splicing in mdx skeletal muscles (diaphragm and paraspinal muscles) was evaluated. The left atria of younger (<6 weeks) and older (>15 months) mdx mice showed consistently lower basal forces and responsiveness to increased calcium, while action potential duration was significantly shorter in young mice (3 weeks) and older mice (9 and 12 months) (P<0.05). Cardiac fibrosis increased with age in mdx atria and ventricles and was elevated in young (6-8 weeks) and old (15 months) mdx compared to control mice (P<0.01). This study provided insights into DMD cardiomyopathy, and suggested that very young or old mdx mice provide the most useful models. Mdx mice show thoracolumbar kyphosis like boys with Duchenne Muscular Dystrophy. A novel radiographic index, the Kyphotic Index (KI), was developed and showed that mdx mice are significantly more kyphotic from 9 months of age, an effect maintained until 17 months (P<0.05). At 17 months, the paraspinal and respiratory muscles (latissimus dorsi, diaphragm and intercostal muscles) are significantly weaker and more fibrotic (P<0.05). Administration of AOs at four sites within the diaphragm at 4 and 5 months of age significantly increased twitch and tetanic forces compared to sham treated mdx (P<0.05). However, no difference in collagen was evident and dystrophin was not detected, possibly due to the low concentration of AO utilised. This study suggested that AOs can provide functional improvement in treated skeletal muscles. Monthly injections with AOs into the paraspinal muscles from 2 months to 18 months of age alleviated kyphosis, without significantly altering twitch and tetanic forces of latissimus dorsi, diaphragm and intercostal muscles. There was evidence of less fibrosis in diaphragm and latissimus dorsi muscles (P<0.05) and reduced central nucleation of the latissimus dorsi and intercostal muscles (P<0.05). Again, dystrophin was not detected by immunoblot. These studies indicate that very young and old mdx mice display previously uncharacterised dystrophic features, and are useful models for testing new therapies such as AOs. Low doses of AOs were shown to be safe and efficacious for long-term use, however there remains a need for testing higher concentrations and improved delivery strategies.

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7

Humbertclaude, Véronique. "Variabilité phénotypique et corrélations génotype – phénotype des dystrophinopathies : contribution des banques de données." Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON1T028/document.

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L'objectif de ce travail est de développer la partie clinique de la banque de données du gène DMD, afin d'étudier l'histoire naturelle des dystrophinopathies et les corrélations génotype–phénotype, et de faciliter la sélection des patients pour les futurs essais thérapeutiques. La méthodologie créée pour le gène DMD peut être généralisée et utilisée pour d'autres banques de données dédiées à des maladies génétiques. La collecte de 70 000 données cliniques chez 600 patients avec un suivi longitudinal moyen de 12 ans permet de décrire l'histoire naturelle des dystrophies musculaires de Duchenne et de Becker et des formes symptomatiques chez les femmes. Nous avons pu préciser l'hétérogénéité phénotypique sur le plan moteur, orthopédique et respiratoire (forme sévère et forme intermédiaire de la dystrophie musculaire de Duchenne), sur le plan cardiaque (absence de corrélation entre les atteintes motrice et cardiaque, variabilité de l'atteinte cardiaque), et sur le plan cérébral (atteinte intellectuelle chez les patients avec dystrophie musculaire de Becker, troubles psychologiques des dystrophinopathies). L'utilisation de cet outil par les cliniciens et les généticiens devrait faciliter le travail de recherche clinique et la réalisation des futurs essais cliniques. Ceci nécessite maintenant de développer l'accessibilité de la banque de données et d'envisager sa pérennisation
The objective of this work is to develop the clinical part of the French dystrophinopathy data-base, in order to study the natural history and the genotype-phenotype correlations, and to facilitate the selection of the patients for the future therapeutic trials. The methodology developed for the DMD gene can be generalized and used for the other databases dedicated to genetic diseases. The collection of 70 000 clinical data for 600 patients with an average lon-gitudinal follow-up of 12 years allows to clarify the natural history of the muscular dystrophies of Duchenne and Becker and in symptomatic females. We were able to specify the pheno-typic heterogeneity of the motor, orthopaedic and respiratory involvements (severe form and intermediary form of the Duchenne muscular dystrophy), of the cardiac disorder (absence of correlation between motor and cardiac involvements, variability of the cardiomyopathy), and of the brain function (mental deficiency in the patients with Becker muscular dystrophy, psychological disorders in dystrophinopathies). The use of this tool by the clinicians and the ge-neticists should facilitate their clinical research work and the realization of the future clinical trials. This requires now to develop the accessibility of the database and to ensure its continued existence

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Thaker, Rajsi Y. "Potential drug treatment for Duchenne muscular dystrophy which could be through upregulation of lipin1." Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1629996330644397.

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9

Papadopoulou, Georgia. "Cognitive profile in advanced Duchenne Muscular Dystrophy (DMD) and the effects of hypoventilation on cognition." Thesis, University of Hull, 2010. http://hydra.hull.ac.uk/resources/hull:3471.

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The portfolio has three parts.Part One is a systematic literature review concerning the nature and severity of the psychological distress experienced by carers (primarily parents) of people with Muscular Dystrophy. Quantitative and qualitative studies investigating distress in these carers have been reviewed and critically evaluated to draw conclusions and implications for clinical practice. Part Two is an empirical paper aimed at creating a cognitive profile for people suffering from Duchenne Muscular Dystrophy in the advanced stages of the illness. The focus of this cross-sectional study is placed on the investigation of whether hypoventilation, inevitably seen to develop in this population, is related to permanent cognitive deficits in memory and/or executive functioning. The participants who have been identified to suffer from hypoventilation (N=17) are compared on measures of memory and executive functioning to a group of DMD participants of similar age (N=16) who have not yet developed hypoventilation. Other measures are also taken in the form of questionnaires to compare the groups on, including demographics, mood (depression and anxiety), health-related quality of life, sleepiness, and beliefs about sleep. Part Three comprises the Appendices.

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Escorcio, Renata. "Elaboração e análise de confiabilidade de escala de avaliação funcional da manobra de Gowers e da passagem de bipedestação para sedestação no solo para portadores de distrofia muscular de Duchenne (DMD)." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5163/tde-09122009-162729/.

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Objetivo: Construir Escala de Avaliação Funcional do Sentar e Levantar do Solo para Portadores de DMD (EAF-2) e testar sua confiabilidade intra e interexaminadores. Método: A construção da escala ocorreu em etapas: 1. Análise do movimento de sentar e levantar do solo em crianças saudáveis. 2. Análise do movimento de sentar e levantar do solo em crianças com DMD. 3. Elaboração da primeira versão da escala e do manual de instrução. 4. Avaliação por peritos e reajustes gerando a versão final. 5. Análise de confiabilidade inter e intraexaminador e correlação com a Escala de Vignos, idade e tempo de execução da atividade. Resultados: A escala abrange três fases para o sentar e cinco para o levantar, cada fase contendo itens que devem ser avaliados e pontuados. O escore pode variar de 0 a 10 para o sentar e de 0 a 15 para o levantar. Foi demonstrado muito boa repetibilidade da medida do sentar e levantar (ICC = 0,89 e 084, respectivamente) e excelente reprodutibilidade (ICC = 0,93 e 0,92, respectivamente). O Coeficiente Kappa para as 8 fases na análise interexaminadores variou de 0,77 a 1,00 (confiabilidade excelente para 5 fases e substancial para 3 fases), e na análise intra-examinador variou de 0,80 a 1,00 (confiabilidade excelente para 6 fases e substancial para 2 fases). Encontrou-se boa correlação entre as variáveis idade x Escala de Vignos (r= 0,58) e levantar x Escala de Vignos (r= 0,56), enquanto que nas variáveis restantes a correlação foi baixa.Conclusão: A EAF-2 é um instrumento de avaliação confiável que permite avaliar a atividade de sentar e levantar em portadores de DMD de forma detalhada e operacionalizada.
Objective: Construct the Scale of Functional Evaluation of Sit-and-Stand from the Ground for Patients with DMD (EAF-2) and to test its reliability intra and interexaminer. Method: The construction of the scale occurred in stages: 1. Analysis of the movement to sit and stand from the ground in healthy children. 2. Analysis of the movement to sit and stand from the ground in children with DMD. 3. Elaboration of the first version of the scale and the manual of instruction. 4. Evaluation by experts and readjustments generating the final version. 5. Analysis of Reliability inter and intra-examiner and correlation with the Vignos Scale, age and time length for the execution of the activity. Results: The scale comprehends three phases for the sitting and five for the standing, each phase with items that must be evaluated and scored. The score may vary from 0 to 10 for the sitting and from 0 to 15 for the standing. A very good repeatability of the measure of sitting as well as of standing was demonstrated (ICC = 0,89 and 084, respectively) and excellent reproducibility (ICC = 0,93 and 0,92, respectively). The Kappa Coefficient for the 8 phases in the interexaminer analysis varied from 0,77 to 1,00 (excellent reliability for 5 phases and substantial for 3 phases), and in the intra-examiner analysis varied from 0,80 to 1,00 (excellent reliability for 6 phases and substantial for 2 phases). Good correlation was found between the variable age x Vignos Scale (r= 0,58) and to stand x Vignos Scale (r= 0,56), whereas in the remaining variable the correlation was low. Conclusion: The EAF-2 is a trustful instrument of evaluation that allows to evaluate the activity of sitting and standing in people with DMD in a detailed and operationalized way.

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Rangan, Apoorva. "CRISPR-Cas9 Mediated Restoration of Dystrophin Expression and Inhibition of Myostatin: A Novel Gene Therapy for Duchenne Muscular Dystrophy." Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1305.

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Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disease, caused by a frame-shift mutation in the dystrophin gene. Current gene therapies for DMD target dystrophin transcripts in existing skeletal and cardiac muscle, rather than adipose and fibrotic tissues. These approaches may be unable to repair muscle functionality in DMD patients who have already undergone extensive muscle damage and wasting. Thus, successful DMD therapies must consider the underlying genetic cause and pathology. Inhibition of the gene myostatin, a negative regulator of muscle growth, has been shown to ameliorate muscle loss. Here, the CRISPR-Cas9 gene-editing platform is proposed to restore dystrophin expression and inhibit myostatin as a novel gene therapy in DMD patient derived induced pluripotent stem cells. Successful CRISPR-Cas9 mediated gene editing would be determined using PCR amplification, western blot analysis, immunofluorescence staining, and off target sequence analysis in differentiated skeletal muscle cells.

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Tabebordbar, Mohammadsharif. "Improving Stem Cell-Based Therapy and Developing a Novel Gene Therapy Approach for Treating Duchenne Muscular Dystrophy (DMD)." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718751.

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Genetic mutations in muscle structural genes can compromise myofiber integrity, causing repeated muscle damage that ultimately exhausts muscle regenerative capacity and results in devastating degenerative conditions such as Duchenne Muscular Dystrophy (DMD), Congenital Muscular Dystrophy (CMD) and different forms of Limb Girdle Muscular Dystrophy (LGMD). Gene supplementation and autologous stem cell transplant have been put forward as promising, though still unproven, therapeutic avenues for combatting these genetic muscle diseases. Both strategies aim to compensate expression of the missing or mutated protein. For cell therapy, autologous muscle stem cells (satellite cells) from dystrophic muscles undergo in vitro expansion and gene correction and then are transplanted into diseased tissue, where they fuse with resident myofibers to deliver a functional copy of the gene. One of the major obstacles for the autologous adult stem cell transplantation is that adult satellite cells account for a very rare population in muscle and they need to be expanded in culture, while retaining their engraftment potential, to generate sufficient number of cells for gene correction and transplantation. I tackled this problem by developing a culture condition that allows engraftable mouse satellite cells to expand in culture. This study also provides evidence for the feasibility of in vitro expansion, gene correction and transplantation of dystrophic satellite cells to restore DYSTROPHIN expression in dystrophic muscle. In gene therapy, engineered gene products are delivered directly to muscle fibers as transgenes carried by viral vectors, such as Adeno Associated Viruses (AAVs). Viral- mediated delivery of a normal copy of the mutated genes into dystrophic muscle fibers holds big promise as a therapeutic avenue for Muscular Dystrophies. However, considering the indispensible role of satellite cells in muscle regeneration, an effective and long-term therapy for genetic muscle diseases requires restoration of gene expression in both dystrophic muscle fibers and satellite cells. Conventional gene therapy approaches lack the potential for long-term restoration of the mutated gene expression in satellite cells. In order to address this limitation, this study provides the proof of concept evidence for the use of a novel gene editing approach, which allows irreversible correction of the mutations in both dystrophic skeletal muscle fibers and satellite cells.
Biology, Molecular and Cellular

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13

Guilbaud, Marine. "Identification d'ARNs non-codants impliqués dans les dystrophinopathies." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS042/document.

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Les dystrophies musculaires de Duchenne (DMD) et de Becker (BMD) sont dues à des mutations dans le gène DMD codant la Dystrophine. De nombreux aspects des mécanismes pathophysiologiques de ces maladies ne sont pas encore expliqués. Nous nous sommes intéressés à l'étude d'ARN non-codants pouvant participer à ces processus. Une première étude a été centrée sur l’identification de micro-ARNs (miARNs) impliqués dans la régulation de l’oxyde nitrique synthase neuronale (nNOS) une protéine partenaire de la Dystrophine et associée à des caractéristiques de ces pathologies telles que la fatigabilité musculaire. 617 miARNs ont été criblés par Taqman Low Density Array dans des muscles de sujets sains et de patients BMDdel45-55. 4 miARNs candidats ont été sélectionnés de cette étude pour leur surexpression chez les patients BMDdel45-55 et leur capacité théorique à cibler nNOS. Des expériences de modulation de l’expression de ces miARNs dans des myoblastes humains sains ou dystrophiques nous ont permis d’identifier que le miR-708-5p et le miR-34-5p pouvaient cibler nNOS et moduler son expression.Un deuxième axe a été mené sur l’étude des longs ARNs non-codants (lncARNs). Les introns 44 et 55, qui bornent les exons 45 à 55 délétés chez les patients BMDdel45-55, sont de grandes régions contenant des lncARNs décrits comme régulant la Dystrophine. Les points de cassure introniques des mutations de ces patients n’étant pas décrites, nous avons supposé l’existence de profils de lncARNs différents. L’analyse de l’ADN de ces patients montre en effet des profils de lncARNs différents, révélant ainsi l’importance d’une étude plus précise des zones de délétion des patients BMDdel45-55
Duchenne (DMD) and Becker (BMD) muscular dystrophies are due to mutations in DMD gene, encoding Dystrophin. Many aspects of pathophysiological mechanisms of these diseases are not yet well understood. We were interested in the study of non-coding RNAs that could be involved in these pathological processes. A first study focused on micro-RNAs (miRNAs) that could modulate expression of the neuronal nitric oxide synthase (nNOS), a partner of Dystrophin which is linked to pathological features as muscular fatigability. 617 miRNAs were screened by Taqman Low Density Array in muscle biopsies of healthy subjects or BMDdel45-55 patients. 4 candidate miRNAs were selected from this study since they were overexpressed in BMDdel45-55 patients and for their theoretical ability to target nNOS. Experiments modulating the expression of these miRNAs in healthy or dystrophic human myoblasts enabled us to identify that miR-708-5p and miR-34-5p could target nNOS and modulate its expression.A second axis was conducted on long non-coding RNA (lncRNA). Introns 44 and 55, which bound exons 45-55 deleted in BMDdel45-55 patients, are large regions containing lncRNAs described as regulating Dystrophin. Since intronic breakpoints of DMD mutations of these pateints were not described, we have assumed the existence of different profiles of lncRNAs. DNA analysis of these patients actually showed different lncRNAs profiles, thus revealing the significance of a more precise analysis of deletion areas in DMD gene of BMDdel45-55 patients

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14

Simmons, Tabatha Renee. "Treatment of DMD 5’ Mutations through Two Different Exon 2 Skipping Strategies: rAAV9.U7snRNA Mediated Skipping and Antisense Morpholino Oligomers." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1469122227.

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15

van, Erp Christel. "Modifying function and fibrosis of cardiac and skeletal muscle from mdx mice." University of Southern Queensland, Faculty of Sciences, 2005. http://eprints.usq.edu.au/archive/00001521/.

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Duchenne Muscular Dystrophy (DMD) is a fatal condition occurring in approximately 1 in 3500 male births and is due to the lack of a protein called dystrophin. Initially DMD was considered a skeletal myopathy, but the pathology and consequences of cardiomyopathy are being increasingly recognised. Fibrosis, resulting from continual cycles of degeneration of the muscle tissues followed by inadequate regeneration of the muscles, is progressive in both cardiac and skeletal dystrophic muscle. In the heart fibrosis interferes with contractility and rhythm whereas it affects contractile function and causes contractures in skeletal muscles. This study utilised the mdx mouse which exhibits a pathological loss of muscle fibres and fibrosis characteristic of DMD, to examine a range of mechanisms that can influence muscle function and fibrosis. Ageing and workload both appear to contribute to the development of dystrophic features in cardiac and skeletal muscle of the mdx mouse. Therefore the effect of eccentric exercise on cardiac and skeletal muscle was examined in older mdx mice. Mice ran in 30 minute sessions for five months, 5 days per week. Downhill treadmill running did not exacerbate the contractile function or fibrosis of the mdx heart or the EDL, SOL or diaphragm muscles suggesting that cytokines influence function and fibrosis to a greater extent than workload alone. The role of the cytokine TGF-beta was examined by treating mdx mice with the TGF-beta antagonist pirfenidone at 0.4, 0.8 or 1.2 per cent in drinking water for six months. Pirfenidone improved cardiac contractility (P<0.01) and coronary flow (P<0.05), to levels comparable to control mice, despite no reduction in cardiac fibrosis. Pirfenidone did not reduce fibrosis or improve function in skeletal muscle. A deficiency of neuronal nitric oxide synthase (nNOS) in DMD and mdx mice causes a lowered production of nitric oxide indicating that the substrate of nNOS, l-arginine, may be beneficial to cardiac and skeletal muscle function in mdx mice. Oral l-arginine (5 mg/g bw) improved cardiac contractility, coronary flow and reduced cardiac fibrosis (P<0.05) without improving skeletal muscle function or fibrosis. In contrast, 10 mg/g bw l-arginine improved cardiac function and coronary flow (P<0.01), despite also elevating cardiac collagen. This increment in collagen was prevented by co-administration of prednisone. The experiments described in this dissertation reveal for the first time that pharmacological treatments in mdx mice can improve cardiac structure and function. Further elucidation of the optimum time and doses of such treatments may result in future pharmacological treatments to improve cardiac function and fibrosis in DMD.

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16

Forman, Casey-Garnett. "Exploring the lived experiences of parents raising a child diagnosed with Duchenne Muscular Dystrophy (DMD) in South Africa : challenges and coping strategies." Diss., University of Pretoria, 2020. http://hdl.handle.net/2263/77200.

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This study set out to explore the lived experiences of parents raising a child with Duchenne Muscular Dystrophy (DMD) in South Africa. It addressed the challenges and coping strategies faced by three married couples of children, specifically male children, who are affected by this degenerative and fatal genetic condition. Purposive sampling was used and themes were highlighted through semi-structured interviews, employing interpretative phenomenological analysis (IPA). Major themes found included the reactions to the diagnosis; facing many losses and experiencing anticipatory grief; and learning to adapt. It was found that parents tended to vacillate between hope, grief, avoidance and presence, depending on their perceived level of support, contextual factors, and social and economic challenges. It was important for the parents to plan in advance and gain practical information about the illness in order to implement the necessary changes. The adjustment process was shown to be complicated. The final theme entailed what it meant for each family to create a meaningful life beyond the loss, and to remain hopeful about what lies ahead. It was concluded that amidst the unique and far-ranging challenges experienced on a daily basis, the parents started making changes that have had a positive impact on the lives of their sons and the entire family. These parents have found ways of cultivating meaning and hope in their everyday lives, doing everything in their power to grant their sons fulfilling lives. The findings support the need to incorporate strategies into existing services and health promotion programmes to build on the parents’ support structures, enabling them to adapt to the challenges they face on a regular basis. Further research into the disease impact in a South African context is necessary to improve care provision and inform policy. Keywords: Duchenne Muscular Dystrophy (DMD); degenerative; fatal; genetic condition; male children; parents; lived experiences; challenges; coping strategies.
Mini Dissertation (MA (Counselling Psychology))--University of Pretoria, 2020.
Psychology
MA (Counselling Psychology)
Unrestricted

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17

Rodrigues, Marcos Rojo. "Estudo do efeito de três exercícios de ioga na capacidade respiratória em pacientes com distrofia muscular progressiva tipo Duchenne (DMD)." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-30102007-150437/.

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A evolução da Distrofia Muscular de Duchenne (DMD) culmina na morte dos pacientes por problemas respiratórios, que aparentemente estão relacionados com a fraqueza de sua musculatura. O propósito deste estudo foi avaliar o efeito de três exercícios respiratórios de ioga na função respiratória em pacientes com DMD. A escolha dos exercícios foi motivada pelo fato de não se encontrar similares nos procedimentos fisioterápicos atuais no ocidente e por poderem ser praticados sem a necessidade de aparatos ou ajuda externa, facilitando sua execução diária. Os exercícios foram ensinados individualmente no ambulatório do Hospital das Clínicas da Universidade de São Paulo em dias regulares de consultas dos pacientes. As séries, bem como a sua progressão, levaram em consideração as limitações individuais. Foi realizada uma avaliação inicial das condições respiratórias (função pulmonar e pressões respiratórias) em 85 pacientes com idade entre 6 e 14 anos. Estas avaliações foram repetidas a cada 5 meses (em média) ao longo do treinamento. Os dados foram analisados de diferentes maneiras: pacientes que fizeram todas as avaliações ao longo de 10 meses (N=39); ao longo de 20 meses (N=18) e com os resultados dos pacientes que fizeram pelo menos uma avaliação além da inicial ao longo de 10 meses (N=70). Os grupos foram divididos por faixa etária em dois subgrupos (6 a 9 anos e 10 a 14 anos de idade). Constatou-se na análise com N=39 e N=70 que os pacientes mais novos que executaram os exercícios aplicados, apresentaram depois de 10 meses de treinamento, elevação nos valores absolutos e relativos da capacidade vital forçada (CVF), volume expiratório forçado em 1 segundo (VEF1) e pressão expiratória máxima (PEmax) e que os pacientes mais velhos, depois de 10 meses de treinamento, apresentaram melhora nos índices de pressão expiratória máxima (PEmax) em valores absolutos e relativos. Na análise com N=18 observou-se que os pacientes obtiveram melhora nos valores absolutos da função pulmonar (CVF e VEF1) até os 20 meses de treinamento quando comparamos com os valores do início e para a PEmax em valores absolutos, os resultados aumentam até 10 meses de treinamento e depois se mantém estáveis. Observou-se diminuição no declínio dos índices de função pulmonar dos pacientes quando comparados com crianças normais (porcentagem do predito). Constatou-se na análise determinada pela curva dos resultados da PEmax por faixa etária em valores relativos, que após 10 meses de prática dos exercícios de ioga, o declínio de seus valores foi retardado. O grande fator de melhora destes pacientes foi o aumento da força muscular expiratória forçada conseguido especialmente com a prática da técnica denominada kapalabhati. Recomendamos que estes exercícios sejam incorporados à prática clínica dos pacientes com DMD com a intenção de minimizar os danos causados pela perda da capacidade respiratória.
Duchenne Muscular Dystrophy (DMD) has a progression that culminates in the death of the patients for respiratory problems, which are apparently related to the weakness of the respiratory muscles. The objective of this study was to investigate the effects of three respiratory techniques of yoga in the respiratory function of patients with DMD. The selection of the exercises was conducted taking into account that there are no similar ones in the actual western physiotherapeutic procedures, and due to the fact that all of them may be practiced without the need of any apparatus or external help, making their daily practice easy. The exercises were taught individually in the Ambulatory of the General Hospital of the University of São Paulo during the regular appointments of the patients. The series of exercises, as well as their progressions, took into consideration the individual limitations. In order to establish the respiratory conditions (FVC, FEV1, PImax, and PEmax) of the group, an initial evaluation was conducted with 85 patients between 6 and 14 years old. The follow-up evaluations were carried out on an average 5-month interval, during the training period. Data were analyzed in different ways: subjects which had all the evaluations during 10 months of training (N=39); during 20 months of training (N=18) and with the results of patients that had at lest one evaluation besides the initial in the first 10 months (N=70). Furthermore, the total group was divided by age into 2 subgroups: (from 6 to 9 years old, and from 10 to 14 years old). The analysis of the groups with N=39, and N=70 revealed that, after 10 months of training, the younger subjects had increased their absolute and relative values of forced vital capacity (FVC), expiratory forced volume in 1 sec (FEV1), and maximal expiratory pressure (PEmax) , and that the older subjects, after the same period, had their absolute and relative PEmax also increased. In the analysis of the subgroup with N=18, there was an increase in the absolute values for pulmonary function (FVC and FEV1) until 20 months of training, while for PEmax this increase was seen only until 10 months, and afterwards there was a maintenance of its values. There was a reduction in the decline of the pulmonary function indexes of the patients when compared with healthy subjects (percentage of the predicted). The curve results of relative PEmax according to age revealed that after 10 months of practicing the prescribed exercises, the decline of its values was postponed. The greatest improvement in these children was found in the expiratory muscle power, attained through the practice of the technique called kapalabhati. We recommend the inclusion of these exercises to the clinical treatment of the DMD patients with the intention of minimizing the damage caused by the loss of respiratory capacity.

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18

Etienne, Jessy. "Caractérisation des progéniteurs cellulaires exprimant les aldéhydes déshydrogénases (ALDH) dans des modèles sains et dystrophiques." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066721/document.

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La thérapie cellulaire est une envisagée pour traiter des pathologies cardiaques ou squelettiques basée sur la médecine régénérative. Les progéniteurs cellulaires classiquement utilisés (myoblastes ou cellules mésenchymateuses) n'ont démontré qu'une efficacité limitée. Dans ce contexte, notre laboratoire a identifié une nouvelle catégorie de progéniteurs, sur la base de leur activité enzymatique aldéhyde déshydrogénase (ALDH) mise en évidence par un substrat fluorescent, l'Aldéfluor, et en association avec le marqueur CD34. Les ALDH sont impliquées dans le métabolisme et la détoxification des aldéhydes, et constituent un nouveau marqueur des cellules souches. Ce travail de thèse a permis de mieux caractériser les progéniteurs myogéniques (ALDH+/CD34-) et non myogéniques (ALDH+/CD34+), dans différents contextes physiopathologiques. Leur présence dans différents muscles de primates humains ou non humains, leur persistance au cours du vieillissement naturel ou lors d'atteinte par la dystrophie musculaire de Duchenne (DMD) chez l'Homme et dans des modèles animaux, suggèrent une utilisation possible des cellules ALDH+/CD34- pour des développements thérapeutiques ultérieurs. L'étude phénotypique révèle que des marqueurs transmembranaires sont associés à des sous-populations de cellules ALDH myogéniques ou non myogéniques dont la comparaison permettra de proposer de meilleurs candidats de thérapie cellulaire. En parallèle, les caractérisations histologiques et cytologiques ont identifié des sous-populations exprimant des isoenzymes et les analyses d'expressiongénique réalisées ex vivo et en culture suggèrent que certaines sont impliquées dans l'homéostasie musculaires
Cell therapy is a regenerative medicine strategy considered for the treatment of cardiac or skeletal muscle diseases. The cellular progenitors used to date (myoblasts or mesenchymal stem cells) provided mitigated success, thus mandating the identification and characterization of new categories of progenitors. Our laboratory has identified new populations of progenitors, based on their Aldehyde Deshydrogenase activity (ALDH) detectable using the fluorescent substrate Aldefluor, associated with the expression of the CD34 marker. ALDH are involved in metabolism and detoxification of aldehydes, they play important roles in cell survival and differentiation and are considered a new marker of stem cells. The present project allowed characterizing extensively the myogenic (ALDH+/CD34-) and non myogenic (ALDH+/CD34+) progenitors, in several physiopathological contexts and animal models. The presence of ALDH+/CD34- cells in distinct muscle groups in Human and non-human Primates, their persistence through natural ageing and despite the ongoing degenerative process observed in Duchenne muscular dystrophy in Human patients and animal models suggest their future use for therapeutic applications. The phenotypic characterization indicated that membrane markers are associated to myogenic or non myogenic sub-populations of ALDH cells. The comparison on their efficacies in vito and in vivo will allow proposing new candidates for cell therapy. In parallele, histological and cytological analysis identified cell populations expressing isoenzymes The analysis of gene expressions suggested that, at least, some of them are involved in muscle homeostasis in situ or in vitro

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19

Escorcio, Renata. "Responsividade da escala de avaliação funcional do sentar e levantar do solo para distrofia muscular de Duchenne (FES-DMD - D4), no período de um ano." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5170/tde-20052016-163309/.

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OBJETIVO: Avaliar a responsividade da escala de avaliação funcional para pacientes com distrofia muscular de Duchenne (FES-DMD-D4), sentar e levantar do solo, no período de um ano. MÉTODO: Estudo observacional, longitudinal e retrospectivo. Foi estudada, utilizando o software FES-DMDDATA, uma amostra com 25 pacientes na atividade sentar no solo e 28 pacientes para a atividade levantar do solo. As avaliações ocorreram a cada três meses no período de um ano. Para análise estatística da capacidade de resposta foram utilizados índices de tamanho de efeito, como, effect size (ES) e Standardized Response Mean (SRM). RESULTADOS: A responsividade da atividade de sentar no solo foi considerada baixa a moderada em intervalos de três meses (ES de 0.28 a 0.54 e SRM de 0.38 a 0.71), moderada a alta em intervalos de seis meses (ES de 0.69 a 1.07 e SRM de 0.86 a 1.19), alta em intervalos de nove meses (ES de 1.3 a 1.17 e SRM de 1.26 a 1.55) e doze meses (ES de 1.9 e SRM de 1.72). Na atividade levantar do solo, a responsividade variou em baixa, moderada e alta em intervalos de três meses (ES de 0.21 a 0.33 e SRM de 0.45 a 0.83), baixa a alta em intervalos de seis meses (ES de 0.46 a 0.59 e SRM de 0.73 a 0.97), moderada a alta em intervalos de nove meses (ES de 0.76 a 0.88 e SRM de 1.03 a 1.22) e alta em doze meses (ES de 1.14 e SRM de 1.25). CONCLUSÃO: Para detectar alterações clinicamente significativas e consistentes nas atividades funcionais sentar e levantar do solo recomendamos a utilização da FES-DMD-D4 em intervalos a partir de seis meses, pois foi neste período de tempo que a capacidade de resposta variou de moderada a alta
OBJECTIVE: To evaluate responsiveness of functional scale for Duchenne muscular dystrophy - sitting and standing from the ground (FES-DMD - D4) in three months evaluation intervals in a one year follow up. METHODS: Observational, longitudinal and retrospective study. It was studied, using FESDMD- DATA software, films of sample of 25 patients performing sitting on the activity of soil and 28 patients performing the activity of from the ground. The evaluations were performed every three months within one year. The analysis for statistical responsiveness of the instrument we use effect size (ES) and Standardized Response Mean (SRM) tests. RESULTS: The responsiveness of the activity of sitting on the ground was considered low to moderate every three months (ES 0.28 to 0.54 and 0.38 to 0.71 SRM), moderate to high in intervals of six months (ES 0.69 the 1.07 and the 1.19 0.86 SRM), High at intervals of nine months (1,3 ES of the 1.17 and the 1.55 1.26 SRM), and twelve months (ES SRM 1.9 and 1.72). In raising from the ground activity, the responsiveness varied at low, moderate and high in intervals of three months (ES 0.21 to 0.33 and 0.45 to 0.83 SRM), low to high in intervals of six months (ES 0.46 to 0.59 and 0.73 to 0.97 SRM), moderate to high at intervals of nine months (ES 0.76 to 0.88 and 1.03 to 1.22 SRM ) and high in twelve months (ES 1.14 and SRM 1.25). CONCLUSION: To detect clinically significant changes and consistent in functional activities of sitting and standing from the ground we recommend using the FES-DMD-D4 at intervals from six months because it was at this time that the responsiveness was moderate to high

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20

Condin, Christopher J. "Families’ experiences with medical research for pediatric rare diseases : a qualitative ethnographic study of parents and children participating in clinical trials for Duchenne muscular dystrophy (DMD)." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50780.

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The biopharmaceutical industry has recently expanded its focus on developing new cures for rare diseases. As a growing number of personalised genomic treatments are tested in clinical trials, there is uncertainty about how to account for patient perspectives, and how to measure functional changes reported by patients and caregivers. The illness experiences of patients and families are also being reshaped as they adopt roles as collaborative stakeholders and participants in clinical studies. This dissertation examines these changes using data from qualitative ethnographic research conducted with families of children with Duchenne muscular dystrophy, a progressive and fatal genetic disease diagnosed in boys. Canadian and American families were followed using semi-structured interviews and observational methods as they participated in clinical trials testing a genomic treatment for DMD, called ataluren (formerly known as PTC124). Ethnographic work was also carried out with physicians, patient-advocates, and other professionals engaged in clinical neuromuscular research. The dissertation contributes to scholarly understanding of families’ everyday experiences in the clinical trial, the significance and meaning of investigational treatments from the patient perspective, and the social context in which pharmaceutical development for rare diseases occurs. I show how genetic research is reconfiguring patient communities and altering moral sensibilities about treatment and care, by revealing “lucky mutations” and new axes of biosocial commonality and difference. I explore the paths families take to the clinical trial, and the “stories of waiting” they tell about their experience in it. Finally, I examine how families navigate the uncertainty and liminality of their experience as trial subjects. I discuss how the trial unsettles taken-for-granted social roles, constraining clinical relationships and leaving parents to construct the significance of an experimental treatment in the context of limited information. In so doing, parents assemble and tell “narratives of efficacy” while administering study-drug to their children, drawing on their observations and those made by others. Though parents’ narratives are often dismissed as mere anecdote, I suggest they also offer insight for developing more personalised approaches to clinical research and outcome measurement for rare diseases, by restoring focus on the nuance, idiosyncrasy, and context of families’ experiences with investigational treatments.
Arts, Faculty of
Anthropology, Department of
Graduate

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21

Hukuda, Michele Emy. "Responsividade da escala de avaliação funcional do sentar e levantar da cadeira para pacientes com distrofia muscular de Duchenne (FES-DMD-D1), no período de um ano." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5170/tde-12052015-101633/.

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Objetivo: Avaliar a responsividade da escala de avaliação funcional para pacientes com distrofia muscular de Duchenne (DMD), domínio 1 - sentar e levantar da cadeira (FES-DMD-D1). Método: Estudo observacional, retrospectivo e longitudinal (seguimento por um ano). Foi estudada, utilizando o software FES-DMD-DATA, uma amostra de 150 avaliações da atividade de sentar e levantar da cadeira, a partir de um banco de imagens com filmes de 30 crianças com DMD, executando atividades funcionais, avaliadas a cada três meses, em um período de um ano. A avaliação da FES-DMD-D1 foi aplicada por fisioterapeuta treinado, considerando os escores das fases de flexão, de contato e de extensão da atividade de sentar na cadeira e, das fases de flexão, de transferência e de extensão da atividade de levantar da cadeira. Para avaliar a responsividade da FES-DMD-D1 foram analisadas as avaliações dos períodos de seguimento de três, seis, nove e doze meses, por meio do tamanho do efeito (TE) e da média de resposta padronizada (MRP). Resultados: A responsividade da atividade de sentar na cadeira foi considerada de pequena a moderada nas avaliações a cada três meses (TE de 0,22 a 0,49 e MRP de 0,32 a 0,54), de pequena a moderada a cada seis meses (TE de 0,50 a 0,61 e MRP de 0,41 a 0,61), de pequena a grande a cada nove meses (TE de 0,69 a 1,11 e MRP de 0,49 a 0,79) e grande no período de um ano (TE de 1,07 e MRP de 0,80). Na atividade de levantar da cadeira, a responsividade foi pequena a cada três meses (TE de 0,21 a 0,35 e MRP de 0,28 a 0,45), de pequena a grande a cada seis meses (TE de 0,45 a 0,62 e MRP de 0,50 a 0,96), de moderada a grande a cada nove meses (TE de 0,76 a 0,89 e MRP de 0,74 a 1,47) e grande em um ano (TE de 1,28 e MRP de 1,24). Conclusão: A FES-DMD-D1 mostrou responsividade de moderada a grande, aumentando gradativamente nos intervalos de seis, nove e doze meses. Dessa forma, é indicado o uso da FES-DMD-D1 a partir de seis meses
Objective: To evaluate the responsiveness of the functional evaluation scale for patients with Duchenne muscular dystrophy (DMD) - domain 1: sitting and standing from the chair (FES-DMD-D1). Method: Observational, retrospective and longitudinal study with one year follow-up. A sample of 150 evaluations of sitting and rising from the chair was studied, using the FES-DMD-DATA software, from a bank of images of 30 children with DMD performing functional activities, evaluated every three months in a period of one year. FES-DMD-D1, which explores the scores of the phases of flexion, contact, extension of the activity of sitting on the chair, and of the phases of flexion, transference, extension of the activity of rising from the chair was applied by a trained physiotherapist. To evaluate the responsiveness of FES-DMD-D1 we considered the follow-up evaluations after three, six, nine and twelve months. The analysis used the effect size (ES) and standardized response mean (SRM). Results: The responsiveness of sitting on the chair was considered low to moderate in evaluations with three months intervals (ES from 0.22 to 0.49 and SRM from 0.32 to 0.54), low to moderate with six months intervals (ES from 0.50 to 0.61 and SRM from 0.41 to 0.61), low to high in nine months intervals (ES from 0.69 to 1.11 and SRM from 0.49 to 0.79) and high in the reassessment after one year (ES from 1.07 and SRM from 0.80). The responsiveness of the rising from the chair was low in three months (ES from 0.21 to 0.35 and SRM from 0.28 to 0.45), from low to high in six months (ES from 0.45 to 0.62 and SRM from 0.50 to 0.96), moderate to high in nine months (ES from 0.76 to 0.89 and SRM from 0.74 to 1.47) and high in a year (ES from 1.28 and SRM from 1.24). Conclusion: FES-DMD-D1 showed moderate to high responsiveness, gradually increasing for intervals of six, nine and twelve months. Thus, the use of FES-DMD-D1 is indicated from six months

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22

Brouilly, Nicolas. "Dégénérescence musculaire chez Caenorhabditis elegans : caractérisation morphologique et étude de suppresseurs." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10143/document.

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Les dystrpohies musculaires sont des maladies génétiques rares qui se caractérisent par une dégénérescence musculaire progressive. la Dystrophie Musculaire de Duchenne (DMD) qui est la plus sévère d'entre elles est due à des mutations dans le gène de la dystrophine. Les mécanismes cellulaires impliqués dans le processus de dégénérescence des muscles restent peu compris et aucun traitement efficace n'existe à ce jour. Notre équipe a développé un modèle de la DMD chez le nématode C. elegans qui présente une dégénérescence musculaire progressive. Pendant ma thèse, j'ai caractérisé le processus de dégénérescence musculaire chez ce modèle par microscopie électronique. J'ai également contribué à une étude du rôle des mitochondries dans la dégénérescence musculaire dystrophine-dépendante chez le nématode. Par ailleurs, j'ai étudié l'effet de suppresseurs pharmacologique et génétiques de la dégénérescence musculaire dystrophine-dépendante. Enfin, j'ai pu mettre en évidence que la force exercée par le muscle influence le taux de dégénérescence musculaire. L'ensemble des résultats obtenus au cours de ma thèse, suggèrent que la perte de fonctions de la dystrophine affecte chez le nématode l'intégrité du sarcolemme et des structures d'ancrage des sarcomères et déclenche ainsi une cascade d'événements intracellulaires conduisant in fin à la mort de la cellule musculaire. Ainsi mes travaux dethèse mettent en évidence de nouveau mécanismes cellulaires impliqués dans la dégénérescence musculaire et ouvrent de nouvelles perspectives pour le développement de thérapie visant à cibler les défauts primaires ou secondaires induits par la perte de fonction de la dystrophine
Muscle dystrophies are genetic diseases caraterized by progressive muscle degeneration. Duchenne Muscular Dystrophy (DMD) is the most severe and is due to a mutation in the gene coding the dystrophin protein. The cellular mechanisms implicated in the degenerating process arte not understood yet and there is still no efficient treatment to cure the disease. Our group decvelopped a DMD model in C. elegans that presents progressive muscle degeneration. During my PhD thesis, I characterized the process of muscle degeneration in this model by electron microscopy. I also contribued to an investigation of the role of mitochondira in dystophin-dependant muscle degeneration. I also studied the effect of pharmacological and genetic suppressors of muscle degeneration. Finally, I showed that the force developped by the worm to move influences the level of muscle degeneration. Altogether, the results I obtained during my PhD thesis, suggest that the loss of funciotnof the dystrophin protein affects the integrity of the muscle plasma membrane and the sarcomeres anchoring structures triggering a cascade of intracellular events leading to the muscle cell death in C. elegans. Therefore, my results highlight new cellular mechanisms implicated in the phenomenon of muscle degeneration and open new perspectives for the development of therapies targeting primary and secondary defects induced by the dystrophin loss of function

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23

Grunwald, Stefanie. "Identifizierung und Charakterisierung von Muskeldystrophie Duchenne modifizierenden Genen und Stoffwechselwegen." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16108.

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Hintergrund und Zielsetzung: DMD ist die häufigste Form der Muskeldystrophie im Kindesalter und bis heute unheilbar. Sie wird durch das Fehlen des Proteins Dystrophin verursacht, welches verschiedene Signaltransduktionswege beeinflusst. Das Anliegen der Arbeit ist die Untersuchung und Modulation von Signaltransduktionswegen, die als alternative Therapiestrategie den Verlust von Dystrophin kompensieren könnten. Experimentelle Strategie: Für die Charakterisierung von Dystrophin nachgeschalteten Prozessen wurden mRNA-Expressionsanalysen in Muskelgeweben von DMD-Patienten und einem DMD-Brüderpaar mit einem infrafamiliär unterschiedlichen Verlauf der DMD durchgeführt. Aus diesen Expressionsdaten wurde erstmalig ein Petri-Netz entwickelt, welches Dystrophin mit in diesem Zusammenhang bisher unbekannten Signaltransduktionswegen verknüpft. Das Petri-Netz wurde auf Netzwerkintegrität und –verhalten mittels Invarianten- (INA) und theoretischen Knockout- (Mauritius Maps) Analysen untersucht. Durch beide Methoden läßt sich der maßgebliche Teilsignalweg bestimmen. In diesem Signalweg wurden die Proteinaktivität und die Genexpression durch siRNA, Vektor-DNA und chemische Substanzen in humanen SkMCs moduliert. Anschließend wurden die Proliferation und die Vitalität der Zellen sowie auch die Expression auf mRNA- und Protein-Niveau untersucht. Ergebnisse: RAP2B und CSNK1A1 waren in dem DMD-Brüderpaar differentiell exprimiert und konnten erstmalig in einem neuen, komplexen Signalweg in Zusammenhang mit Dystrophin nachgeschalteten Prozessen dargestellt werden. Mittelpunkt dieses Signalweges ist die De- und Aktivierung des Transkriptionsfaktors NFATc. Seine Zielgene umfassen neben anderen den negativen Proliferationsfaktor p21, das Dystrophin homologe UTRN und den Differenzierungsfaktor MYF5. Folglich würde ein Anstieg von UTRN eine unerwünschte Reduktion der Proliferationsrate von Myoblasten implizieren. Letzteres konnte bereits nachgewiesen werden und stellte das Motiv für weitere Studien dar. Jedoch zeigten siRNA- und Vektor-DNA-Experimente, daß NFATc nicht der ausschlaggebende Faktor für diese Zielgene ist. Die Substanzen Deflazacort (DFZ) und Cyclosporin A (CsA) wurden dagegen beschrieben, die Aktivierung von NFATc zu beeinflussen. Die Ergebnisse zeigten, daß beide Substanzen die Proliferation von Myoblasten erhöhen können. Die gleichzeitige Applikation von DFZ und CsA führte zu einem Anstieg der UTRN-Expression. Schlußfolgerung: Die Modulation der Proliferation und UTRN-Expression ist unabhängig von einander möglich. Entsprechend der Grundidee der Arbeit zeichnet sich eine neue Therapiestrategie ab, welche Dystrophin nachgeschaltete Prozesse einbezieht.
Background and aim: DMD is the most common muscular dystrophy in childhood and incurable to date. It is caused by the absence of dystrophin, what influences several signal transduction pathways. The thesis is interested in the investigation and modulation of signal transduction pathways that may compensate the lack of dystrophin as an alternative therapy strategy. Experimental strategy: To study Dystrophin downstream pathways the mRNA expression of DMD patients and two DMD siblings with an intra-familially different course of DMD were analysed in muscle tissue. On the basis of these expression data a Petri net was first developed implicating signal transduction pathways and Dystrophin downstream cascades. Invariant (INA) and theoretical knockout (Mauritius Maps) analyses were applied for studying network integrity and behaviour. Both methods provide information about the most relevant part of the network. In this part modulation of protein activity and of gene expression using siRNA, vector-DNA, and chemical substances were performed on human SkMCs. Subsequently, the cells were studied by proliferation and vitality tests as well as expression analyses at mRNA and protein level. Results: RAP2B and CSNK1A1 were differently expressed in two DMD siblings, and first are part of a signal transduction pathway implicating Dystrophin downstream processes. The central point of this pathway is the de- and activation of the transcription factor NFATc. Its target genes are, among others, the negative proliferation factor p21, the Dystrophin homologue UTRN, and the differentiation factor MYF5. Consequently, an increase in UTRN implicates an undesirably reduced myoblast proliferation rate. Latter was found in DMD patients and was target for further studies. But, siRNA and vector DNA experiments showed that NFATc is not the decisive factor for the target genes. Deflazacort and cyclosporin A are known to influence the activation of NFATc. The results first showed that both substances do induce myoblast proliferation. The use of deflazacort in combination with cyclosporin A resulted in an increase of UTRN expression. Conclusion: The modulation of proliferation and UTRN-expression independently of each other is possible. According to the basic idea of this study, a new therapeutic strategy becomes apparent, which considers Dystrophin downstream processes.

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Giacomotto, Jean. "C. elegans, un outil de criblage pour la recherche de traitements contre les maladies rares." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00707724.

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Les techniques de criblage actuelles (in vitro et in silico) sont dépendantes des efforts menés en biologie médicinale pour identifier des cibles biologiques pertinentes ; cibles difficiles à définir pour les maladies génétiques dites "perte de fonction". De plus, les composés issus de ces cribles s'avèrent souvent inefficaces et/ou toxiques une fois confrontés à la complexité physiologique d'un organisme entier. Pour contourner ce problème, nous proposons d'utiliser le nématode C. elegans, notamment pour des maladies répondant aux critères suivants : i) physiopathologie complexe et/ou mal comprise excluant le développement à court terme de médicaments sur une base rationnelle, ii) peu d'espoir de thérapie génique/cellulaire à court terme, iii) conservation chez C. elegans du gène relié à la maladie humaine et induisant un phénotype exploitable une fois inactivé. Nous démontrons ici que ce petit nématode permet de tester, à moindre coût, un grand nombre de composés chimiques tout en conservant la complexité physiologique d'un animal entier. De plus, la souplesse génétique de cet animal permet d'apporter rapidement des informations sur le mode d'action des composés identifiés. Ainsi, en plus du but initial visant à identifier des molécules bioactives à intérêt thérapeutique, cette approche peut permettre de dégager de nouvelles cibles moléculaires utiles pour l'industrie chimique, et cruciales pour la recherche de traitements contre les maladies perte de fonction. Finalement, nous présentons comment mettre en place une telle stratégie, notamment pour la myopathie de Duchenne, l'amyotrophie spinale et le syndrome de Schwartz-Jampel. Enfin, nous présentons les résultats obtenus lors des différentes campagnes de criblage, les validations des molécules les plus prometteuses et les travaux effectués pour tenter de comprendre leur mode d'action chez le nématode.

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Aupy, Philippine. "Le développement préclinique des tcDNA pour la Dystrophie Musculaire de Duchenne Evaluating the impact of variable phosphorothioate content in tricyclo-DNA antisense oligonucleotides in a Duchenne Muscular Dystrophy mouse model Identifying and avoiding tcDNA-ASO sequence specific toxicity for the development of DMD exon 51 skipping therapy Long term efficacy of AAV9-U7snRNA mediated exon 51 skipping in mdx52 mice The use of tricyclo-DNA for the treatment of Genetic Disorders Exon-skipping advances for Duchenne Muscular Dystrophy." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV083.

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La Dystrophie Musculaire de Duchenne est une maladie génétique mortelle qui touche un garçon sur 3500. Elle se manifeste par une faiblesse musculaire progressive conduisant à une perte de la marche autour de l’âge de 10 ans, puis des problèmes respiratoires et cardiaques. Elle est due à des mutations dans le gène DMD conduisant à une absence de la protéine dystrophine. Il n’existe à l’heure actuelle aucun traitement satisfaisant. L’une des stratégies thérapeutiques les plus prometteuses pour cette maladie consiste à moduler l’épissage de l’ARN pré-messager. Cette stratégie appelée aussi « saut d’exon » utilise principalement des oligonucléotides antisens qui vont permettre de restaurer le cadre de lecture et ainsi entrainer la production de protéine.Le laboratoire Biothérapie des Maladies du Système Neuromusculaire a développé une nouvelle chimie d’oligonucléotide antisens, les tricyclo-DNA (tcDNA), ayant fait leur preuve pour effectuer un saut de l’exon 23 efficace dans des modèles murins de la DMD. En effet, les chercheurs de l’équipe ont pu démontrer la présence de saut d’exon et de restauration de dystrophine dans l’ensemble de la musculature et dans le système nerveux central, permettant d’obtenir une amélioration fonctionnelle. Lors de ma thèse, je me suis intéressée au développement pré-clinique d’un tcDNA ciblant l’exon 51 humain, puisqu’il s’agit de l’exon permettant de traiter la plus grande proportion de patients (13%).La première partie de mon projet a été consacrée à l’amélioration de la tolérabilité des tcDNAs à travers deux approches : la modification de la séquence et la modification du design de la molécule. En effet, la cause principale de la toxicité des tcDNAs est la formation de structures homodimériques associée à la présence de liens phosphorothioates (PS). Cette première étude a permis, d’une part, de démontrer qu’une modification de la séquence entraine une élimination des structures homodimériques et permet ainsi d’obtenir une meilleure tolérabilité de la molécule. D’autre part nous avons pu mettre en évidence qu’une diminution du contenu en liens PS permet de limiter l’apparition d’une toxicité à long terme sans impacter significativement l’efficacité.La deuxième partie de mon projet de thèse a été consacrée à l’optimisation de l’efficacité des tcDNAs. Pour cela deux approches ont été investiguées : d’une part l’amélioration de la biodisponibilité de la molécule et d’autre part l’optimisation de la séquence cible. Nous avons ainsi pu démontrer que la conjugaison d’un acide gras à un tcDNA entraine une amélioriation significative de sa biodistribution et de l’efficacité du tcDNA. En parallèle, un criblage de nombreuses séquences ciblant différentes régions de l’exon 51 a permis de sélectionner une séquence candidate présentant une efficacité nettement supérieure à celle de la séquence initiale. Cette séquence, conjuguée à un acide palmitique, a démontrée des résultats extremement encourageants pour les futurs essais cliniques et est actuellement en phase finale de développement préclinique
Duchenne Muscular Dystrophy is a fatal genetic disorder affecting 1/3500 newborn males. It is characterized by progressive muscle weakness causing loss of ambulatory functions and respiratory and cardiac failures. This disease is due to mutations in the DMD gene leading to complete loss of protein expression. There is currently no satisfactory treatment but one of the most promising therapeutic strategy is splicing modulation. This strategy also called “exon skipping” is achieved through the use of antisense oligonucleotides allowing a restoration of the reading frame, and thus leading to protein rescue.The laboratory Biothérapie des Maladies du Système Neuromusculaire has developped a new chemistry of antisense oligonucleotide, tricyclo-DNA (tcDNA). They have demonstrated the therapeutic potential of tcDNA in different mouse models of DMD. Indeed, after systemic treatment significant exon 23 skipping and dystrophin restoration were found in all tested muscles as well as in the central nervous system, leading to functional improvement. During my phD project, I worked on the pre-clinical development of a tcDNA targeting human exon 51, which could be applicable to a large proportion of DMD patients (13%).The first part of my project was dedicated to the improvement of tcDNA tolerability through the modification of the sequence itself and the modification of the chemical design. Indeed, the major cause of tcDNA toxicity is the formation of homodimeric structure associated with the presence of phosphorothioates linkages (PS). In this study, we were able to demonstrate that modification of the toxic sequence impairs homodimerization, thus suppressing toxicity. Moreover, we have demonstrated that a decrease in the PS content prevent the apparition of long term toxicity without impairing significatively exon skipping efficacy but.The second part of my project focused on the optimisation of tcDNA efficacy through improvement of their biodisponibility and optimisation of the targeted sequence. We first demonstrated that fatty acid conjugation to tcDNA significantly improves biodistribution and efficacy. In parallel, we screened numerous sequences targeting different regions of the exon 51 and selected a novel sequence with a significantly higher efficacy than the initial sequence. This novel tcDNA sequence, once conjugated with palmitic acid demonstrated extremely encouraging results for the treatment of DMD and we are currently finalizing its development for future clinical trials

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CAFFARINI, MIRIAM. "Mesoderm stem cells and inflammation: role in the Pathogenesis and potential therapy of selected Gynecological Deseases and primary Myopathies." Doctoral thesis, Università Politecnica delle Marche, 2019. http://hdl.handle.net/11566/263543.

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Le cellule staminali mesenchimali (MSCs) sono un tipo specifico di cellule staminali adulte con un elevato potenziale proliferativo e differenziativo verso cellule specializzate di derivazione mesodermica. Le MSCs svolgono anche una funzione paracrina attraverso il rilascio di molteplici fattori di crescita, chemochine e citochine. Le MSCs si comportanto da sentinelle che percepiscono il microambiente e agiscono di conseguenza, passando da un fenotipo pro-infiammatorio ad uno immunosoppressivo in base ai segnali che ricevono. Nel seguente lavoro sono valutati l’esistenza e il ruolo delle MSCs nella patogenesi e nella potenziale terapia di selezionate patologie ginecologiche con una componente infiammatoria come il leiomioma uterino, la neoplasia intraepiteliale cervicale (CIN) e in miopatie primarie, quali la Distrofia Muscolare di Duchenne (DMD). Nel primo studio, sono state identificate le cellule progenitrici nel leiomioma e nel miometrio sano ed è stata investigata la correlazione tra tali cellule e l’infiammazione nell’insorgenza del leiomioma. I dati suggeriscono che una overespressione di citochine relative all’infiammazione cronica nei progenitori del leiomioma potrebbe favorire un microambiente adeguato per l’insorgenza di questa patologia. Nel secondo studio, le MSCs sono state isolate da cervici di pazienti giovani (yC-MSCs) e pazienti vecchie (oC-MSCs) e i risultati mostrano come la loro immunobiologia sia condizionata dall’età dei donatori, influenzando anche il tasso di regressione della CIN. Inoltre, nel crosstalk con le cellule HeLa, yC-MSCs svolgono maggiormente un ruolo anti-tumorale sostenendo un’infiammazione acuta. L’obiettivo del terzo studio è stato quello di trovare una corretta strategia per aumentare la produzione di distrofina nella DMD mediante terapia genica. Pertanto, i mioblasti isolati da donatori di DMD sono stati trasdotti con la proteina fluorescente verde (GFP) e un vettore lentivirale esprimente l’snRNA per indurre il salto dell’esone; i dati indicano che i mioblasti trasdotti erano abili a differenziare in senso miogenico esprimendo la distrofina funzionale.
Mesenchymal stem or stromal cells (MSCs) are a specific type of adult stem cells with an extensive proliferation and differentiation potential towards specialized cells developing from the mesoderm. MSCs are also characterized by paracrine function through the release of multiple growth factors, chemokines and cytokines. MSCs play as sentinel that feel the microenvironment and act consequently, switching from a pro-inflammatory phenotype to an immunosuppressive phenotype according to the signals they receive. In the present work the existence and the role of MSCs in the pathogenesis and potential therapy of selected gynecological diseases with an inflammatory component as uterine leiomyoma, cervical intraepithelial neoplasia (CIN), and in primary myopathies, as Duchenne Muscular Dystrophy (DMD) were evaluated. In the first study, progenitor cells were identified both in leiomyomas and normal myometrium, and the correlation between these cells and inflammation in leiomyoma onset has been investigated. The data suggest that the upregulation of cytokines related to chronic inflammation in leiomyoma progenitors could favour a microenvironment suitable for the onset of this pathology. In the second study, MSCs from cervix of young (yC-MSCs) and old patients (oC-MSCs) were isolated and results show as their immunobiology is affected by the age of donors, influencing in turn the regression rate of CIN. In addition, in the crosstalk with HeLa cells, yC-MSCs play an anti-tumoral role sustaining an acute inflammatory environment. The goal of the third study was to find a correct strategy to enhance the production of dystrophin protein in DMD through gene therapy. Therefore, myoblasts isolated from DMD donor were transduced with green fluorescent protein (GFP) and a lentiviral vector expressing the snRNA to induce exon skipping; data indicate that transduced myoblasts were able to perform myogenic differentiation expressing a functional dystrophin protein.

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Bensalah, Mona. "Fibrose musculaire : acteurs cellulaires et stratégies thérapeutiques." Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS031.pdf.

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La fibrose est une accumulation excessive de protéines de la matrice extracellulaire qui remplace le tissu et en altèrent la fonction. Dans le muscle squelettique c’est une caractéristique pathologique commune à plusieurs dystrophies dont la dystrophie musculaire oculopharyngée et la dystrophie musculaire de Duchenne (DMD). Dans de nombreux tissus, les cellules résidentes appelées fibroblastes semblent avoir un rôle clé dans l’établissement et le maintien de la fibrose, cependant, la nature exacte et le rôle de ces cellules dans la fibrose musculaire humaine sont peu connus. Nous avons caractérisé les populations cellulaires non-myogéniques (CD56-) de muscles contrôles et fibrotiques et montré que les cellules CD56- de muscles fibrotiques ont un phénotype différent des cellules de muscles contrôles (capacité proliférative, sensibilité au TGFβ, sécrétion, impact sur la fusion et la régénération). Notre étude met en évidence l’importance de la communication entre types cellulaires au sein du muscle, en particulier du muscle fibrotique et dystrophique. Actuellement, de nombreuses stratégies anti-fibrotiques se développent mais aucune n’a encore été capable de réduire une fibrose pré-existante. Nous avons comparé 10 sérotypes d’AAV par injection intramusculaire afin d’évaluer si un sérotype était capable de transduire les fibroblastes in vivo et si la fibrose gênait la transduction des fibres musculaires. Puis, nous avons testé le potentiel anti-fibrotique d’un AAV-Relaxine sur des souris DBA/2-mdx, modèle pour DMD. L’ensemble de ce travail permettra d’améliorer la compréhension des mécanismes en jeu dans la fibrose musculaire et de développer des thérapies efficaces
Fibrosis is described as an excessive accumulation of extracellular matrix proteins that replace tissue and alter its function. In skeletal muscle, fibrosis is a pathological feature common to many dystrophies including Oculopharyngeal Muscular Dystrophy (OPMD) and Duchenne Muscular Dystrophy (DMD). In many tissues, resident cells called fibroblasts seem to have a key role in establishing and maintaining fibrosis, however, the exact nature and role of these cells in human muscle fibrosis are still very poorly defined. In this context, we characterized the non-myogenic cell population (CD56- cells) of control and fibrotic muscles and showed that CD56- fibrotic muscle cells have a different phenotype than control muscle cells (proliferative capacity, sensitivity to TGF-β, secretion, impact on fusion and regeneration). Our study highlights the importance of the cross-talk between cell types within the muscle, especially fibrotic and dystrophic muscle. Currently, many anti-fibrotic gene therapy strategies are being developed but while most of them prevent the apparition of fibrosis, none has yet been able to revert pre-existing fibrosis. In this context, we first compared 10 serotypes of AAV by intramuscular injection to evaluate whether one of these serotype was able to transduce fibroblasts in vivo and whether fibrosis impair the transduction of muscle fibers. Then we tested the anti-fibrotic therapeutic potential of AAV-Relaxin (RLN) on DBA/2-mdx mice, model for DMD. Altogether these studies will allow us to improve our understanding of the pathophysiological mechanisms involved in muscle fibrosis and to develop effective anti-fibrotic strategies

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Rabinowitz, Adam Howard. "Antisense therapies for Duchenne muscular dystrophy." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444590.

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Smith, T. J. "Molecular analysis of Duchenne muscular dystrophy." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233559.

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Hodgson, Shirley V. "Genetic studies in Duchenne muscular dystrophy." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235878.

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Wakefield, Philip M. "Gene therapy for duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365743.

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Koppaka, Sisir. "Imaging biomarkers for Duchenne muscular dystrophy." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/106959.

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Thesis: S.M., Massachusetts Institute of Technology, School of Engineering, Center for Computational Engineering, Computation for Design and Optimization Program, 2015.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 75-78).
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood and affects 1 in 3600 male births. The disease is caused by mutations in the dystrophin gene leading to progressive muscle weakness which ultimately results in death due to respiratory and cardiac failure. Accurate, practical, and painless tests to diagnose DMD and measure disease progression are needed in order to test the effectiveness of new therapies. Current clinical outcome measures such as the sixminute walk test and North Star Ambulatory Assessment (NSAA) can be subjective and limited by the patient's degree of effort and cannot be accurately performed in the very young or severely affected older patients. We propose the use of image-based biomarkers with suitable machine learning algorithms instead. We find that force-controlled (precise acquisition at a certain force) and force-correlated (acquisition over a force sweep) ultrasound helps to reduce variability in the imaging process. We show that there is a high degree of inter-operator and intra-operator reliability with this integrated hardware-software setup. We also discuss how other imaging biomarkers, segmentation algorithms to target specific subregions, and better machine learning techniques may provide a boost to the performance reported. Optimizing the ultrasound image acquisition process by maximizing the peak discriminatory power of the images vis-à-vis force applied at the contact force is also discussed. The techniques presented here have the potential for providing a reliable and non-invasive method to discriminate, and eventually track the progression of DMD in patients.
by Sisir Koppaka.
S.M.

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Tay, Shaun Li Jian. "Duchenne Muscular Dystrophy—Insight and Treatment." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/595055.

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Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive degeneration of muscle fibers and dystrophic changes on muscle biopsy¹. DMD accounts for approximately 50% of all dystrophinopathies, with around 21,000 male babies born with the disease each year², ³, ⁴, ⁵. It is also the most lethal X-linked recessive disorder as phenotypic traits are not immediately present at birth¹¹, ³. Patients usually do not live past their 20's without medical intervention to treat associated respiratory and cardiac dysfunctions¹¹, ³. For these reasons DMD remains one of the greatest threats, amongst a range of pediatric pathologies, to the normalcy of child development and parental care. Although treatment options have shown to mitigate the progression of DMD, most are controversial and costly - the estimated annual treatment cost of DMD per patient is $50,953⁵⁸. In light of this, disease awareness and public health education are critical components for acquiring funds needed for research towards a cure¹². My hope is that through this integrated overview of DMD, the medical layman will better understand the depths of this lethal disease, and how it can be detrimental to both the affected child and his caretaker.

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Smith, Philip E. M. "Breathing during sleep in Duchenne muscular dystrophy." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235539.

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Babaria, Arati. "Molecular Mechanisms that Underlie Duchenne Muscular Dystrophy." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612573.

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Duchenne muscular dystrophy is an inherited, X-linked recessive skeletal muscle disorder that is characterized by mutations in the dystrophin gene [1]. Therefore, the disease affects primarily males and women are typically carriers. 1 in 3500 males in the United States are affected [1]. Dystrophin is a critical, large scaffolding protein in the dystrophin-glycoprotein complex found at the sarcolemma of skeletal muscle [1]. The complex helps maintain sarcolemma integrity and stability during muscle contractions by coupling the extracellular matrix proteins to the intracellular cytoskeleton in skeletal muscle [1]. Loss-of-function mutations in the dystrophin protein affect all skeletal muscle found throughout the human body. The 427 kD protein is also present in cardiac muscle, the brain, and peripheral nerves, thus affecting these tissues over time, as well [1]. One theory suggests the weakened stability of the dystrophin-glycoprotein complex when dystrophin is not expressed results in transient membrane tears during contraction, which permit pathological calcium influx [1]. Damaged skeletal muscle results in repair and regeneration of the tissue however, continual damage over time (referred to as muscle wasting) results in extensive fibrosis and loss of muscle fibers. The purpose of this thesis is to provide a comprehensive review on several molecular mechanisms that underlie Duchenne muscular dystrophy and to investigate current treatments and propose potential therapeutic targets for future research.

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36

Skyrme, Sarah Louise. "Research decisions : living with Duchenne muscular dystrophy." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2678.

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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy that affects males. Muscle deterioration leads to increasing levels of disability during childhood and adolescence, with death commonly occurring in the late teens or early twenties, although changes in care and treatment are leading to increasing numbers of boys with DMD living into adulthood. Parents and parent-led charities are raising funds to find effective treatments and a cure, and much of the medical research they promote requires the participation of those with DMD. This raises questions about children and young people’s involvement in research, including their role and approach to consent and how willing they are to be involved in the medical research their parents and DMD charities advocate. Through qualitative interviews with nine boys and young men with DMD and one young woman with muscular dystrophy, I explored their thoughts on medical research and the broader issue of how they live and cope with their condition. As part of this discussion I examined how they might make a decision to participate in medical research, focusing on the processes, interactions and individuals they consider important in helping them to decide. My approach privileges the participants’ thoughts and opinions, positioning them as able social actors (James & Prout 1997) who can provide insight into their experiences. Currently little is known about the lives of children and young people with a significant, degenerative disability, particularly around their thoughts on medical research participation and decision-making (Dixon-Woods 2006). The views of my participants provide the basis for this research, with work from the sociology of childhood and from disability studies informing and contextualising it. The way in which parents are involved in daily life is discussed to gain an understanding of how the participants work with those they trust. This relationship may provide understandings of how decisions are influenced by family input and how support assists those who are young and have a degenerative condition. It is possible that this model of working with the significant people in their lives promotes agency and independence, aiding the participants towards, rather than away from autonomy.

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Dunant, Patrick. "Strategies for Molecular Therapy of Duchenne Muscular Dystrophy." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-12429.

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Bia, Britta Lydia. "Cardiomyopathy in mouse models of Duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301799.

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39

Winnard, Alissa Vira. "Exception patients in Duchenne and Becker muscular dystrophy /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487847309050842.

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40

Johansson, Camilla. "Exploring genotype to phenotype correlations in Duchenne muscular dystrophy." Thesis, KTH, Skolan för bioteknologi (BIO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215302.

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41

Roberts, Thomas C. "Duchenne muscular dystrophy : RNA-based therapeutics and microRNA biology." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:f53ea1f3-92db-4f90-ba95-01f2a56eae8f.

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Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by absence of functional dystrophin protein. This thesis describes investigations into the role of small non-coding RNAs in both DMD pathology, and as potential therapeutic molecules. MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression and are implicated in wide-ranging cellular processes and pathological conditions. This study has compared differential miRNA expression in proximal and distal limb muscles, diaphragm, heart and serum in the mdx dystrophic mouse model relative to wild-type controls. Global transcriptome analysis revealed muscle-specific patterns of differential miRNA expression as well as commonalities between tissues, including previously identified dystromirs. miR-1, miR-133a and miR-206 were found to be highly abundant in mdx serum, suggesting that these miRNAs are promising disease biomarkers. Indeed, the relative serum levels of these miRNAs were normalised in response to peptide-PMO mediated dystrophin restoration therapy. This study has revealed further complexity in the miRNA transcriptome of the mdx mouse, an understanding of which will be valuable for the development of novel DMD therapeutics and for monitoring their efficacy. Myostatin is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as DMD. This study describes a novel myostatin inhibition approach in which small interfering RNAs (siRNAs) complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS) in cultured myotubes. Silencing was sensitive to treatment with the histone deacetylase inhibitor Trichostatin A, and the silent state chromatin mark H3K9me2 was enriched at the myostatin promoter following siRNA transfection, suggesting epigenetic remodelling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for myostatin and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders. The work in this thesis therefore demonstrates the potential of small RNAs as therapeutic agents and as disease biomarkers in the context of DMD.

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42

Geisemeyer, Sarah. "Duchenne muscular dystrophy : a genetic, cognitive and psychosocial approach." Thesis, Kingston University, 2017. http://eprints.kingston.ac.uk/40678/.

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Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder that affects 1 in 3600 male births. It is caused by genetic mutations in the dystrophin gene. This study investigated several aspects of the neuromuscular disorder within a population of Brazilian DMD boys and their families. This study's framework was laid out within the prism of an interacting cycle of genetic factors, cognitive functioning, and psychosocial aspects that underlie the neuromuscular disorder. It focuses on DMD's aetiology, history and previous research on genetic, cognitive and psychosocial aspects. Mixed methods were adopted to allow for a more encompassing view of the neuromuscular disorder: cognitive tests, an emotion recognition battery, genetic analyses, well-being questionnaires, and interviews were applied. Correspondent, quantitative and qualitative data analysis was carried out. The findings of 32 DMD patients (mean age 10.4 years, SD= 2 years) and 31 control subjects (mean age 9.4 years, SD= 3 years) revealed severe cognitive dysfunctioning in all assessed cognitive domains in the DMD population, as well as in the ability of emotion recognition. In the DMD group, it could be shown that poor executive functioning stood in a positive correlation with a poor ability of emotion recognition. The DMD patients' cognitive phenotypes were correlated with the genetic mutations in their dystrophin gene, but no relationship between the patients' genotype and cognitive phenotype could be confirmed. These results were contrary to previous research, which suggested that specific mutations in the dystrophin gene cause cognitive impairment. The DMD group scored poorly on the emotion recognition task, which is also a characteristic of autism spectrum disorder. However, when diagnosing for autistic characteristics through means of an interview, only a few similarities between the two disorders could be found. In order to assess the psychosocial components that come along with the disorder, well-being questionnaires were supplied. Interestingly, DMD boys scored higher on well-being than the boys in the control group. Moreover, 30 of the DMD caregivers (mean age app. 31 years) also revealed high levels of well-being, which correlated positively with the well-being of their sons, suggesting high levels of resilience. Given the participants' socio-economic hardship and the lack of governmental help, it was concluded that participants showed an incredible level of resilience that most likely resided within their faith, which nearly all of them stated to be the reason for their strength to strive. The relevant and new information about cognitive, genetic and social aspects of DMD uncovered in this study will pave the way for further (and much needed) studies into psychosocial aspects of the disorder.

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Buser, Karen N. Kamiri. "Parental Attitudes Regarding Newborn Screening for Duchenne Muscular Dystrophy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1307627473.

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Moura, Maria Clara Drummond Soares de. "Alterações atencionais na distrofia muscular de duchenne." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-31072009-151351/.

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A Distrofia Muscular de Duchenne (DMD) é uma doença de herança genética recessiva que gera um quadro de fraqueza muscular progressiva muitas vezes associada à deficiência mental. A atenção, considerada como o mecanismo cerebral que permite o processamento de uma informação em detrimento de outras, poderia estar alterada na doença contribuindo pelo menos em parte para o comprometimento cognitivo global observado. OBJETIVO: Investigou-se o desempenho atencional de meninos portadores de DMD utilizando-se testes psicofísicos específicos. MÉTODOS: Testou-se 30 meninos com DMD (GD) e 30 meninos saudáveis (GC), com idade entre 10 e 16 anos, em uma tarefa de tempo de reação de escolha, que consistia em responder o mais rapidamente possível a um estímulo alvo visual lateralizado com mão do mesmo lado. Antes do aparecimento deste estímulo, orientava-se a atenção automática do participante por meio de um estímulo visual periférico não-informativo espacialmente ou então sua atenção voluntária, por meio de um estímulo visual central que informava o local de maior probabilidade de aparecimento do estímulo alvo. RESULTADOS: Os tempos de reação (TR) foram maiores para o GD do que para o GC tanto no teste de atenção automática (p<0,001) quanto no teste de atenção voluntária (p<0,001). Os TR no teste de atenção voluntária foram menores do que no teste de atenção automática no caso do GD (p<0,001) mas não no caso do GC (p=0,20). O efeito atencional (diferença entre o TR na condição oposta/inválida e o TR na condição mesma/válida) não diferiu entre os dois grupos no caso da atenção automática (p=0,846), mas foi maior no GD do que no GC no caso da atenção voluntária (p<0,001). Não foram observadas quaisquer assimetrias interlaterais. DISCUSSÃO: Os resultados sugerem que os meninos com DMD apresentam prejuízo na capacidade de orientar a atenção no tempo e também gerenciam de modo anômalo para a idade a atenção espacial voluntária. O grande efeito atencional apresentado por eles é compatível com um atraso na maturação do seu sistema atencional.
OBJECTIVE: Considering the divergence in the literature regarding the base of the cognitive deficits in Duchenne Muscular Dystrophy (DMD) patients, the objective of this work was to investigate their attention performance using psychophysical tests. METHODS: 25 boys with DMD (GD) and 25 healthy boys (GC), which were 10 to 16 years old, were tested in a choice reaction time task. They were instructed to respond as fast as possible to a lateralized visual target stimulus with the same side hand. Attention was automatically oriented by a peripheral spatially non-informative prime stimulus or, alternatively, voluntarily oriented by a central spatially informative cue. RESULTS: Reaction times (RT) were higher for GD than for GC in both automatic attention (p<0,001) and voluntary attention tests (p<0,001), as expected. RTs in voluntary attention tests were smaller than on automatic attention tests for GD (p<0,001) but not for GC (p=0,200). The attentional effect (difference between RT in the opposite/invalid condition and RT in the same/valid condition) was found not to differ between the two groups in the case of automatic attention (p=0,846); however it was greater for GD than for GC in the case of voluntary attention (p<0,001). Interlateral asymmetries have not been observed. CONCLUSION: These results suggest that patients with DMD are less efficient to allocate both automatic and voluntary attention. The lack of the expected motor preparation by the patients when the peripheral prime stimulus was used suggests a disturbance of temporal attention. The larger cost and benefit observed when the endogenous visual cue was used suggests a delay in maturation of the executive functions necessary to adequately allocate voluntary attention.

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Coovert, Daniel David. "Analysis of dystrophin in duchenne muscular dystrophy and SMN in spinal muscular atrophy /." The Ohio State University, 1998. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487951595500021.

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46

Burkhardt, Katinka. "Generation of a tailored pig model of Duchenne muscular dystrophy." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-142430.

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Thomas, Karen. "The mdx mouse as a model for Duchenne muscular dystrophy." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386990.

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Terry, Rebecca Louise. "Modification of skeletal muscle phenotype to treat Duchenne muscular dystrophy." Thesis, Royal Veterinary College (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618307.

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49

HARNOIS, MELISSA. "ANALYSIS OF MYOGENIC MARKERS IN DUCHENNE MUSCULAR DYSTROPHY CELL MODELS." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612963.

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The goal of this study is to compare the in vitro differentiation potential of Duchenne Muscular Dystrophy (DMD) and non-diseased patient-derived skeletal muscle myoblasts during myogenesis. The differentiation and fusion of myoblasts into multinucleate myotubes and the maturity of these myotubes was assessed based on morphology, immunohistochemistry (IHC) analysis of myotubes, as well as transcript profiles of myogenic markers. Human skeletal muscle myoblasts derived from three non-diseased and three DMD human patients were evaluated in multiple time course studies. Morphological evaluation as well as IHC analysis indicated that the DMD patient-derived myoblasts have diminished capacity to differentiate and form mature myotubes. Gene expression profiling also revealed significantly reduced basal transcript levels of myogenic markers in DMD patient-derived cells as well as the impaired induction of these transcripts during differentiation.

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50

Wells, Kim Elizabeth. "Optimisation of constructs for gene therapy of Duchenne muscular dystrophy." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392669.

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