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Dissertations / Theses on the topic 'Dystrophin'

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Published: 4 June 2021

Last updated: 12 October 2024

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1

Gaschen, Lorrie. "Cardiomyopathy in dystrophin-deficient hypertrophic feline muscular dystrophy /." [S.l.] : [s.n.], 1998. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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2

Howard, Judith. "Electrodiagnostic evaluation of dystrophin-deficient hypertrophic feline muscular dystrophy /." [S.l.] : [s.n.], 2000. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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3

Thorley, Matthew. "Analysis of the dystrophin interactome." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066619/document.

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Le but de ce projet était d'identifier de manière méthodique et standardisée les partenaires interagissant avec la protéine dystrophine dans les cellules musculaires squelettiques humaines différenciées et découvrir de nouveaux rôles de la dystrophine. Des cellules immortalisées ont été obtenue en sur-exprimant de manière stable hTERT / CDK4. Nous avons réalisé une analyse transcriptomique comparant des lignées immortalisées avec leurs populations primaires correspondantes, à l’état de prolifération et de différentiation. Nous avons constaté que l'immortalisation n'a pas d'effet mesurable sur le programme myogénique ou sur tout autre processus cellulaires, et qu'elle avait un effet protecteur contre le processus de sénescence. Les lignées de cellules musculaires humaines constituent donc de bon model in vitro pour l’étude de l’interactome de la dystrophine. Nous avons déterminé l’interactome de la dystrophine en utilisant l’approche proteomique ‘QUICK’. Nous avons identifié 18 nouveaux partenaires directs de la dystrophine, partenaires étant impliqués dans le transport vésiculaire ou étant des protéines d'adhésion. Ces résultats renforcent les données précédemment publiées suggérant un lien entre la dystrophine et le trafic vésiculaire, ainsi que dystrophine et adhesion cellulaire. Ces nouveaux partenaires ont été ajoutés à l’interactome de la dystrophine, interactome accessible sur le Web: sys-myo.rhcloud.com/dystrophin-interactome. Ce site web est dédié à être un outil facile d’utilisation permettant d’explorer et de visualiser l’interactome de la dystrophine du muscle squelettique
The aim of this project was to systematically identify new interaction partners of the dystrophin protein within differentiated human skeletal muscle cells in order to uncover new roles in which dystrophin is involved, and to better understand how the global interactome is affected by the absence of dystrophin. hTERT/cdk4 immortalized myogenic human cell lines represent an important tool for skeletal muscle research however, disruption of the cell cycle has the potential to affect many other cellular processes to which it also linked. A transcriptome-wide analysis of healthy and diseased lines comparing immortalized lines with their parent primary populations in both differentiated and undifferentiated states testing their myogenic character by comparison with non-myogenic cells found that immortalization has no measurable effect on the myogenic cascade or on any other cellular processes, and that it was protective against the senescence. In this context the human muscle cell lines are a good in vitro model to study the dystrophin interactome. We investigated dystrophin’s interactors using the high-sensitivity proteomics ‘QUICK’ approach. We identified 18 new physical interactors of dystrophin which displayed a high proportion of vesicle transport related proteins and adhesion proteins, strengthening the link between dystrophin and these roles. The proteins determined through previously published data together with the newly identified interactors were incorporated into a web-based data exploration tool: sys-myo.rhcloud.com/dystrophin-interactome, intended to provide an easily accessible and informative view of dystrophins interactions in skeletal muscle

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4

Acharyya, Swarnali. "Elucidating molecular mechanisms of muscle wasting in chronic diseases." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1180096565.

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5

Thorley, Matthew. "Analysis of the dystrophin interactome." Electronic Thesis or Diss., Paris 6, 2016. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2016PA066619.pdf.

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Le but de ce projet était d'identifier de manière méthodique et standardisée les partenaires interagissant avec la protéine dystrophine dans les cellules musculaires squelettiques humaines différenciées et découvrir de nouveaux rôles de la dystrophine. Des cellules immortalisées ont été obtenue en sur-exprimant de manière stable hTERT / CDK4. Nous avons réalisé une analyse transcriptomique comparant des lignées immortalisées avec leurs populations primaires correspondantes, à l’état de prolifération et de différentiation. Nous avons constaté que l'immortalisation n'a pas d'effet mesurable sur le programme myogénique ou sur tout autre processus cellulaires, et qu'elle avait un effet protecteur contre le processus de sénescence. Les lignées de cellules musculaires humaines constituent donc de bon model in vitro pour l’étude de l’interactome de la dystrophine. Nous avons déterminé l’interactome de la dystrophine en utilisant l’approche proteomique ‘QUICK’. Nous avons identifié 18 nouveaux partenaires directs de la dystrophine, partenaires étant impliqués dans le transport vésiculaire ou étant des protéines d'adhésion. Ces résultats renforcent les données précédemment publiées suggérant un lien entre la dystrophine et le trafic vésiculaire, ainsi que dystrophine et adhesion cellulaire. Ces nouveaux partenaires ont été ajoutés à l’interactome de la dystrophine, interactome accessible sur le Web: sys-myo.rhcloud.com/dystrophin-interactome. Ce site web est dédié à être un outil facile d’utilisation permettant d’explorer et de visualiser l’interactome de la dystrophine du muscle squelettique
The aim of this project was to systematically identify new interaction partners of the dystrophin protein within differentiated human skeletal muscle cells in order to uncover new roles in which dystrophin is involved, and to better understand how the global interactome is affected by the absence of dystrophin. hTERT/cdk4 immortalized myogenic human cell lines represent an important tool for skeletal muscle research however, disruption of the cell cycle has the potential to affect many other cellular processes to which it also linked. A transcriptome-wide analysis of healthy and diseased lines comparing immortalized lines with their parent primary populations in both differentiated and undifferentiated states testing their myogenic character by comparison with non-myogenic cells found that immortalization has no measurable effect on the myogenic cascade or on any other cellular processes, and that it was protective against the senescence. In this context the human muscle cell lines are a good in vitro model to study the dystrophin interactome. We investigated dystrophin’s interactors using the high-sensitivity proteomics ‘QUICK’ approach. We identified 18 new physical interactors of dystrophin which displayed a high proportion of vesicle transport related proteins and adhesion proteins, strengthening the link between dystrophin and these roles. The proteins determined through previously published data together with the newly identified interactors were incorporated into a web-based data exploration tool: sys-myo.rhcloud.com/dystrophin-interactome, intended to provide an easily accessible and informative view of dystrophins interactions in skeletal muscle

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6

Pearce, Marcela. "Genomic structure of the human utrophin gene." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318897.

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7

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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8

Reza, Mojgan. "Engineering and optimisation of mini-dystrophin constructs for Duchenne muscular dystrophy gene therapy." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2827.

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Muscular dystrophies (MDs) are inherited disorders characterised by muscle weakness and atrophy. One of the most severe forms is Duchenne muscular dystrophy (DMD) which together with the milder allelic form Becker muscular dystrophy (BMD) are known as the dystrophinopathies and result from defects in the X-linked gene encoding dystrophin. Dystrophin is a structural protein of the muscle that connects the internal cytoskeleton of muscle fibres to the extracellular matrix. DMD is also amongst the most common forms of muscular dystrophy, affecting ~1 in 4000 live male birth and manifests as rapidly progressive muscle degeneration leading to loss of ambulation and death in the second or third decade from respiratory or cardiac failure. Currently, there is no cure for this devastating disease. Clinical management of symptoms and complications is limited to stabilising the condition, slowing deterioration over time and palliative care. Since discovery of the DMD gene in 1986, researchers have dedicated substantial effort into vector technologies, facilitating the use of gene therapy to reintroduce a functional copy of the dystrophin gene into muscle fibres, a potential approach to treat DMD patients. However, this approach poses additional challenges relative to many gene therapy approaches since the full-length dystrophin cDNA is ~14 kb, exceeding the packaging capacity of most viral vectors. A number of large internal in-frame dystrophin deletions have been identified in patients that produce a relatively mild phenotype with later age of onset and a slower rate of disease progression than classical DMD. This observation has inspired the construction of internally truncated, but largely functional versions of dystrophin suitable for gene transfer using viral vectors. So far the most widely used miniaturised dystrophin transgenes have been tested in AAV-mediated gene delivery which has identified several limitations indicating the use of more favourable transgenes that have smaller deletions, yet carrying more functional parts of dystrophin. In this study human mini-dystrophin constructs of 4.3-7.7 kb in size were designed that retain key functional elements of dystrophin molecule and their relative functionality investigated in mdx mice. The ultimate aim of this study is the characterisation and optimisation of these mini-dystrophin constructs for gene delivery studies via viral vectors as a therapeutic tool for treatment of Duchenne muscular dystrophy.

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9

Johnson, Eric K. "A new model for the dystrophin associated protein complex in striated muscles." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354554580.

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10

Steen, Michelle Sabrina. "Analyses of alpha-dystrobrevin-null mice implicate Niemann-Pick C1 in muscular dystrophy /." Thesis, Connect to this title online; UW restricted, 2008. http://hdl.handle.net/1773/10537.

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11

Howard, Perry Leigh. "The functional diversity of dystrophin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0001/NQ41177.pdf.

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12

Bestard, Jennifer. "Dystrophin gene regulation in muscle." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0016/MQ54086.pdf.

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13

Ajdukovic, Boris. "Dystrophin expression during skeletal myogenesis." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=56988.

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The factors that regulate dystrophin accumulation, and its association with other proteins in culture, are largely unknown. In this study I have examined the effects of chemical agents on dystrophin accumulation in culture, as well as determined whether dystrophin in culture has associations with glycoproteins in a similar fashion to that found in normal muscle tissue. My results show that the onset of detectable dystrophin accumulation occurs shortly after myoblast fusion has taken place, and increases rapidly thereafter as a percentage of total cell protein. The effects of depolarizing concentrations of potassium ion, resulting in the inhibition of myotube contraction, are negligible, consistent with the fact that dystrophin is a cytoskeletal protein. I have found that 5-bromo-2$ sp prime$-deoxyuridine, known to affect terminal differentiation in myoblasts, markedly inhibits dystrophin accumulation in culture. Finally, I have found that dystrophin in cultured cells associates with Wheat Germ Agglutinin-binding proteins, as reported for adult skeletal muscle tissue, implying that the expression of these glycoproteins either precedes or occurs coordinately with dystrophin expression in culture.

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14

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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15

Anderson, Jennifer Louise Medical Sciences Faculty of Medicine UNSW. "Cerebellar synaptic plasticity in two animal models of muscular dystrophy." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43524.

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Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy 1A (MDC1A) are the two most common forms of muscular dystrophy in humans, caused by mutations in dystrophin and laminin α2 genes respectively. Both are severe forms of the disease that lead to premature death due and are both now known to have a significant effect on the central nervous system. This project investigated the role of both proteins involved in each of these diseases in cerebellar Purkinje cells of two murine models of disease: the mdx mouse a dystrophin-deficient model of DMD and the dy2J a laminin α2-deficient murine model of MDC1A. In the case of dystrophin further studies were undertaken in order to determine if increasing age had any effects on cerebellar function. It was found that there is no difference in electrophysiological characteristics (RMP, IR, eEPSP) of the cells when compared to appropriate control groups, nor was there any difference when young and aged dystrophin-deficient mdx groups were compared. Evoked IPSP characteristics were examined in young mdx cerebellar Purkinje cells and again no difference was found when compared to wildtype. There was a significant difference in response to the GABAA antagonist bicuculline, with wildtype increasing eEPSP amplitude by almost double that found in mdx. There was no difference in short term plasticity as measured by paired pulse facilitation in any of these groups. There was no difference in paired pulse depression at the inhibitory interneuron- Purkinje cell synapse of young wildtype and mdx cerebellar Purkinje cells. There a significant blunting of long term depression (LTD, (a form of long term synaptic plasticity) between young wildtype and mdx. When young wildtype animals were compared to aged wildtype animals LTD was found to be similar, when young mdx was compared to aged mdx, there was a recovery of LTD seen in the aged population. There was also significant differences in LTD found when littermate controls were compared to dy2J (laminin α2 mutants). A third of the phenotypic animals (dy2J) potentiated. Finally when rebound potentiation (a GABA-ergic form of long term synaptic plasticity in the cerebellum) was compared in young wildtype and mdx mice, mdx mice displayed depression, rather than the expected potentiation in contrast to potentiation (or no change) as seen in all wildtype cells.

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16

Montanaro, Federica. "The role of dystroglycan in muscular dystrophy and synaptogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ55361.pdf.

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17

Lekan, Jaimy Marie. "Exercise-induced mechanisms of muscle adaptation in mdx mice." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1095372379.

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18

Milad, Nadia. "Effects of hyperlipidemia on dysferlin- and dystrophin-deficient muscular dystrophies in double-disease mouse models." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60999.

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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate

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19

England, Sarah Beatrice. "Molecular studies of the dystrophin gene." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257954.

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20

Thanh, Le Thiet. "Exon-specific monoclonal antibodies against dystrophin." Thesis, University of Salford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261661.

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21

SPITALI, Pietro. "ANTISENSE MEDIATED DYSTROPHIN READING FRAME RESTORATION." Doctoral thesis, Università degli studi di Ferrara, 2010. http://hdl.handle.net/11392/2389323.

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Exon skipping using antisense oligonucleotides (AONs) has successfully been used to reframe the mRNA in various DMD (Duchenne muscular dystrophy) patients carrying deletions and in the mdx mouse model. This study can be devided in two parts: in the first part we have tested the feasibility of the exon skipping approach for patients with small mutations in in-frame exons, while in the second part a quantitative comparison of exon skipping revealing techniques is addressed. We first identified 55 novel disease-causing point mutations. We selected 5 patients with nonsense or frameshifting mutations in exons 10, 16, 26, 33 and 34. Wild type and mutation specific 2‟OMePS AONs were tested in cell-free splicing assays and in cultured cells derived from the selected patients. The results obtained confirm cell-free splicing assay as an alternative system to test exon skipping propensity when patients‟ cells are unavailable. In myogenic cells, similar levels of exon skipping were observed for wild type and mutation specific AONs for exons 16, 26 and 33, while for exon 10 and exon 34 the efficiency of the AONs was significantly different. Interestingly, in some cases skipping efficiencies for mutated exons were quite dissimilar compared to what previously reported for the respective wild type exons. This behaviour may be related to effect of the mutations on exon skipping propensity and highlights the complexity of identifying optimal AONs for skipping exons with small mutations. In the second part we compared different techniques to reveal the exon skipping levels in the muscles of 7 different mdx mice. An absolute quantification of the dystrophin transcript amount was possible using a digital array. Results underline the low expression of the dytrophin gene and the amount needed to correctly quantify the exon skipping percentage.

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22

Betts, Corinne A. "Exon skipping peptide-pmos for correction of dystrophin in mouse models of duchenne muscular dystrophy." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:545d586a-ad7b-4089-8537-b2677957b874.

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Duchenne muscular dystrophy (DMD) is a fatal, muscle-wasting disorder due to mutations/deletions in the dystrophin gene. Whilst improvements in palliative care have increased the life expectancy of patients, cardiomyopathy and respiratory complications are still the leading causes of death. A potential therapy for the treatment of DMD is antisense oligonucleotides (AOs), which modulate dystrophin pre-mRNA splicing to restore the dystrophin reading frame and generate a truncated functional protein. Conjugation of AOs to cell penetrating peptides (CPP), such as Pip5e-, significantly improves delivery to skeletal muscles and to the heart, which is imperative given the impact of cardiomyopathy to mortality. However, it should be noted that the contribution of skeletal muscles, such as the core respiratory muscle, the diaphragm, in dystrophic cardiopulmonary function is poorly understood. The specific aims of the work in this thesis were to (i) understand the effect of the diaphragm on cardiac function using magnetic resonance imaging (MRI), (ii) screen a number of derivatives of Pip5e (Pip6) in an effort to discover further promising peptides and define the properties integral to heart penetrating capacity, and (iii) assess whether Pip6-PMOs restore cardiac function (MRI) following a repeat, low dose regimen. In short, the specific restoration of dystrophin in the diaphragm of the dystrophic mouse model, the mdx mouse, did not improve cardiac function, highlighting the importance of a body-wide therapy. The screening of multiple Pip5e-PMO derivatives revealed 3 promising peptides with improved cardiac splicing capacity; however, serial deletions of amino acids from the central core resulted in the diminution of dystrophin restoration, possibly due to a reduction in hydrophobicity. Finally, the Pip6-PMO treatment regimen substantially restored dystrophin protein (28% in heart) and stabilised cardiac function, even with an increased work load. In conclusion, this study illustrates the importance of a body-wide treatment, such as the CPP strategy (Pip-PMO). These Pip-PMO conjugates demonstrate high dystrophin restoration in a number of muscles, including cardiac muscle, and have a beneficial effect on cardiac function.

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23

Al-Rewashdy, Hasanen. "Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31470.

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Duchenne Muscular Dystrophy (DMD) results from the absence of a functional dystrophin protein. Among its possible therapeutic options is the upregulation of dystrophin’s autosomal analogue, utrophin A. This can be achieved by a pharmacologically induced shift towards a slower, more oxidative skeletal muscle phenotype, which has been shown to confer morphological and functional improvements on models of DMD. Whether these improvements are a result of the utrophin A upregulation or other beneficial adaptations associated with the slow, oxidative phenotype, such as improved autophagy, has not been determined. To understand the importance of utrophin A to the therapeutic value of the slow, oxidative phenotype, we used the utrophin/dystrophin double knockout (dKO) model of DMD. We found the dKO mouse to have a similar skeletal muscle signaling capacity and phenotype to mdx mice. When treated with the adenosine monophosphate activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), both dKO and mdx mice expressed a shift towards a slower, more oxidative phenotype. In the mdx mice, this shift caused improvements in muscle fiber central nucleation, IgM penetration, damage from eccentric contractions, and forelimb grip strength. These morphological and functional benefits were not seen in the AICAR treated dKO mice. This study highlights the importance of utrophin A upregulation to the benefits of the slow, oxidative myogenic program to dystrophic mice. It confirms utrophin A as a therapeutic target in DMD and the slow, oxidative myogenic program as clinically relevant avenue towards treatment of the disease.

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24

Deol, Jatinderpal. "Development of helper-dependent adenovirus for gene expression in muscle." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33745.

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Duchenne muscular dystrophy (DMD) is characterized by necrosis and progressive loss of muscle fibers. DMD patients have a mutation in the gene encoding dystrophin, a large membrane-associated cytoskeletal protein on the cytoplasmic side of the sarcolemma. Gene therapy using fully deleted adenoviral vectors shows great potential for the eventual treatment of DMD and other genetic diseases. These vectors are less immunogenic than their predecessors and have the capacity to carry large DNA inserts such as the full-length dystrophin (12 kb). However, the lack of viral genes results in a weakened and subsiding (short) transgene expression in muscle. Findings in the lung and liver have shown the adenoviral E4 region, in particular E4 open reading frame 3 (ORF3) to contribute to the maintenance of transgene expression. We constructed an adenovirus in which E4 ORF3 was reintroduced into a fully-deleted adenovirus along with full-length dystrophin (AdCBDysORF3). Dystrophin levels produced by AdCBDysORF3 were found to be not sustained in mdx mice, dropping significantly by day 90. However, expression levels did increase when AdCBDysORF3 was complemented with other viral proteins such as EIB. Likewise, increasing the expression of the primary adenovirus receptor (CAR) in muscle also resulted in a higher initial dystrophin expression in myofibers.

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25

Judge, Luke Milburn. "Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex in skeletal muscle /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/4989.

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26

Dutton, Anna Louise. "An investigation into the effects of dystrophin on the lateral mobility of muscle membrane components." Thesis, Durham University, 1999. http://etheses.dur.ac.uk/4576/.

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Dystrophin is the product of the Duchenne Muscular Dystrophy gene locus, whose absence results in progressive skeletal muscle breakdown. Despite considerable work on the localisation of dystrophin and its associated complex, its role in muscle function remains unclear. In the light of the structural and mechanical instability of the dystrophic membrane, the idea was tested that dystrophin might impart membrane integrity and strength by anchoring membrane proteins and/or delineating the surface into specialised subcellular functional domains. Specifically, because dystrophin shows high sequence, structural and spatial similarities to the cytoskeletal protein spectrin; and because spectrin is proven to sterically restrict protein lateral diffusion through a subplasmalemmal network; the capacity of dystrophin to act as a 'molecular fence' to membrane diffusion was studied by comparing lateral mobility of membrane glycoproteins by fluorescence photobleach recovery in mdx and normal tissue. Secondly, as dystrophin has been proven to interact directly with proteins of the dystrophin associated glycoprotein complex in vivo, experiments addressed whether specific binding and immobilisation of the complex by dystrophin at the membrane was essential for function. Finally, given the homology of dystrophin and spectrin, the presence of dystrophin at the neuromuscular junction, and the importance of spectrins in immobilisation of voltage gated sodium channels in the nervous system, the role of dystrophin in regulating voltage gated sodium channel distribution at the neuromuscular junction was investigated. The results show that membrane glycoproteins were immobile in the presence and absence of dystrophin, suggesting dystrophin is not an essential molecular fence component. Alternatively, viability may have been the major influence on protein and lipid diffusion in these fibres and suggestions are made as to how this may be recognised and overcome for subsequent investigation. Three novel exon specific anti-dystrophin peptide antibodies were generated during the work that will be useful for studies into Duchenne muscular dystrophy in general, and dystrophin revertant fibres in particular.

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27

Thorogood, Francesca Clare. "Modulation of dystrophin pre-mRNA splicing by antisense oligonucleotides : a potential therapy for Duchenne muscular dystrophy." Thesis, Royal Holloway, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504809.

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Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disorder caused by mutations in the gene for dystrophin, a 427kDa cytoskeletal protein important for maintaining the integrity of muscle fibres. A number of DMD mutations result in an absence of functional protein due to disruption of the translational reading frame. It has been shown previously that antisense oligonucleotide (AON) reagents can modulate dystrophin pre-mRNA splicing to specifically exclude an out-of-frame exon from the mRNA. This restores the open reading frame resulting in production of a semi-functional internally-truncated dystrophin protein, mimicking what occurs in the milder allelic Becker muscular dystrophy (BMD). Previous work in this laboratory demonstrated successful exclusion of nonsense mutation carrying exon 23 in the mdx mouse model of DMD. This thesis is concerned with extension of the investigation by examining the bioactivity of alternative AON backbone chemistries 2' -O-methyl phosphorothioate (20Me), peptide nucleic acid (PNA) and phosphorodiamidate morpholino oligomer (PMO) targeting the 5'splice site of exon 23 in vitro and in vivo. In cultured murine muscle cells both the 20Me and PMO-based AON reagents induced detectable exon 23 exclusion. In the mdx mouse model intramuscular delivery of the 20Me-based AON reagent resulted in de novo dystrophin expression correctly localised at the sarcolemma that persisted for up to 4 weeks after a single dose. The PMO-based reagent resulted in de novo dystrophin expression that persisted for up to 10 weeks after a single intramuscular dose and for up to 8 weeks after a single intravenous dose. To broaden the investigation nine additional murine dystrophin exons were selected and AON regents designed targeting the 5'splice site and putative exonic splicing enhancer (ESE) sequences. Overall the results demonstrate that the AONs employed here induce detectable, reproducible exclusion of exon 23. The PMO-based reagent is currently superior for modulation of dystrophin pre-mRNA splicing.

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Tandon, Animesh. "Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophy using cardiac magnetic resonance imaging." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1396453528.

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Thorley, Matthew [Verfasser]. "Analysis of the dystrophin interactome / Matthew Thorley." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1128646315/34.

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30

Guibinga, Ghiabe H. "Molecular therapeutic interventioan for dystrophin-deficient muscles." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36945.

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Duchenne muscular dystrophy (DMD) is common and fatal X-linked genetic disorder. The overall objective of this thesis was to carry out a prospective study for dystrophin gene therapy in dystrophic muscles, using the X-linked muscular dystrophy (mdx) mouse model. Recombinant adenovirus (AdV) is presently the vehicle of choice for gene therapy for a number of diseases including DMD. However AdV possess two major limitations when utilized as vectors in skeletal muscles: (i) the maturation-dependency of AdV-infectivity in skeletal muscles, (ii) the host immune response against adenoviral proteins as well as the transgene product. Thus, the work presented in this thesis addresses these two major limiting factors. By modifying either the host or the vectors, we have attempted to optimize AdV-mediated therapeutic gene transfer in dystrophic muscle. Our strategy has consisted firstly to evaluate the regenerative response of dystrophic muscle with advanced disease after experimentally-induced regeneration, in an attempt to recapitulate the myogenic program. We report that mdx mice with severe dystrophic pathology can still show a substantial level of muscle repair with attendant generation of immature myofibers. Secondly, by taking advantage of this level of regeneration and the concomitant generation of immature myofibers, we have upregulated expression of the coxsackie adenovirus receptor (CAR) present in mdx muscles. We have delivered AdV containing a dystrophin gene (AdV-Dys) at a period corresponding to this peak level of CAR expression and we have reported a significant increase of the number of dystrophin expressing myofibers with a net trend toward muscle function amelioration.
The work of this thesis also reports that the combined blockade of calcineurin and CD28 signaling, two key and distinct elements needed for an effective immune response, effectively blunted the immune-mediated destruction of dystrophin expressing myofibers expressed after AdV-Dys delivery. As an alternative to host modification (regeneration and immunosuppression) that can be associated with potential toxic effects, we have explored a strategy where by the recombinant AdV vector contains a less immunogenic transgene utrophin. We report that overexpression of utrophin and dystrophin by AdV-mediated gene transfer in adult immunocompetent mdx mice produces differential effects on muscle cell function in adult immunocompetent (mdx) mice. (Abstract shortened by UMI.)

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31

James, Marian. "Monoclonal antibody studies of dystrophin and utrophin." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360455.

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Cisternas, Felipe A. "The function of alternatively spliced isoforms of dystrophin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/MQ49767.pdf.

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Ditta, Stephanie Doreen. "Matrix attachment regions in the human dystrophin gene." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/NQ53801.pdf.

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Demacio, Paula Constance. "Characterization of dystrophin protein complexes in the retina." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63719.pdf.

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35

Geng, Yan. "Molecular genetic studies of the mouse dystrophin gene." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239374.

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Loh, Nellie Y. "Characterisation of #beta#-dystrobrevin, a dystrophin-related protein." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299483.

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Yazid, Muhammad Da'In Bin. "Analysis of cell signalling in dystrophin-deficient myoblasts." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7342/.

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An absence of dystrophin in muscle has a massive impact throughout muscle development, and Duchene Muscular Dystrophy (DMD) is one of the consequences. The disruption of the dystrophin-glycoprotein complex (DGC) is caused by a mutation in the dmd gene, which effects muscle integrity, resulting in progressive muscle degeneration and weakness. In this study, dfd13 (dystrophin-deficient) and C2C12 (non-dystrophic) myoblasts were cultured in low mitogen conditions for 10 days to induce differentiation; however, dfdl3 myoblasts did not achieve terminal differentiation. It has been suggested that Pax7 may play a major role during myogenesis, therefore its expression pattern and transport protein were examined for any impairments. It was established that Pax7 localises in the cytoplasm of dystrophindeficient myoblasts and high expression is retained during differentiation. Colocalisation of Pax7 with subcellular markers analysis indicated that Pax7 is synthesised during the proliferative state. Pax7 was shown to possess a nuclear location signal and KPNA2 was suggested as escort protein for Pax7 translocation into the nucleus. The PTEN-PI3K/Akt signalling pathway was investigated and protein synthesis regulation and Fox03 was found to be impaired. Autophagy related genes were found to be highly expressed; however, LC3 lipidation and autophagy flux showed a reduction upon differentiation, indicating defective autophagy. The contribution of PTEN overexpression was assessed in relation to endoplasmic reticulum (ER) stress and activation of the unfolding protein response (UPR). It was established that a reduction in ER stress and changes to UPR activation lead to apoptosis. Finally, minidystrophintransfection of both types of myoblasts was utilised to examine the effect, especially in dystrophin-deficient myoblasts. Minidystrophin improved protein synthesis activation and increased autophagy (increased LC3 lipidation), suggesting that minidystrophin ameliorates dystrophic events at the level of autophagosome formation. To conclude, destabilisation of the plasma membrane owing to a dystrophin mutation causes cell signalling alterations which minidystrophin restoration can partly improve.

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Li, Hongmei. "Precise Correction of the Dystrophin Gene in Duchenne Muscular Dystrophy Patient iPS Cells by TALEN and CRISPR-Cas9." Kyoto University, 2015. http://hdl.handle.net/2433/199179.

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Sako, Yukiya. "Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy." Kyoto University, 2017. http://hdl.handle.net/2433/226771.

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Thompson, Shannon. "Exploring Dystrophin-Mediated Control of Neural Stem Cell Fate Associated with Intellectual Disability In Duchenne Muscular Dystrophy Patients." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38110.

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Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disease characterized by progressive muscle-wasting and loss of mobility. One-third of patients with DMD are also affected by cognitive impairments such as a lower than average IQ and impaired working memory, comorbid with neuropsychiatric disorders such as anxiety and autism-related behaviours. DMD is caused by mutations in the DMD gene resulting in the deletion of the full-length dystrophin protein (Dp427) and, dependent on mutation, other dystrophin isoforms. These isoforms are predominantly found in the brain and deletion may impact on cognition. The most commonly used animal model to study DMD is the mdx mouse which completely lacks Dp427 but no other DMD isoforms. Although the muscle phenotype is well-established, behavioural characterization of the mdx mouse model has been inconclusive. In this thesis I investigated the hippocampal and amygdala cellular and behavioural phenotypes of the mdx mouse. I show that post-natal neural stem-like cell division in the SGZ is altered in the absence of Dp427 resulting in enhanced symmetric division. I show in vitro that primary mdx cultures are fewer and smaller than wild-type, consistent with an increase in symmetrical self-renewal whereas secondary cultures are fewer and larger, consistent with a shift in symmetric division producing transit-amplifying type 2a daughter cells. I next characterized the mdx mouse model using a battery of behavioural tests. Data presented here show that mdx mice do not exhibit an anxious phenotype, do not display autism-related behaviours, and do not display impairments in and spatial learning or memory. However, associative learning, as measured in the fear conditioning paradigm is enhanced in mdx mice. Lastly, I attempted to generate three different brain-specific dystrophin knock-out mouse models to examine role of other dystrophin isoforms. While none of the models were able to deplete dystrophin from brain, given the inverse relationship between Cre-mediated efficiency and the genetic distance of the loxP sites in the fDMDH mouse employed, I do provide important insight into the presence and absence of the muscle-specific enhancers in constructs commonly used to generate brain-specific mouse models. Taken together, this thesis provides converging evidence to indicate that loss of Dp427 impacts on fear associative learning and stem-cell like division in the SGZ but likely does not underlie the non-progressive cognitive impairments affecting one-third of all DMD patients.

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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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42

Gardner, Katherine Lynn. "New insights into the disease mechanisms of Duchenne Muscular Dystrophy through analyses of the Dystrophin, IκBβ, and CASK proteins." The Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1153530409.

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43

Hance, Jacqueline Elizabeth. "Identification of novel components of the dystrophin glycoprotein complex." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ40057.pdf.

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Sommer, Barbara. "Changes of skeletal muscle in adult dystrophin-deficient cats /." [S.l.] : [s.n.], 2000. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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Oliveira, Daniela Moraes de. "Análise de expressão da distrofina, miostatina, tgf-β e nf-kappa β, durante a fase embrionária e fetal no modelo canino GRMD (Golden Retrivier Muscular Dystrophy)." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-27022018-121625/.

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A Distrofia Muscular de Duchenne (DMD) é uma doença genética neuromuscular hereditária, ligada ao cromossomo X, sendo encontrada em humanos do sexo masculino. Esta doença muscular é descrita em outras espécies. O modelo de estudo pré-clínico GRMD (Golden Retrievier Muscular Dystrophy) apresenta sintomas clínicos fenotipicamente característicos da DMD em humanos e, por esta razão, tem sido amplamente utilizado como modelo de estudos pré-clínicos. O objetivo da presente pesquisa foi avaliar o tecido muscular, no modelo canino distrófico, ao longo da gestação. Quatro fêmeas, portadoras do gene distrófico, foram inseminadas com sêmen fresco de cães distróficos. No 25º dia, pós-inseminação, as fêmeas foram submetidas a exames de ultrassonografia para confirmar a gestação. As fêmeas gestantes passaram por uma ovariosalpingohisterectomia (OSH) para a retirada dos embriões e fetos nos seguintes períodos gestacionais: 28º , 33º , 38º e 42º dias. Em seguida fragmentos de tecido muscular foram analisados macroscopicamente e microscopicamente. Para verificar expressões proteicas, amostras de tecido foram submetidas a técnicas imunológicas, e PCR para distrofina, miostatina, e utrofina. Aos, 33º e 38º dias de gestação, no grupo distrófico, foram observadas características teciduais que corroboram com desenvolvimento tardio do tecido muscular. Os resultados para detecção proteica sugerem que, a distrofina, miostatina e utrofina foram expressas igualmente nos grupos controle e distrófico, durante todos os períodos do desenvolvimento gestacional analisado. Por fim, os dados sugerem que animais distróficos apresentam músculo sadio durante a fase gestacional, o que pode ser benéfico para testes farmacológicos em idade precoce.
Duchenne Muscular Dystrophy (DMD) is a hereditary neuromuscular genetic disease linked to the X chromosome, being found in male humans. This muscle disease is described in other species. The pre-clinical GRMD (Golden Retrievier Muscular Dystrophy) study model presents phenotypically characteristic clinical symptoms of DMD in humans and,for this reason, has been widely used as a model for preclinical studies. The aim of the present study was to evaluate the muscular tissue, in the dystrophic canine model, throughout the gestation. Four females, carriers of the dystrophic gene, were inseminated with fresh semen from dystrophic dogs. On the 25th day, post-insemination, the females were submitted to ultrasonography to confirm the pregnancy. The pregnant females underwent an ovariosalpingohisterectomy (OSH) for the removal of the embryos and fetuses in the following gestational periods: 28º, 33º, 38º and 42º days. Then fragments of muscle tissue were analyzed macroscopically and microscopically. To verify protein expression, tissue samples were submitted to immunological techniques, and PCR for dystrophin, myostatin, and utrophin. At the 33 and 38th days of gestation, tissue characteristics were observed in the dystrophic group, which corroborate the late development of muscle tissue. The results for protein detection suggest that dystrophin, myostatin and utrophin were also expressed in the control and affected groups, during all periods of the gestational development analyzed. Lastly, the data suggest that dystrophic animals present healthy muscle during the gestational phase, which may be beneficial for pharmacological tests at an early age.

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Kaspar, Rita Wen. "Genotype-Phenotype Association Analysis of Dilated Cardiomyopathy in Becker Muscular Dystrophy." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243469474.

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47

Palmieri, Laura. "Development of 3D muscle tissues for gene therapy screening and therapeutic evaluation of novel Midi-Dystrophins in Duchenne Muscular Dystrophy context." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL056.

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La dystrophie musculaire de Duchenne (DMD), encore incurable, est due à l'absence de dystrophine, une protéine essentielle pour préserver l'intégrité musculaire continuellement mise à l'épreuve par les contractions. La thérapie génique utilisant le virus adéno-associé (AAV) pour délivrer des formes tronquées de dystrophine (µDys) est actuellement l'approche thérapeutique la plus prometteuse. Cependant, les résultats obtenus chez les patients diffèrent de ceux des études animales, ce qui souligne la nécessité de disposer de modèles permettant de prédire avec précision la réponse humaine. En outre, la µDys est dépourvue de domaines fonctionnels et présente un sauvetage incomplet, ce qui suggère que l'expression de dystrophines plus grandes avec des domaines supplémentaires est nécessaire pour une correction phénotypique complète. Au cours de mon doctorat, j'ai généré les MYOrganoids, une plateforme musculaire en 3D dérivée de cellules souches pluripotentes induites humaines (iPSC), dont la maturation est améliorée par l'incorporation de fibroblastes. J'ai ensuite employé des fibroblastes DMD pour exacerber les caractéristiques pathogènes des MYOrganoids DMD, telles que la fibrose et la perte de force musculaire. J'ai montré que le transfert de gène μDys dans les MYOrganoids DMD améliorait la résistance musculaire ; cependant, seule une correction partielle de la signature DMD a été observée, soulignant le potentiel de notre approche de bio-ingénierie pour le criblage de la thérapie génique. En outre, j'ai généré trois nouvelles midi-dystrophines (midi-Dys) avec des domaines fonctionnels supplémentaires. En validant leur efficacité in vitro et in vivo, j'ai constaté que midi-Dys était 50 % moins exprimé que µDys à des doses équivalentes, tout en conservant des effets thérapeutiques similaires sur la fibrose et le sauvetage fonctionnel. Notamment, dans le diaphragme, midi-Dys a surpassé µDys dans la réduction des zones fibrotiques, suggérant la supériorité de midi-Dys comme option thérapeutique pour la dystrophie musculaire de Duchenne. Dans l'ensemble, ce travail aborde les limitations importantes du remplacement de gènes par AAV et présente une nouvelle méthode pour exprimer efficacement des protéines extra-larges et hautement fonctionnelles
The yet incurable Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a protein essential to preserve muscle integrity continuously challenged by contractions. Gene therapy exploiting adeno-associated virus (AAV) to deliver truncated forms of dystrophin (µDys) is currently the most promising therapeutic approach. However, patient outcomes differed from animal studies, emphasizing the necessity for models to predict accurately human response. Additionally, µDys is missing functional domains and it shows incomplete rescue, suggesting that the expression of larger dystrophins with additional domains is required for a complete phenotypical correction. During my PhD, I generated the MYOrganoid, a 3D muscle platform derived from human induced pluripotent stem cells (iPSC), whose maturation is enhanced by fibroblast incorporation. I then employed DMD fibroblasts to exacerbate pathogenic hallmarks of DMD MYOrganoids, such as fibrosis and muscle force loss. I showed that μDys gene transfer in DMD MYOrganoids improved muscle resistance; however, only partial correction of the DMD signature was observed, underlining the potential of our bioengineering approach for gene therapy screening. Furthermore, I generated three novel midi-dystrophins (midi-Dys) with additional functional domains. Validating their efficacy in vitro and in vivo, I found midi-Dys to be 50% less expressed than µDys at equivalent doses yet maintaining similar therapeutic effects on fibrosis and functional rescue. Notably, in the diaphragm, midi-Dys outperformed µDys in reducing fibrotic areas, suggesting the superiority of midi-Dys as a therapeutic option for Duchenne muscular dystrophy. Overall, this work addresses important limitations of AAV-based gene replacement and presents a novel method to efficiently express large and highly functional extra-large proteins

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48

Murphy, Stephen James. "Adenovirus vectors for gene transfer of full-length dystrophin cDNAs." Thesis, Royal Holloway, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300462.

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49

Ferrer, Roig Aurora. "Immune responses to dystrophin : implications for gene therapy of DMD." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395118.

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Byth, Barbara Christian. "Molecular analysis of an autosomal homologue of the dystrophin gene." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302841.

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