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DMD gene therapy

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https://www.readbyqxmd.com/read/28440464/proteomic-profiling-of-mdx-4cv-serum-reveals-highly-elevated-levels-of-the-inflammation-induced-plasma-marker-haptoglobin-in-muscular-dystrophy
#1
Sandra Murphy, Paul Dowling, Margit Zweyer, Michael Henry, Paula Meleady, Rustam R Mundegar, Dieter Swandulla, Kay Ohlendieck
X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation‑contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whether these substantial changes within the skeletal musculature are reflected by an altered rate of protein release into the circulatory system or other plasma fluctuations, we used label‑free mass spectrometry to characterize serum from the mdx‑4cv model of Duchenne muscular dystrophy...
April 18, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28416280/progress-toward-gene-therapy-for-duchenne-muscular-dystrophy
#2
REVIEW
Joel R Chamberlain, Jeffrey S Chamberlain
Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups...
April 14, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28398005/nanotherapy-for-duchenne-muscular-dystrophy
#3
REVIEW
Michael E Nance, Chady H Hakim, N Nora Yang, Dongsheng Duan
Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials...
April 11, 2017: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
https://www.readbyqxmd.com/read/28390761/the-aav-mediated-and-rna-guided-crispr-cas9-system-for-gene-therapy-of-dmd-and-bmd
#4
REVIEW
Jing-Zhang Wang, Peng Wu, Zhi-Min Shi, Yan-Li Xu, Zhi-Jun Liu
Mutations in the dystrophin gene (Dmd) result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which afflict many newborn boys. In 2016, Brain and Development published several interesting articles on DMD treatment with antisense oligonucleotide, kinase inhibitor, and prednisolone. Even more strikingly, three articles in the issue 6271 of Science in 2016 provide new insights into gene therapy of DMD and BMD via the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)...
April 5, 2017: Brain & Development
https://www.readbyqxmd.com/read/28344992/mechanism-of-deletion-removing-all-dystrophin-exons-in-a-canine-model-for-dmd-implicates-concerted-evolution-of-x-chromosome-pseudogenes
#5
D Jake VanBelzen, Alock S Malik, Paula S Henthorn, Joe N Kornegay, Hansell H Stedman
Duchenne muscular dystrophy (DMD) is a lethal, X-linked, muscle-wasting disorder caused by mutations in the large, 2.4-Mb dystrophin gene. The majority of DMD-causing mutations are sporadic, multi-exon, frameshifting deletions, with the potential for variable immunological tolerance to the dystrophin protein from patient to patient. While systemic gene therapy holds promise in the treatment of DMD, immune responses to vectors and transgenes must first be rigorously evaluated in informative preclinical models to ensure patient safety...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28338606/dystrophic-cardiomyopathy-potential-role-of-calcium-in-pathogenesis-treatment-and-novel-therapies
#6
REVIEW
Victoria P A Johnstone, Helena M Viola, Livia C Hool
Duchenne muscular dystrophy (DMD) is caused by defects in the DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly true following respiratory interventions that reduce death rate and increase ambulation and consequently cardiac load. Cardiomyopathy shows an increasing prevalence with age and disease progression, and over 95% of patients exhibit dilated cardiomyopathy by the time they reach adulthood...
March 24, 2017: Genes
https://www.readbyqxmd.com/read/28325301/increased-expression-of-laminin-subunit-alpha-1-chain-by-dcas9-vp160
#7
Arnaud Perrin, Joël Rousseau, Jacques P Tremblay
Laminin-111 protein complex links the extracellular matrix to integrin α7β1 in sarcolemma, thus replacing in dystrophic muscles links normally insured by the dystrophin complex. Laminin-111 injection in mdx mouse stabilized sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscles from exercised-induced damages. These results suggested that increased laminin-111 is a potential therapy for DMD. Laminin subunit beta 1 and laminin subunit gamma 1 are expressed in adult human muscle, but laminin subunit alpha 1 (LAMA1) gene is expressed only during embryogenesis...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28303972/lentiviral-vectors-can-be-used-for-full-length-dystrophin-gene-therapy
#8
John R Counsell, Zeinab Asgarian, Jinhong Meng, Veronica Ferrer, Conrad A Vink, Steven J Howe, Simon N Waddington, Adrian J Thrasher, Francesco Muntoni, Jennifer E Morgan, Olivier Danos
Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28289221/gentamicin-b1-is-a-minor-gentamicin-component-with-major-nonsense-mutation-suppression-activity
#9
Alireza Baradaran-Heravi, Jürgen Niesser, Aruna D Balgi, Kunho Choi, Carla Zimmerman, Andrew P South, Hilary J Anderson, Natalie C Strynadka, Marcel B Bally, Michel Roberge
Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy...
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28250438/lentiviral-vectors-can-be-used-for-full-length-dystrophin-gene-therapy
#10
John R Counsell, Zeinab Asgarian, Jinhong Meng, Veronica Ferrer, Conrad A Vink, Steven J Howe, Simon N Waddington, Adrian J Thrasher, Francesco Muntoni, Jennifer E Morgan, Olivier Danos
Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28247611/-research-progress-on-disease-models-and-gene-therapy-of-duchenne-muscular-dystrophy
#11
Tongyu Li, Ping Liang
Duchenne muscular dystrophy (DMD) is an X-linked, recessive and lethal genetic disease, which usually caused by gene mutations and the underlying mechanisms are complicated and diverse. The causal gene of DMD is the largest one in human that locates in the region of Xp21.2, encoding dystrophin. Currently there is no effective treatment for DMD patients. The treatment of DMD depends on gene mutation and molecular mechanism study of the disease, which requires reliable disease models such as mdx mouse model. Recently, researchers have increasingly discovered gene therapy strategies for DMD, and the efficacy has been demonstrated in DMD animal models...
May 25, 2016: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
https://www.readbyqxmd.com/read/28195574/muscle-specific-crispr-cas9-dystrophin-gene-editing-ameliorates-pathophysiology-in-a-mouse-model-for-duchenne-muscular-dystrophy
#12
Niclas E Bengtsson, John K Hall, Guy L Odom, Michael P Phelps, Colin R Andrus, R David Hawkins, Stephen D Hauschka, Joel R Chamberlain, Jeffrey S Chamberlain
Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx(4cv) mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation...
February 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28116794/genetic-profile-of-brazilian-patients-with-dystrophinopathies
#13
Paula Abreu Ducceschi de Almeida, Marcela Câmara Machado-Costa, Gabrielle Novais Manzoli, Leticia Sauma Ferreira, Maria do Carmo de Souza Rodrigues, Larissa Souza Mario Bueno, Jonas Alex Morales Saute, Filippo Pinto Vairo, Ursula da Silveira Matte, Marina Siebert, Silvia Liliana Cossio, Gabriel S Macedo, Pablo Brea Winckler, Michele Michelin Becker, Lucas Vilas Boas Magalhães, Marcus Vinicius Magno Gonçalves, Carlo Domenico Marrone, Anamarli Nucci, Marcondes C França
Different types of mutations in the DMD gene underlie Duchenne (DMD) and Becker (BMD) muscular dystrophies. Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included MLPA and NGS analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and one 1...
January 24, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28089792/pharmacological-inhibition-of-pkc%C3%AE-counteracts-muscle-disease-in-a-mouse-model-of-duchenne-muscular-dystrophy
#14
V Marrocco, P Fiore, A Benedetti, S Pisu, E Rizzuto, A Musarò, L Madaro, B Lozanoska-Ochser, M Bouché
Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20)...
February 2017: EBioMedicine
https://www.readbyqxmd.com/read/28042944/comparison-of-serum-raav-serotype-specific-antibodies-in-patients-with-duchenne-muscular-dystrophy-becker-muscular-dystrophy-inclusion-body-myositis-or-gne-myopathy
#15
Deborah A Zygmunt, Kelly E Crowe, Kevin M Flanigan, Paul T Martin
Recombinant adeno-associated virus (rAAV) is a commonly used gene therapy vector for the delivery of therapeutic transgenes in a variety of human diseases, but pre-existing serum antibodies to viral capsid proteins can greatly inhibit rAAV transduction of tissues. Serum was assayed from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), inclusion body myositis (IBM), and GNE myopathy (GNE). These were compared to serum from otherwise normal human subjects to determine the extent of pre-existing serum antibodies to rAAVrh74, rAAV1, rAAV2, rAAV6, rAAV8, and rAAV9...
December 29, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/28028563/whole-genome-sequencing-reveals-a-7-base-pair-deletion-in-dmd-exon-42-in-a-dog-with-muscular-dystrophy
#16
Peter P Nghiem, Luca Bello, Cindy Balog-Alvarez, Sara Mata López, Amanda Bettis, Heather Barnett, Briana Hernandez, Scott J Schatzberg, Richard J Piercy, Joe N Kornegay
Dystrophin is a key cytoskeletal protein coded by the Duchenne muscular dystrophy (DMD) gene located on the X-chromosome. Truncating mutations in the DMD gene cause loss of dystrophin and the classical DMD clinical syndrome. Spontaneous DMD gene mutations and associated phenotypes occur in several other species. The mdx mouse model and the golden retriever muscular dystrophy (GRMD) canine model have been used extensively to study DMD disease pathogenesis and show efficacy and side effects of putative treatments...
April 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/27997693/genetic-ablation-of-p65-subunit-of-nf-%C3%AE%C2%BAb-in-mdx-mice-to-improve-muscle-physiological-function
#17
Xi Yin, Ying Tang, Jian Li, Anna T Dzuricky, Chuanqiang Pu, Freddie Fu, Bing Wang
INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genetic muscle disease characterized by dystrophin deficiency. Beyond gene replacement, the question of whether ablation of the p65 gene of nuclear factor-kappa B (NF-κB) in DMD can improve muscle physiology function is unknown. In this study, we investigated muscle physiological improvement in mdx mice (DMD model) with a genetic reduction of NF-κB. METHODS: Muscle physiological function and histology were studied in 2-month-old mdx/p65(+/-) , wild-type (WT), mdx, and human minidystrophin gene transgenic mdx (TghΔDys/mdx) mice...
December 20, 2016: Muscle & Nerve
https://www.readbyqxmd.com/read/27974813/comparison-of-the-phenotypes-of-patients-harboring-in-frame-deletions-starting-at-exon-45-in-the-duchenne-muscular-dystrophy-gene-indicates-potential-for-the-development-of-exon-skipping-therapy
#18
Akinori Nakamura, Naoko Shiba, Daigo Miyazaki, Hitomi Nishizawa, Yuji Inaba, Noboru Fueki, Rika Maruyama, Yusuke Echigoya, Toshifumi Yokota
Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45-55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45-55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45...
December 15, 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27908661/uniform-low-level-dystrophin-expression-in-the-heart-partially-preserved-cardiac-function-in-an-aged-mouse-model-of-duchenne-cardiomyopathy
#19
Nalinda B Wasala, Yongping Yue, Jenna Vance, Dongsheng Duan
Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice...
January 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27854202/current-translational-research-and-murine-models-for-duchenne-muscular-dystrophy
#20
Merryl Rodrigues, Yusuke Echigoya, So-Ichiro Fukada, Toshifumi Yokota
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD...
March 3, 2016: Journal of Neuromuscular Diseases
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