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DMD gene therapy

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https://www.readbyqxmd.com/read/28624206/crispr-cas9-mediated-genome-editing-corrects-dystrophin-mutation-in-skeletal-muscle-stem-cells-in-a-mouse-model-of-muscle-dystrophy
#1
Pei Zhu, Furen Wu, Jeffrey Mosenson, Hongmei Zhang, Tong-Chuan He, Wen-Shu Wu
Muscle stem cells (MuSCs) hold great therapeutic potential for muscle genetic disorders, such as Duchenne muscular dystrophy (DMD). The CRISP/Cas9-based genome editing is a promising technology for correcting genetic alterations in mutant genes. In this study, we used fibrin-gel culture system to selectively expand MuSCs from crude skeletal muscle cells of mdx mice, a mouse model of DMD. By CRISP/Cas9-based genome editing, we corrected the dystrophin mutation in expanded MuSCs and restored the skeletal muscle dystrophin expression upon transplantation in mdx mice...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623422/effects-of-omega-3-on-matrix-metalloproteinase-9-myoblast-transplantation-and-satellite-cell-activation-in-dystrophin-deficient-muscle-fibers
#2
Samara Camaçari de Carvalho, Sajedah M Hindi, Ashok Kumar, Maria Julia Marques
In Duchenne muscular dystrophy (DMD), lack of dystrophin leads to progressive muscle degeneration, with DMD patients suffering from cardiorespiratory failure. Cell therapy is an alternative to life-long corticoid therapy. Satellite cells, the stem cells of skeletal muscles, do not completely compensate for the muscle damage in dystrophic muscles. Elevated levels of proinflammatory and profibrotic factors, such as metalloproteinase 9 (MMP-9), impair muscle regeneration, leading to extensive fibrosis and poor results with myoblast transplantation therapies...
June 17, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28607562/cellular-reprogramming-genome-editing-and-alternative-crispr-cas9-technologies-for-precise-gene-therapy-of-duchenne-muscular-dystrophy
#3
REVIEW
Peter Gee, Huaigeng Xu, Akitsu Hotta
In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28566768/moving-towards-successful-exon-skipping-therapy-for-duchenne-muscular-dystrophy
#4
REVIEW
Akinori Nakamura
Duchenne muscular dystrophy (DMD) is an X chromosome-linked lethal muscular disorder with progressing muscle wasting and weakness caused by mutations in the gene encoding a subsarcolemmal protein dystrophin. For a long time, there was no effective cure; however, advances in molecular biology have allowed the development of radical treatment approaches. Among them, exon-skipping therapy using antisense oligonucleotides is very promising, because it corrects the reading frame of the dystrophin-encoding gene and restores protein expression, resulting in the conversion of DMD to a clinically milder form, Becker muscular dystrophy (BMD)...
June 1, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28555643/development-of-an-orally-available-inhibitor-of-clk1-for-skipping-a-mutated-dystrophin-exon-in-duchenne-muscular-dystrophy
#5
Yukiya Sako, Kensuke Ninomiya, Yukiko Okuno, Masayasu Toyomoto, Atsushi Nishida, Yuka Koike, Kenji Ohe, Isao Kii, Suguru Yoshida, Naohiro Hashimoto, Takamitsu Hosoya, Masafumi Matsuo, Masatoshi Hagiwara
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein...
May 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526070/the-golden-retriever-model-of-duchenne-muscular-dystrophy
#6
REVIEW
Joe N Kornegay
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development...
May 19, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28505980/creation-of-a-novel-humanized-dystrophic-mouse-model-of-duchenne-muscular-dystrophy-and-application-of-a-crispr-cas9-gene-editing-therapy
#7
Courtney S Young, Ekaterina Mokhonova, Marbella Quinonez, April D Pyle, Melissa J Spencer
Duchenne muscular dystrophy is caused by mutations in DMD which disrupt the reading frame. Therapeutic strategies that restore DMD's reading frame, such as exon skipping and CRISPR/Cas9, need to be tested in the context of the human DMD sequence in vivo. We have developed a novel dystrophic mouse model by using CRISPR/Cas9 to delete exon 45 in the human DMD gene in hDMD mice, which places DMD out-of-frame. We have utilized this model to demonstrate that our clinically-relevant CRISPR/Cas9 platform, which targets deletion of human DMD exons 45-55, can be directly applied in vivo to restore dystrophin...
2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28472288/oxidative-stress-in-duchenne-muscular-dystrophy-focus-on-the-nrf2-redox-pathway
#8
Sara Petrillo, Laura Pelosi, Fiorella Piemonte, Lorena Travaglini, Laura Forcina, Michela Catteruccia, Stefania Petrini, Margherita Verardo, Adele D'Amico, Antonio Musarò, Enrico Bertini
Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression...
May 3, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28469083/microrna-29-overexpression-by-adeno-associated-virus-suppresses-fibrosis-and-restores-muscle-function-in-combination-with-micro-dystrophin
#9
Kristin N Heller, Joshua T Mendell, Jerry R Mendell, Louise R Rodino-Klapac
Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency resulting in progressive muscle weakness and fibrotic scarring. Muscle fibrosis impairs blood flow, hampering muscle repair and regeneration. Irrespective of the success of gene restoration, functional improvement is limited without reducing fibrosis. The levels of miR-29c, a known regulator of collagen, are reduced in DMD. Our goal is to develop translational, antifibrotic therapy by overexpressing miR-29c. We injected the gastrocnemius muscle with either self-complementary AAV...
May 4, 2017: JCI Insight
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
#10
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...
June 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28416280/progress-toward-gene-therapy-for-duchenne-muscular-dystrophy
#11
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...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28398005/nanotherapy-for-duchenne-muscular-dystrophy
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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