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DMD gene therapy

Amanda Faria Assoni, Giuliana Castello, Marcos Valadares, Melinda Beccari, Juliana Gomes, Mayra Pelatti, Miguel Mitne-Neto, Valdemir Melechco Carvalho, Mayana Zatz
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by null mutations in the dystrophin gene. Although the primary defect is the deficiency of muscle dystrophin, secondary events, including chronic inflammation, fibrosis and muscle regeneration failure are thought to actively contribute to disease progression. Despite several advances, there is still no effective therapy for DMD. Therefore, the potential regenerative capacities, as well as immune-privileged properties of Mesenchymal Stromal Cells (MSCs), have been the focus of intense investigation in different animal models aiming the treatment of these disorders...
October 20, 2016: Stem Cells and Development
Hong-Hao Yu, Heng Zhao, Yu-Bo Qing, Wei-Rong Pan, Bao-Yu Jia, Hong-Ye Zhao, Xing-Xu Huang, Hong-Jiang Wei
Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease...
October 9, 2016: International Journal of Molecular Sciences
Alice Todeschini, Francesca Gualandi, Cecilia Trabanelli, Annarita Armaroli, Anna Ravani, Marina Fanin, Silvia Rota, Luca Bello, Alessandra Ferlini, Elena Pegoraro, Alessandro Padovani, Massimiliano Filosto
We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript...
October 2016: Neuromuscular Disorders: NMD
Hayder Abdul-Razak, Alberto Malerba, George Dickson
Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments...
2016: F1000Research
James A Loehr, Gary R Stinnett, Mayra Hernández-Rivera, Wesley T Roten, Lon J Wilson, Robia G Pautler, George G Rodney
KEY POINTS: Inhibiting Nox2 reactive oxygen species (ROS) production reduced in vivo calcium influx in dystrophic muscle. The lack of Nox2 ROS production protected against decreased in vivo muscle function in dystrophic mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was able to detect alterations in basal calcium levels in skeletal muscle and differentiate disease status. Administration of Mn(2+) did not affect muscle function or the health of the animal, and Mn(2+) was cleared from skeletal muscle rapidly...
August 24, 2016: Journal of Physiology
Candice Brinkmeyer-Langford, Cynthia Balog-Alvarez, James J Cai, Brian W Davis, Joe N Kornegay
BACKGROUND: Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies...
2016: BMC Genomics
Jacqueline N Robinson-Hamm, Charles A Gersbach
Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength...
September 2016: Human Genetics
Maria Sofia Falzarano, Domenico D'Amario, Andrea Siracusano, Massimo Massetti, Antonio Amodeo, Federica La Neve, Camilla Reina Maroni, Eugenio Mercuri, Hana Osman, Chiara Scotton, Annarita Armaroli, Rachele Rossi, Rita Selvatici, Filippo Crea, Alessandra Ferlini
A ready source of autologous myogenic cells is of vital importance for drug screening and functional genetic studies in Duchenne Muscular Dystrophy (DMD), a rare disease caused by a variety of dystrophin gene mutations. As stem cells (SCs) can be easily and non-invasively obtained from urine specimens, we set out to determine whether they could be myogenic-induced and useful in DMD research. To this end, we isolated stem cells from the urine of two healthy donors and one patient with DMD, and performed surface-marker characterization, myogenic differentiation (MyoD), and then transfection with antisense oligoribonucletoides to test for exon skipping and protein restoration...
August 16, 2016: Human Gene Therapy
Jean K Mah
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing...
2016: Neuropsychiatric Disease and Treatment
Lindsey A Muir, Charles E Murry, Jeffrey S Chamberlain
In Duchenne muscular dystrophy (DMD) and other muscle wasting disorders, cell therapies are a promising route for promoting muscle regeneration by supplying a functional copy of the missing dystrophin gene and contributing new muscle fibers. The clinical application of cell-based therapies is resource intensive, and it will therefore be necessary to address key limitations that reduce cell engraftment into muscle tissue. A pressing issue is poor donor cell survival following transplantation, which in preclinical studies limits the ability to effectively test the impact of cell-based therapy on whole muscle function...
September 7, 2016: Stem Cells and Development
Mikako Ito, Yuka Ehara, Shin Li, Kosuke Inada, Kinji Ohno
Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by loss-of-function mutations in <i>DMD</i> encoding dystrophin. No rational therapy is currently available. Utrophin is a paralog of dystrophin and is highly expressed at the neuromuscular junction. In <i>mdx</i> mice, utrophin is naturally upregulated throughout the muscle fibers, which mitigates muscular dystrophy. We previously reported the protein-anchoring therapy, in which a recombinant extracellular matrix protein is delivered to and anchored to a specific target using its proprietary binding domains...
August 2, 2016: Human Gene Therapy
Mojgan Reza, Steven Hector Laval, Stephanie Jan Carr, Hanns Lochmuller
Duchenne muscular dystrophy is a severe, genetic muscle disease caused by the absence of the sarcolemmal protein dystrophin. Gene replacement therapy is considered as a potential strategy for treatment of DMD, aiming to restore the missing protein. One of the major challenges of this method is the large size of the dystrophin cDNA of ~14 kb, exceeding the packaging capacity of conventional viral vectors. Although the elements of the dystrophin molecule have been identified and studies in transgenic mdx mice have explored the importance of a number of these structural domains, the resulting modified dystrophin protein products that have been developed so far are only partially characterised in relation to their structure and function in vivo...
July 31, 2016: Human Gene Therapy Methods
Junling Zhao, Kasun Kodippili, Yongping Yue, Chady H Hakim, Lakmini Wasala, Xiufang Pan, Keqing Zhang, Nora N Yang, Dongsheng Duan, Yi Lai
Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemma is essential for dystrophin to protect muscle from contraction-induced injury. It has long been thought that membrane binding of dystrophin depends on its cysteine-rich (CR) domain. Here, we provide in vivo evidence suggesting that dystrophin contains three additional membrane-binding domains including spectrin-like repeats (R)1-3, R10-12 and C-terminus (CT). To systematically study dystrophin membrane binding, we split full-length dystrophin into ten fragments and examined subcellular localizations of each fragment by adeno-associated virus-mediated gene transfer...
July 4, 2016: Human Molecular Genetics
Bailey Miskew Nichols, Yoshitsugu Aoki, Mutsuki Kuraoka, Joshua J A Lee, Shin'ichi Takeda, Toshifumi Yokota
Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic diseases worldwide, caused by mutations in the dystrophin (DMD) gene. Exon skipping employs short DNA/RNA-like molecules called antisense oligonucleotides (AONs) that restore the reading frame and produce shorter but functional proteins. However, exon skipping therapy faces two major hurdles: limited applicability (up to only 13% of patients can be treated with a single AON drug), and uncertain function of truncated proteins. These issues were addressed with a cocktail AON approach...
2016: Journal of Visualized Experiments: JoVE
A I Esterhuizen, L J Greenberg, R Ballo, R G Goliath, J M Wilmshurst
Duchenne muscular dystrophy (DMD) is one of the most common and severe of the inherited dystrophies, with an incidence of 1 in 3 500 live, male births worldwide. Becker muscular dystrophy (BMD) has a lower incidence of 1:14 000 - 18 000 boys and a milder progression and longer life expectancy. Over the last two decades, better understanding of the underlying disease aetiology as well as major advances in medical technology have brought about significantly improved genetic diagnosis and clinical care for B/DMD patients...
June 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
Forum Kamdar, Daniel J Garry
Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies...
May 31, 2016: Journal of the American College of Cardiology
Ignazio Maggio, Xiaoyu Chen, Manuel A F V Gonçalves
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding DMD gene. The DMD gene, spanning over 2.4 megabases along the short arm of the X chromosome (Xp21.2), is the largest genetic locus known in the human genome. The size of DMD, combined with the complexity of the DMD phenotype and the extent of the affected tissues, begs for the development of novel, ideally complementary, therapeutic approaches. Genome editing based on the delivery of sequence-specific programmable nucleases into dystrophin-defective cells has recently enriched the portfolio of potential therapies under investigation...
2016: Genome Medicine
Leonela N Luce, Viviana Dalamon, Marcela Ferrer, Diana Parma, Irene Szijan, Florencia Giliberto
Dystrophinopathies are X-linked recessive diseases caused by mutations in the DMD gene. Our objective was to identify mutations in this gene by Multiplex Ligation Probe Amplification (MLPA), to confirm the clinical diagnosis and determine the carrier status of at-risk relatives. Also, we aimed to characterize the Dystrophinopathies argentine population and the DMD gene. We analyzed a cohort of 121 individuals (70 affected boys, 11 symptomatic women, 37 at-risk women and 3 male villus samples). The MLPA technique identified 56 mutations (45 deletions, 9 duplications and 2 point mutations)...
June 15, 2016: Journal of the Neurological Sciences
Nicholas P Whitehead, Min Jeong Kim, Kenneth L Bible, Marvin E Adams, Stanley C Froehner
Duchenne muscular dystrophy (DMD) is the most common and severe inherited neuromuscular disorder. DMD is caused by mutations in the gene encoding the dystrophin protein in muscle fibers. Dystrophin was originally proposed to be a structural protein that protected the sarcolemma from stresses produced during contractions. However, more recently, experimental evidence has revealed a far more complicated picture, with the loss of dystrophin causing dysfunction of multiple muscle signaling pathways, which all contribute to the overall disease pathophysiology...
2016: Rare Diseases
Jean-Baptiste Dupont
Despite the unprecedented beneficial effects of rAAV gene therapy in animal models of Duchenne muscular dystrophy (DMD), the need to inject large amounts of vector in vivo to improve phenotype raises obvious biosafety concerns. While rAAV vectors generally exhibit a good safety profile, specific pathological phenotypes such as those observed in dystrophin-deficient muscles may promote immunotoxic/genotoxic effects. Increasing the therapeutic index of rAAV in DMD muscles by reducing the effective dose could be a pivotal means of ensuring efficient clinical translation...
2016: Current Gene Therapy
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