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DMD 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
Svitlana Pasteuning-Vuhman, Johanna Boertje-van der Meulen, Maaike van Putten, Maurice Overzier, Peter Ten Dijke, Szymon M Kiełbasa, Wibowo Arindrarto, Ron Wolterbeek, Ksenia V Lezhnina, Ivan V Ozerov, Aleksandr M Aliper, Willem M Hoogaars, Annemieke Aartsma-Rus, Cindy J M Loomans
Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice...
October 12, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Juliette Ropars, Mathieu Lempereur, Sylvain Brochard, Carole Vuillerot, Vincent Tiffreau, Jean-Marie Cuisset, Yann Péréon, Fabien Leboeuf, Raphaël Gross, Ludovic Delporte, Yannick Delpierre
OBJECTIVE: The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). MATERIALS/PATIENTS AND METHODS: Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analyzed quantitatively and qualitatively...
September 2016: Annals of Physical and Rehabilitation Medicine
Stéphanie Fontaine Carbonnel, Pascal Rippert, Isabelle Poirot, Dominique Gachet, Capucine de Lattre, Carole Vuillerot
OBJECTIVE: Since 2005, in France, corticosteroid therapy is now widely used in Duchenne muscular dystrophy (DMD). This treatment has changed our practice of pediatric rehabilitation teams. We describe here our 10-year clinical experience in treating DMD patients by CS according to international guidelines i.e. prednisone 0.75mg/kg/day started from the plateau of motor function. MATERIALS/PATIENTS AND METHODS: We conducted a prospective study. Information was given on the expected effects and side effects...
September 2016: Annals of Physical and Rehabilitation Medicine
Valeria Ricotti, Matthew R B Evans, Christopher D J Sinclair, Jordan W Butler, Deborah A Ridout, Jean-Yves Hogrel, Ahmed Emira, Jasper M Morrow, Mary M Reilly, Michael G Hanna, Robert L Janiczek, Paul M Matthews, Tarek A Yousry, Francesco Muntoni, John S Thornton
OBJECTIVE: A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function...
2016: PloS One
Ilene L Hollin, Holly Peay, Susan D Apkon, John Bridges
Objective This study quantifies caregiver and patient preferences for a therapeutic agent with demonstrated pulmonary benefits for Duchenne muscular dystrophy (DMD). Caregivers and patient differences are also explored. Methods A best-worst scaling survey (BWS) was administered to caregivers and patients. Across 9 profiles, respondents selected the best and worst attributes. Utility scores were estimated using mixed logistic regression. Results Respondents indicated greatest preference for therapies that maintain their current level of cough strength for 10 years or for 2 years...
September 20, 2016: Muscle & Nerve
Juliette Ropars, Mathieu Lempereur, Carole Vuillerot, Vincent Tiffreau, Sylviane Peudenier, Jean-Marie Cuisset, Yann Pereon, Fabien Leboeuf, Ludovic Delporte, Yannick Delpierre, Raphaël Gross, Sylvain Brochard
The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group...
2016: PloS One
Shouta Miyatake, Yuko Shimizu-Motohashi, Shin'ichi Takeda, Yoshitsugu Aoki
Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects...
2016: Drug Design, Development and Therapy
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
Cuixia Tian, Brenda L Wong, Lindsey Hornung, Jane C Khoury, Lauren Miller, Jean Bange, Irina Rybalsky, Meilan M Rutter
Osteoporosis is a major problem in boys with Duchenne Muscular Dystrophy (DMD), attributable to muscle weakness and glucocorticoid therapy. Consensus regarding bone health assessment and management is lacking. Lumbar spine areal bone mineral density by dual-energy X-ray absorptiometry (DXA) is frequently the primary measure used, but has limitations for boys with DMD. We retrospectively studied 292 ambulant glucocorticoid-treated boys with DMD categorized by functional mobility score, FMS 1, 2 or 3. We assessed DXA whole body and lumbar spine areal bone mineral density and content Z-scores adjusted for age and height, lateral distal femur areal bone mineral density Z-scores, frequency of fractures, and osteoporosis by International Society for Clinical Densitometry 2013 criteria...
August 22, 2016: Neuromuscular Disorders: NMD
Claudia Godi, Alessandro Ambrosi, Francesca Nicastro, Stefano C Previtali, Corrado Santarosa, Sara Napolitano, Antonella Iadanza, Marina Scarlato, Maria Grazia Natali Sora, Andrea Tettamanti, Simonetta Gerevini, Maria Pia Cicalese, Clementina Sitzia, Massimo Venturini, Andrea Falini, Roberto Gatti, Fabio Ciceri, Giulio Cossu, Yvan Torrente, Letterio S Politi
OBJECTIVE: The aim of this study was to evaluate the usefulness of magnetic resonance imaging (MRI) in detecting the progression of Duchenne muscular dystrophy (DMD) by quantification of fat infiltration (FI) and muscle volume index (MVI, a residual-to-total muscle volume ratio). METHODS: Twenty-six patients (baseline age: 5-12 years) with genetically proven DMD were longitudinally analyzed with lower limb 3T MRI, force measurements, and functional tests (Gowers, 10-m time, North Star Ambulatory Assessment, 6-min walking test)...
August 2016: Annals of Clinical and Translational Neurology
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
Nicholas P Whitehead, Kenneth L Bible, Min Jeong Kim, Guy L Odom, Marvin E Adams, Stanley C Froehner
KEY POINTS: Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease that is commonly studied using the mdx mouse. The mdx diaphragm muscle closely mimics the pathophysiological changes in DMD muscles. mdx diaphragm force is commonly assessed ex vivo, precluding time course studies. Here we used ultrasonography to evaluate time-dependent changes in diaphragm function in vivo, by measuring diaphragm movement amplitude. In mdx mice, diaphragm amplitude decreased with age and values were much lower than for wild-type mice...
August 28, 2016: Journal of Physiology
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
John Cw Hildyard, Dominic J Wells
Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block...
2016: PLoS Currents
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
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