http://www.institut-myologie.org/anglais/ewb_pages/a/actu_news_myologie.phpMyology research highlights.fr-frhttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4227.phpLaminopathies comprise a group of inherited diseases with variable clinical phenotypes. They are caused by mutations in the lamin complexes (LMNA) of the nuclear envelope. An EU-funded study, EURO-Laminopathies, sought to identify the molecular mechanisms underlying these mutations in order to understand how their effect on lamins might reduce a cell's stress resistance. The study examined the molecular properties of lamin complexes and how these properties impact both disease and normal ageing. Led by Professor Roland Foisner of the Medical University of Vienna in Austria, the researchers found that lamins are responsible for producing new tissue-specific cells in adult organisms, and thereby play a key role in the maintenance and regeneration of high-turnover tissues such as skin and muscle. The findings have major implications for inherited disorders such as muscular dystrophy, cardiomyopathy, diabetes and premature aging. The researchers studied cells in culture and in mice and confirmed that lamin A is essential for the regulation of the cell cycle. They observed that lamin A was responsible for regulating the proliferation and differentiation of progenitor cells, which are similar to stem cells, in highly regenerative tissues such as skin and muscle.Thu, 13 Nov 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4227.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4226.phpA Foundation Building Strength (AFBS) is a non-profit organisation striving to stimulate, advance and move forward the science of treating the Nemaline Myopathies while supporting the community of Nemaline Myopathy (NM) with information, resources and solutions. The organisation has just announced its first request for proposals aimed at scientists who perform either basic science or clinical research related to Nemaline Myopathy. The objective of the Nemaline Myopathy research grant is to provide funding to investigators performing research that will i) advance the understanding of the pathogenesis of NM in order to design and optimize treatment and management strategies ii) explore the effectiveness of potential therapies and/or treatments for NM and iii) investigate ways to improve muscle strength and quality of life for those living with NM by conducting clinical trials. Funding for the award period will be made for up to $75,000 per year, with the expectation of renewing funding for additional year(s) at an increased level. The deadline for applications is January 31st, 2009.> For further information about the organization> To download the grant application and information formThu, 13 Nov 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4226.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4225.phpIn Duchenne muscular dystrophy mutations in dystrophin provoke the loss of dystrophin and the entire dystrophin-glycoprotein complex (DGC) from the sarcolemma. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. Sarcospan is a component of the DGC that forms a tight subcomplex with the sarcoglycans. To determine the role played by sarcospan in stabilizing the membrane complex Dr. Peter and colleagues examined the effects of increasing sarcospan expression in dystrophin deficient mdx mice. The increase did not improve the dystrophin–glycoprotein interaction, but sarcospan stabilized the sarcolemma by increasing levels of the utrophin-glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin, thus improving muscular dystrophy in these mice. The extra sarcospan prompted higher levels of utrophin in the cell, but did not increase its transcription. These data highlight the significance of protein stability in the prevention of muscular dystrophy and may have great potential for human therapeutics.Thu, 13 Nov 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4225.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4223.phpAccording to a new University of Iowa study led by Dr. Yvonne Kobayashi, Viagra, a drug designed to increase blood flow, can overcome the signalling defect and relieve exercise-induced fatigue associated with muscular dystrophies. Muscular dystrophy (MD) refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness. Using animal models, the researchers showed that if an enzyme called neuronal nitric oxide synthase (nNOS) is not present at its normal location on the muscle membrane, then blood vessels that supply active muscles do not relax normally and the animals experience post-exercise fatigue. Early clues about the role of nNOS came from observing that the significant inactivity of dystrophic mice following mild exercise was very similar to the fatigue experience by muscular dystrophy patients after a short period of walking. Working with mouse models of muscular dystrophy and normal mice engineered to lack nNOS, showed that mice with misplaced or missing nNOS exhibited prolonged fatigue after mild exercise. The mice without nNOS have normal muscles and can exercise quite well, but after just mild exercise, they had an intense fatigue response. The signalling pathway probably maintains blood flow into the muscle during exercise and keeps the blood flow going after exercise. However, when nNOS is missing or mislocalized, this pathway breaks down. To determine if nNOS was affected in humans with muscular dystrophy, muscle biopsies from 425 patients with many different forms of muscular dystrophy were examined. It was found that nNOS was missing or reduced in most cases, suggesting a common mechanism of fatigue. The enzyme nNOS makes a signalling molecule called nitric oxide, which stimulates production of a chemical called cGMP that causes smooth muscle around blood vessels to relax thereby increasing blood flow. This nitric oxide signalling pathway is turned off by phosphodiesterase (PDE), an enzyme that breaks down cGMP. Viagra inhibits PDE and prolongs the existence of the cGMP molecules that promote blood vessel dilation. The study is published in Nature Advance Online Publication.Tue, 04 Nov 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4223.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4220.phpNeuromuscular junction (NMJ) formation requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signals are transduced from agrin to MuSK remains unclear. Researchers from the Medical College of Georgia (MCG) have now discovered that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, is expressed specifically in myotubes and binds to neuronal agrin. Its expression enables agrin binding and MuSK signaling in cells that otherwise do not respond to agrin. LRP4 and MuSK thus become major components of the receptor needed for the muscle cell to receive the message agrin is sending. The authors have solved a long-standing enigma by demonstrating that LRP4 forms a bridge between agrin and MUSK. The agrin-MuSK signaling pathway has been implicated in muscular dystrophy. Some studies have suggested that a mutant MuSK may be the cause of muscular dystrophy and autoantibodies to MuSK have been found in the blood of some patients. Now that the critical role of LRP4 is known, the authors will examine patient samples where they suspect they will also discover mutant forms and autoantibodies to it as well. The role of LRP4 in later development and maintenance of the neuromuscular junction will also be investigated.Mon, 27 Oct 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4220.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4219.phpAcceleron Pharma, Inc., a biopharmaceutical company developing novel therapeutics that modulate the growth of tissues including bone and muscle, will initiate a Phase 1 clinical study of ACE-031, its lead compound for treating diseases involving the loss of muscle mass and function. ACE-031, a protein therapeutic based on the activin receptor type IIB (ActRIIB), is the first of several compounds Acceleron is developing for the treatment of diseases involving the loss of muscle mass, strength and function. ActRIIB binds to myostatin (GDF-8) and other negative regulators of muscle mass and strength. Over-expression of myostatin has been shown to cause a loss in muscle mass and strength, and inhibition of myostatin results in the selective increase in skeletal muscle mass and strength. In preclinical models, ACE-031 increased skeletal muscle mass and strength in disease models of amyotrophic lateral sclerosis (ALS), muscular dystrophy, glucocorticoid-induced muscle loss and age-related muscle loss (sarcopenia). ACE-031 offers the potential for an entirely new type of therapy for the treatment of various muscle wasting conditions. The Phase 1 trial is a randomized, placebo-controlled single-dose, dose-escalating study to evaluate the safety and pharmacokinetics of ACE-031. This clinical trial is the first-in-human study in the global development of ACE-031 and will be conducted in Canada.Mon, 27 Oct 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4219.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4218.phpThe European Medicines Agency (EMEA) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending orphan medicinal product designation for AVI-4658, AVI BioPharma's Drug for Duchenne Muscular Dystrophy (DMD). Furthermore, the Company received notification from the Gene Therapy Advisory Committee (GTAC) in the UK granting provisional approval for the Company's planned clinical trial for systemic delivery of AVI-4658 to treat DMD. These events add further momentum to the development of AVI's portfolio of exon skipping drugs to treat this devastating and debilitating disease. AVI BioPharma is currently engaged in a clinical trial at the Imperial College of London where patients with DMD are receiving a single-dose, intramuscular (IM) administration of AVI-4658. This study is being conducted in collaboration with the United Kingdom-based MDEX Consortium. AVI-4658 is designed to skip exon 51 of the dystrophin gene, thus repairing the mutated reading frame in the mRNA sequence coding for dystrophin, a vital protein that is absent or virtually absent in boys with DMD. By skipping this exon, a truncated, yet functional, form of the dystrophin protein is produced and this could ameliorate the disease process, potentially prolonging and improving the quality of life in these patients.Mon, 27 Oct 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_4218.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4188.phpSpinal muscular atrophy (SMA) is an inherited genetic disorder caused by a defective gene, SMN1, which fails to produce sufficient amounts of a key protein, called SMN (survival motor neuron), needed for normal motor neuron development. This cellular defect is the underlying basis for the loss of control of muscles in the limbs, neck and chest in these patients. In its most severe form, SMA often leads to death in infancy, and there is currently no treatment or cure. The genetic capability to produce SMN protein is not completely eliminated in SMA patients due to the unique presence of a back-up gene, SMN2. Therefore, drugs that increase SMN protein levels in motor neurons are expected to modulate the severity of the disease. In this new study, researchers detail the identification and characterization of a protein that offers a novel biological mechanism for designing new SMA therapeutics. They found that the substance targets a normal cellular protein, DcpS (human mRNA decapping scavenger enzyme), involved in mRNA metabolism whose inhibition causes increased SMN expression. The finding could help guide the development of the first effective drugs for treating SMA and also lead to second-generation drugs targeting this enzyme. These data provide new insight into the physiological mechanisms that can increase SMN expression and will advance the search for potential treatments.Mon, 13 Oct 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4188.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4187.phpA recent study carried out by Dr. James Chelly from the Cochin Institute in France, has identified highly precise, exon-level variants in DNA samples from affected individuals and carriers of a range of human diseases including muscular dystrophies and cystic fibrosis. Current techniques used to identify mutations associated with muscular dystrophies and cystic fibrosis, which include a wide range of point mutations and copy number deletions and duplications, rely on PCR-based targeted approaches such as semi-quantitative fluorescent PCR (QF-PCR) and multiplex ligation-dependent probe amplification (MLPA). However, these techniques are time-consuming, laborious, exhibit a significant false negative rate and are often limited to a small number of exonic regions. To overcome these limitations, the authors used the Roche NimbleGen multiplex comparative genomic hybridization (CGH) technology to design and build custom, targeted CGH arrays which interrogated 158 exons from a set of 8 genes associated with Duchenne and Becker muscular dystrophy (DMD), cystic fibrosis (CF), and sarcoglycanopathies (SG). They accurately detected copy number abnormalities in DMD, SGs, and CF genes down to about 1.5 kb resolution in 50 samples from hemizygous affected individuals and heterozygous carrier females. In addition, even heterozygous deletions and duplications of only one exon, as well as mosaic deletions were detected by this CGH approach. This is a very powerful method that allows simultaneous analysis of a large number of exons and offers the possibility to investigate a large number of samples. These data demonstrate that oligonucleotide-based array CGH is sensitive and robust, even at the resolution of single exons.Mon, 13 Oct 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4187.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4186.phpSanthera Pharmaceuticals is a Swiss specialty pharmaceutical company focused on the discovery, development and marketing of small-molecule pharmaceutical products for the treatment of severe neuromuscular diseases. The company has recently published study results that support the potential efficacy of Santhera's lead compound SNT-MC17/idebenone in Duchenne Muscular Dystrophy. The authors describe the results of a very long-term, blinded and placebo-controlled study in the dystrophin deficient mdx mouse, a well-established animal model for Duchenne Muscular Dystrophy. The main finding of the study is that presymptomatic-initiated and long-term idebenone treatment significantly prevented cardiac diastolic dysfunction, preserved cardiac systolic contractile reserve, thus blocking the development of lethal acute heart failure during a dobutamine-mediated stress protocol, reduced cardiac inflammation and fibrosis, and improved voluntary running performance in the mdx mouse model. The beneficial effects of idebenone have been attributed to its ability to improve mitochondrial respiratory chain function and to reduce oxidative stress, pathways that have been implicated in the pathophysiology of dystrophin deficient muscular dystrophy. The authors conclude that early-initiated and long-term treatment of mdx mice is cardioprotective and improves exercise performance. Santhera's recent Phase II proof-of-concept trial with SNT-MC17/idebenone in a population of young Duchenne Muscular Dystrophy patients showed positive efficacy on cardiac and respiratory functions. A Phase III development program, planned to commence in the first half of 2009, is currently under discussion.Mon, 13 Oct 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4186.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4185.php Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common, disabling and lethal muscle disease. Myostatin has been extensively documented as a negative regulator of muscle growth. Myostatin blockades therefore offers an effective strategy for treating a number of degenerative muscle diseases, including sarcopenia and muscular dystrophy. In this study, Dr. Chunping Qiao and colleagues investigated whether gene delivery of myostatin inhibitors, specifically, the propeptide, could improve muscle growth and ameliorate the pathology in the DMD large animal model golden retriever muscular dystrophy (GRMD) dogs. They delivered the AAV8 vector encoding myostatin propeptide (AAV-MPRO) gene via hydrodynamic limb vein injection in the hindlimb of 3-month-old normal dogs, weighing 6.3 kg and 9.7 kg. The vector was delivered into one limb, the contralateral serving as a control. No vector-related adverse event was observed during and after injection. AAV vector DNA and MPRO gene expression were detected by quantitative PCR, Western blot, and immunofluorescent staining of muscle biopsies. Over-expression of MPRO resulted in enhanced muscle growth without a CTL immune response, as evidenced by larger myofibres in multiple muscles, increased muscle volume via magnetic resonance imaging (MRI), and the lack of CD4 and CD8 T-cell infiltration in the vector-injected limbs. These preliminary data demonstrate that delivering AAV vector encoding myostatin propeptide gene into normal dogs induces muscle hypertrophy and increases their myofibre size, paving the way for future clinical studies.Fri, 03 Oct 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4185.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4178.phpThe NIH has awarded $9 million to launch a unique collaboration of researchers, clinicians, patients, government research agencies and pharmaceutical/biomedical companies to study the causes and potential treatments for facioscapulohumeral muscular dystrophy (FSHD). The award will create the first Senator Wellstone Muscular Dystrophy Cooperative Research Center (MD CRC) to focus on FSHD. This center for excellence in muscular dystrophy will be headquartered at the Boston Biomedical Research Institute (BBRI) and will be the first ever in New England. It will also be the first center to focus on FSHD, the second most prevalent adult muscular dystrophy. The center will be directed by Dr. Charles Emerson, president of BBRI and co-directed by Dr. Louis Kunkel, a professor of Genetics and Pediatrics at Harvard Medical School, director of the Genomics Program at Children's Hospital and an investigator with the Howard Hughes Medical Institute. This prestigious research center is hoped to rapidly bring discoveries from bench to bedside.Mon, 29 Sep 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4178.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4177.phpSatellite cells reside as quiescent cells underneath the basal lamina that surrounds muscle fibres and respond to damage by producing myoblasts that fuse with myofibres and replenishing the population of satellite cells. For years, many researchers have suspected that the satellite cell population included muscle stem cells. The identification of a true stem cell has important clinical applications. However, analyzing the specific properties of a single cell is a technically challenging and laborious task. To overcome these obstacles, a team of researchers from the Stanford University School of Medicine led by Dr. Helen Blau has isolated satellite cells from mice genetically engineered to express luciferase. Using a novel non-invasive in vivo bioluminescence imaging technique developed at Stanford they were able to follow their fate after transplantation into normal mice. Transplantation of a single luciferase-expressing muscle stem cell into the muscles of mice led to extensive proliferation which contributes to muscle fibres. Interestingly, some cells also expressed a satellite cell specific marker, Pax-7, indicating self-renewal of the original cell and confirming that it was a stem cell. Furthermore, they show that the dynamics of muscle stem cell behaviour during muscle repair can be followed in a manner not possible using traditional retrospective histological analyses. By imaging luciferase activity, real-time quantitative and kinetic analyses show that donor-derived muscle stem cells proliferate and engraft rapidly after injection until homeostasis is reached. The persistence of stem cell function was demonstrated by inducing repeated cycles of muscle degeneration/regeneration, which generated massive waves of cell proliferation. This is the first study to confirm that satellite cells harbour an exclusive muscle stem cell. Identifying and isolating such a cell in humans would have profound therapeutic implications for disorders such as muscular dystrophy, injury and muscle wasting due to aging, disuse or disease.Mon, 29 Sep 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4177.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4173.phpIn primary myopathies muscle fibre degeneration is accompanied by inflammation, sclerosis, reduced microvessel density and fat infiltration. These phenomena hinder drug, gene or cell therapy, thus excluding treatment in the majority of Duchenne muscular dystrophy patients. In this study, Dr. Cesare Gargioli and colleagues aimed to bypass this obstacle by using systemic cell therapy. They engineered tendon fibroblasts with vectors expressing either angiogenic factors (Placenta derived Growth Factor: PlGF) or metalloproteinases (MMP9) and injected them into the muscles of dystrophic (a-sarcoglycan-/-) mice more than 12 months. The results show that cells expressing both PlGF and MMP9 restored a vascular network and reduced connective tissue deposition when directly injected into old dystrophic muscle. When wild type mesoangioblasts were injected into the femoral artery of dystrophic mice previously treated with PlGF/MMP9 expressing cells, they colonized downstream muscles and generated a-sarcoglycan expressing fibres with an efficiency ten times higher than that observed in muscles pre-treated with control cells and comparable to that observed in young dystrophic muscle. The authors are aware that for the strategy to be applicable in humans, further improvements are warranted. Nevertheless, these data open the possibility of extending cell therapy to patients who are presently considered untreatable.This study was partly funded by the AFM.Tue, 09 Sep 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4173.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4172.phpThe motor neuron disease Spinal Muscular Atrophy (SMA) is a devastating genetic motoneuron disease without effective treatment. It is the second most common genetic disorder leading to death in childhood. Patients with SMA exhibit muscle weakness and hypotonia. A potential therapy for SMA could be stem cell transplantation both through neuron replacement and/or neuroprotective effect. Dr. Giacomo Comi and colleagues, at the University of Milan, have obtained results using a mouse model of SMA suggesting that spinal cord neural stem cells (NSCs) might be a possible treatment for individuals with SMA. To determine the therapeutic potential of NSC effects on the SMA phenotype, NSCs from mice expressing green fluorescent protein only in motor neurons were intrathecally transplanted into a mouse model of SMA. The transplanted cells developed into a small number of motor neurons and the treated mice showed improved muscular function and increased lifespan, compared with untreated mice. Further gene expression analysis indicated that the major effect of NSC transplantation was that the transplanted cells improved the survival and function of the motor neurons already in the mice, similar to that observed in normal motor neurons. The data presented in this study provide the first evidence that NSC derived may exert a significant therapeutic effect on the SMA phenotype, opening the path for the development of a combined cellular and molecular therapy for this disease.Tue, 09 Sep 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4172.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4168.phpMyasthenia gravis (MG) is a chronic neuromuscular disease leading to varying degrees of skeletal muscle weakness. Some of the symptoms of the disorder include weakness of the eye muscles, difficulty in swallowing and slurred speech. It is caused by the failure of neuromuscular transmission mediated by autoantibodies. About 80 to 85% of patients with MG have autoantibodies against acetylcholine receptors (AChR). A subset of patients with MG does not have antibodies to the acetylcholine receptor that can be detected with routine diagnostic testing (seronegative MG, SNMG). MuSK antibodies are only present in some of these patients, and the number varies worldwide. Patients who have seronegative MG and who have antibodies against MuSK can be referred to as having MuSK-MG to distinguish them from patients who have anti-AChR antibodies (AChR-MG). MuSK-MG can be associated with severe bulbar and facial weakness and tongue atrophy. In this paper, Dr. Maria Leite and colleagues explored the possibility that studying antibody binding to tightly clustered AChRs might demonstrate antibody binding to AChRs for patients who were antibody negative by the traditional assay. Their previous research indicated that some SNMG plasmas contain factors that inhibit AChR function. The effect was acute and reversible with washing. This led them to hypothesize that there might be antibodies that did not bind tightly to the AChR and thus were not able to bind to single AChRs floating in solution. These weakly binding antibodies might be able to bind to AChR that are closely packed, as has been demonstrated on the endplate membrane. In this study, they expressed rapsyn along with AChRs in cultured cells. Rapsyn cross-links AChRs producing clusters of closely packed AChRs. They found that more than 50% of the sera from SNMG patients bound to AChR clusters. Therefore about half of the patients who have SNMG when tested with traditional assay techniques may have anti-AChR antibodies that bind weakly to AChRs. The data from this study have important clinical and technical implications for providing the basis of a new assay to detect AChR and other antibodies in myasthenia gravis.Sun, 24 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4168.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4167.phpThe 6th Annual International Duchenne Conference will take place in London from Friday 31st October to Sunday 2nd November. This is the ideal opportunity to meet leading international Duchenne scientists at the cutting edge of new research and to develop understanding on how to ensure the best medical care. Information about new clinical trials will also be available. The conferences presented will help to raise awareness of Duchenne and give you the chance to meet other families in your region and share experiences.Sun, 24 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4167.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4165.phpResearchers from the Harvard Stem Cell Institute (HSCI) have produced a robust new collection of disease-specific stem cell lines, all of which were developed using the new induced pluripotent stem cell (iPS) technique. The new iPS lines, developed from skin and bone marrow cells of patients ranging in age from one month to 57-years old will be deposited in a new HSCI iPS Core laboratory being established at Massachusetts General Hospital (MGH) and will be made available to researchers worldwide. The cell lines the researchers produced carry the genes or genetic components for 10 different diseases, including Parkinson's Disease, Type I diabetes, Huntington's Disease, Gaucher's Disease, and two forms of Muscular Dystrophy. The researchers hope to add other disease-specific lines to the depository. This marks an important achievement and a very significant advance for patients suffering from degenerative diseases. The most immediate application of the disease-specific stem cells will be to reproduce human diseases in culture to explore their development in different tissues. The technique will even enable researchers to compare how the same disease varies among people, by generating disease-specific stem cell cultures from many individuals. These disease-specific iPS cells are invaluable tools that will allow to explore gene therapies for some conditions, and will aid in the development of drugs to slow or even stop the course of a number of diseases.Tue, 19 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4165.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4154.phpPompe disease is a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase (acid maltase). The disease presents as a spectrum, the most severe being the classic infantile form. Infants present in the first months of life with hypotonia, motor delay and cardiac hypertrophy. Without treatment, most die within the first year of life. Pompe disease may also present as a proximal myopathy in children and adults. The heart is usually not involved. Weakness of skeletal muscles leads to mobility problems and respiratory failure. In recent years, enzyme replacement therapy has been shown to significantly reduce symptoms of the disease, provided it is administered as soon as possible. The efficacy of this therapy has been widely demonstrated in the infantile form but the results of clinical trials in older children and adults are currently awaited. In the present study, Dr. van Capelle and colleagues describe data from three patients with different severities of Pompe disease who were treated by enzyme replacement therapy and followed for 8 years. The two severely affected patients became more confident about their physical condition and more independent in daily life activities. The third and least affected patient showed increasing improvement in muscle strength and function, reaching normal values for age for all muscle groups. These observations highlight the importance of long-term follow-up and early treatment in Pompe disease and provide an important guideline for the broader application of enzyme replacement therapy. Mon, 11 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4154.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4153.phpScientists at Harvard University and Columbia University have converted skin cells from an 82-year-old woman with amyotrophic lateral sclerosis (ALS) into stem cells that formed motor neurons with the same genetic make up as the patient. The breakthrough opens the possibility of modeling a patient's specific disease outside of the patient, to improve investigation and drug screening, and perhaps even to develop new neurons to replace the damaged ones in the patient. ALS, also known as Lou Gehrig's disease, is a progressive degenerative disease that attacks the motor neurons in the spinal cord, leading to paralysis of limbs and respiration. Induced pluripotent stem cells (iPS cells) were generated from fibroblasts taken from the skin of an 82-year-old woman with a familial form of ALS. The patient-specific iPS cells behaved like embryonic stem cells and differentiated successfully into motor neurons. Recent studies have shown it is possible to reprogram human fibroblasts and return them to a pluripotent state, where they become stem cells that can be coaxed into producing a range of other cells. However, this is the first study to show it is possible to do this with the skin cells of an elderly patient with chronic disease. Despite these breakthrough results further studies are warranted because the cells are only useful if they are exactly the same as the ones causing the disease in the patient, partial replicates would be of little use. Sun, 03 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4153.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4151.phpDr. Giulio Cossu from the Milan University and colleagues have developed a new cellular treatment that provides hope for people suffering from advanced forms of muscular dystrophy. Sclerosis and reduced microvessel density characterize advanced stages of muscular dystrophy and hamper cell or gene delivery, precluding treatment of most individuals with Duchenne muscular dystrophy. In this study, modified tendon fibroblasts expressing an angiogenic factor and a metalloproteinase have been successfully tested in aged dystrophic mice, allowing to restore a vascular network and reduce collagen deposition. The modified fibroblasts were injected into muscles where they destroy the fibrous sclerotic tissue by reducing excess collagen deposits produced by scarring and restore a vascular network in the tissue. Once the fibrous tissue was destroyed, the researchers then treated the underlying problem using mesoangioblasts. Although mesoangioblasts treatments have been very successful in animals at an early stage of the disease, advanced sufferers have previously been unable to benefit due to the fibrous tissue created by scarring. This dual cellular treatment technique using modified fibroblasts and mesangioblasts has been successfully achieved in mice at an advanced stage of this disease as well as in young mice. Although technical problems remain to be resolved these data open the possibility of extending new therapies to currently untreatable individuals.Sun, 03 Aug 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4151.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4148.phpGlycogen storage disease type V, also known as McArdle's disease is an autosomal recessive disorder caused by mutations in the gene that encodes myophosphorylase, an enzyme that is essential for glycogenolysis. Exercise intolerance usually develops during childhood in patients with McArdle's disease, along with pain, cramps, and fatigue in exercised muscle. These symptoms are more likely to be induced by brief, intense activities but can also occur after prolonged, low-intensity exercises. Severe muscle damage can lead to myoglobinuria and renal failure. Many patients note a "second-wind" phenomenon, whereby exercise becomes more easily tolerated after approximately 10 minutes of continued activity. This phenomenon is attributable to higher extramuscular fuel delivery to contracting muscle that partially rescues substrate-limited oxidative metabolism. In the present study Dr. Susanne Andersen and colleagues investigated whether ingesting a low dose of sucrose just before exercise would increase the availability of glucose to muscles, thus improving exercise tolerance. They aimed to achieve the benefit of sucrose administration while reducing caloric intake and to make treatment more convenient to patients by decreasing the time between sucrose ingestion and exercise. To this end, six patients were blinded to treatment and tested after ingestion of either 75 g of sucrose or a placebo 40 minutes before exercise or 37 g of sucrose or a placebo 5 minutes before exercise. Treatment effectiveness was analyzed by monitoring heart rate and perceived exertion during exercise. In all patients, sucrose ingestion 5 minutes before exercise alleviates the muscle symptoms and abolishes the second-wind phenomenon that occur during the early stages of exercise, when patients are prone to muscle injury. Compared to the 75 g dose of sucrose 40 minutes before exercise, the lower dose of sucrose was superior in providing an improved and prolonged effect on exercise tolerance in McArdle patients. Pre-exercise sucrose ingestion is not a perfect answer to McArdle disease because of the potential for causing weight gain and for potentiating the early onset of diabetes mellitus. However, until better treatments become available, the oral ingestion of sucrose before exertional activity is a reasonable approach to the management of this difficult myopathy. Tue, 15 Jul 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4148.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4147.phpDuchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy that is characterized by rapidly progressing muscle degeneration. The disease is caused by a genetic mutation for which there is currently no cure. Research by Dr Amy Wagers and her team at Harvard University has demonstrated for the first time that transplanted muscle stem cells can both improve muscle function in a mouse model of DMD and replenish the stem cell population for use in the repair of future muscle injuries. The study was designed to test the concept that skeletal muscle precursor (SMP) cells could function as adult stem cells and that transplantation of these cells could both repair muscle tissue and regenerate the stem cell pool. The data from this new study demonstrate that regenerative muscle stem cells can be distinguished from other cells in the muscle by unique protein markers present on their surfaces. The authors used these markers to select stem cells from normal adult muscle and transferred the cells to diseased muscle of mdx mice, which carry a mutation in the same gene affected in human DMD. When engrafted into muscle of mdx mice, purified SMPs contributed to up to 94% of muscle fibers, restoring defective dystrophin gene expression and significantly improving muscle structure and contractile function. Furthermore, the transplantation of the healthy stem cells replenished the formerly diseased stem cell pool, providing a reservoir of healthy stem cells that could be re-activated to repair the muscle again during a second injury. This study will lead to other studies that will identify pathways that regulate these muscle stem cells in order to determine ways to boost the normal regenerative potential of these cells. These could include drug therapies or genomic approaches. Although stem cell technology is still in it's in infancy, this study is another step towards developing this technology into a viable treatment for people with muscle disease.Tue, 15 Jul 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4147.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4141.phpDuchenne muscular dystrophy (DMD) leads to progressive deterioration in skeletal and cardiac muscle function. It has been hypothesized that the development of ventricular dysfunction associated with DMD can be altered by steroid treatment. Previous studies have shown that both load dependent and load independent measures of cardiac function can be preserved with steroid treatment. Dr. Larry Markham and colleagues have retrospectively reviewed a cohort of DMD boys undergoing cardiac evaluation before and after steroid treatment to determine the benefit of steroid treatment on the development of ventricular dysfunction in DMD. Basic medical characteristics and serial echocardiographic measures were also obtained. The data suggest that the progressive decline in cardiac function of DMD patients can be altered by steroid treatment. This study confirms the link between age and ventricular dysfunction and shows that if corticosteroid treatment is initiated prior to echocardiographic evidence of ventricular dysfunction, there is a significant beneficial effect on the anticipated development of ventricular dysfunction. Despite these observations, the authors highlight that long-term, randomized controlled clinical trails are warranted to reply to many unanswered questions.Mon, 07 Jul 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4141.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4140.phpLaminopathies comprise a group of inherited diseases with variable clinical phenotypes. They are caused by mutations in the lamin complexes (LMNA) of the nuclear envelope. Prominent features of these human disorders are muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria. Most of these diseases have postnatal onset, progressively developed during childhood or adolescence. Early onset at birth or during infancy has rarely been reported. In this paper, Dr. Susana Quijano-Roy and colleagues report for the first time, the involvement of a nuclear envelope protein in a congenital muscular dystrophy (CMD). They describe the clinical, morphological and genetic characteristics in 15 unrelated LMNA mutated children affected with a distinct and early progressive form of muscular dystrophy. Mild-to-severe dystrophic changes were observed in many of the biopsies, serum CK level was generally increased and there was a fairly rapid disease progression. Two clinical phenotypes were evident: a subgroup of patients with severe weakness and minimal or absent motor development and a larger subgroup with milder disease who developed dropped-headed syndrome after acquiring head control. LMNA gene screening identified heterozygous de novo LMNA mutations in all patients. Dominant de novo mutations in the LMNA gene can be associated with a severe progressive myopathy with presentation in the first year of life, associated with a distinct pattern of weakness, invariable respiratory insufficiency and risk for heart rhythm disturbances. The authors suggest that this early onset phenotype best be classified as a CMD, thus further increasing the spectrum of laminopathies. This study was partly supported by the AFM.Mon, 07 Jul 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4140.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4130.phpLimb-girdle muscular dystrophy (LGMD) type 2D is characterized by skeletal muscle weakness and results from mutations occurring in the alpha-sarcoglycan gene. Localized in the sarcolemma, the sarcoglycans (alpha, beta, gamma, delta) are a subcomplex of the dystrophin-associated proteins (DAP). Alpha-sarcoglycan (alpha-SG) deficiency is the most common form of sarcoglycan-LGMD and no therapeutic treatments are currently available. The alpha-SG mouse model provides an opportunity to test translational treatment approaches. Prior studies have suggested that AAV-mediated alpha-SG gene transfer could not sustain expression because of transgene toxicity, potentially precluding clinical gene transfer for LGMD2D. In this paper, Dr. Rodino-Klapac and colleagues describe in vivo studies comparing alpha-SG gene expression from either the ubiquitously expressed cytomegalovirus (CMV) promoter, or muscle specific promoters that included desmin, muscle creatine kinase (MCK), and its further modification, truncated MCK (tMCK) in the alpha-SG KO mouse in the context of rAAV gene delivery. The tibialis anterior (TA) muscle of 4-6 week old alpha-SG KO mice were injected with rAAV1.alpha-SG (CMV, MCK, DES promoter) at low (3 x 109 vg) and high (3 x 1010 vg) doses. Sustained gene expression was observed irrespective of promoters at 6 and 12 weeks post gene transfer. Quantitation of alpha-SG gene expression by fiber counts yielded similar levels of myofiber transduction for CMV and MCK at the 6-week high dose, 61.4% versus 64.4% respectively. However, alpha-SG expression using the DES promoter was significantly lower at the high dose with 34% of the myofibres transduced. Similar levels of expression were seen at the 12 week time point for MCK and DES, while CMV exhibited a 25% reduction in expression. These data demonstrate sustained and robust gene expression for as long as 3 months using AAV1, with no reduction in expression using the muscle specific MCK promoter. This is well beyond the time at which transgene cytotoxic effects were previously reported using rAAV2 CMV.alpha-SG. Mononuclear cell analysis showed no evidence of infiltrating B or T cell subsets or macrophages. These findings enhance the possibility for gene therapy as a potential treatment option for LGMD2D.Mon, 23 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4130.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4129.phpThe largest multicenter study, led by Dr. William J. Groh at the Indiana University School of Medicine, has identified risk factors that can lead to sudden death for adult patients with myotonic dystrophy type 1, the most common form of muscular dystrophies seen in adults. Over 10 years, neurologists and cardiologists assessed 406 adult patients, from 23 neuromuscular disease clinics in the United States, with genetically confirmed myotonic dystrophy type 1 using clinical history, genetic assessment and electrocardiograms (ECG) to determine the risk factors that cause arrhythmias and sudden cardiac death. Sudden death is defined as death that occurs in a stable patient within one hour of the onset of symptoms. With this study, the authors have been able to identify the 20% of patients at highest risk of sudden death. Of those, one-third died of sudden death likely attributable to cardiac arrhythmia. In terms of predictors of sudden death, severe ECG abnormality and a clinical diagnosis of atrial tachyarrhythmia were found to be independent risk factors in this population. These risk factors will enable physicians to evaluate patients with myotonic dystrophy to hopefully prevent sudden death through further evaluation including electrophysiological studies (using catheters in the heart) or by surgically implanting a cardioverter-defibrillator. Another important outcome of the study was the discovery that pacemakers, commonly used to treat some forms of arrhythmia, did not help these patients prevent sudden death.Mon, 23 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4129.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4128.phpThere has been controversy whether oculopharyngodistal myopathy (OPDM) commonly seen in Japan is a distinct disease entity or a variant of oculopharyngeal muscular dystrophy (OPMD) initially described in French-Canadians and has since been reported in other ethnic groups. Both diseases have autosomal dominant inheritance and OPDM patients are clinically similar to OPMD with slowly progressive ptosis, ophthalmoplegia and dysphagia except that most of the former usually have distal as opposed to proximal weakness and most of them are genetically different from the latter. The authors report here the clinical and pathological changes in a Chinese family with OPDM. The main clinical features were ptosis, non-variable ophthalmoplegia, dysphagia, weakness and atrophy of facial and distal limb muscles. Serum CK activity was elevated and EMG showed myopathic changes with myotonic discharges. The main pathological changes included muscle fibre atrophy and hypertrophy, mild to moderate connective tissue proliferation, rimmed vacuoles within muscle fibres and tubular filament inclusions. Intranuclear tubulofilamentous inclusions with a diameter of approximately 20nm were also observed in the proband. The presence of these nuclear inclusions as an occasional phenomenon in OPMD warrants further investigation.Mon, 23 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4128.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4127.phpDeletions and point mutations in the dystrophin gene cause either the severe progressive myopathy Duchenne Muscular Dystrophy (DMD) or the milder Becker Muscular Dystrophy (BMD), depending on whether the translational reading frame is lost or maintained. Since internal in-frame deletions in the protein produce only mild myopathic symptoms it is possible, by skipping specific mutated exons, to restore a partially corrected phenotype. Exon skipping in the dystrophin mRNA can be achieved in the mdx mouse model by the use of chimeric antisense U1snRNA. In this study, Dr. Michela Denti and colleagues have designed and produced adeno-associated viral (AAV) vectors carrying antisense sequences against the splice junctions of dystrophin exon 23 of the mdx mouse and analyzed their activity in vivo. Local intramuscular delivery of AAV-antisense RNAs restores dystrophin and muscle strength. However, a single systemic injection into 6-week-old mice of an AAV1-U1 antisense RNA construct was effective in maintaining the physiological and molecular benefits for the entire life span of the animals. The long-term antisense efficacy was examined 18 months after the injection. Persistence of the transgene and sustained exon skipping sufficient to maintain an effective regeneration capacity and an almost normal muscle phenotype were observed. Furthermore, body-wide colonization was preserved because all the muscles districts analyzed showed dystrophin rescue until old age. The absence of immune response against the transgene, together with data coming from non human primates showing the persistence of expression from AAV vectors in muscle for more than 6 years, suggest that a long-term treatment for human DMD patients might be feasible.Mon, 23 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4127.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4094.phpPompe disease, also referred to as glycogen storage disease type II and acid maltase deficiency, is a rare, progressive, genetic muscle disorder caused by a deficiency of acid á-glucosidase (GAA, also referred to as acid maltose). This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, with cardiac, skeletal, and smooth muscle cells most seriously affected. Clinically, Pompe disease encompasses a range of phenotypes, the late-onset form being distinguished from the infantile-onset form by the absence of severe cardiac involvement. In late-onset Pompe disease, the frequency of cardiac involvement is unknown. The current study carried out by a team of Dutch researchers was designed to assess in detail, cardiac abnormalities with emphasis on left ventricular (LV) dysfunction and hypertrophy in adult patients with Pompe disease. All of the patients included in this study were submitted to a clinical examination, electrocardiography and two-dimensional echocardiography including contrast and tissue Doppler imaging. In addition, the first 20 patients underwent rest and low-dose dobutamine stress echocardiography. The authors found that only one wheelchair-bound patient dependent on assisted ventilation and known with fluid retention showed right ventricular and LV hypertrophy and one patient had a short PR-interval. Otherwise, none of the other patients demonstrated major cardiac abnormalities, indicating that echocardiographic screening does not appear to be effective. This is the first detailed study examining the cardiac involvement in a large, non-selected series of adult patients with Pompe disease.Fri, 13 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4094.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4093.phpFibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant disorder characterized by congenital malformation of the great toes and episodes of soft tissue swelling that lead to progressive heterotopic ossification. The genetic cause of FOP was recently discovered to be a recurrent missense activating mutation in the activin A type I receptor, a bone morphogenetic protein type I receptor in all classically affected individuals worldwide. Awareness of the classic clinical features of FOP prior to the appearance of heterotopic ossification can prompt early clinical diagnosis and confirmation through genetic testing, thus avoiding interventions that lead to irreversible iatrogenic harm. In this study, Dr. Frederick Kaplan and colleagues report for the first time that definitive molecular diagnosis of FOP is possible before the appearance of heterotopic ossification and even before the appearance of soft tissue lesions at early stages of disease development when misdiagnosis is most likely to occur. They evaluated 7 children for the diagnosis of FOP based on the presence of congenital malformations of the great toes with or without sift tissue swelling but without any evidence of heterotopic ossification. All of the children had been examined by orthopedic surgeons for their malformed great toes, but none of the surgeons were aware of the possible association of the toe malformation or if present, soft tissue lesions, with FOP. Radiographic skeletal surveys showed that all 7 children had ³2 associated radiographic features of FOP. Clinical genetic testing for the FOP mutation demonstrated that all 7 children had the classic FOP heterozygous missense mutation. The findings from this study have important implications for the diagnosis and long-term management of patients with FOP.Fri, 13 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4093.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_4016.php Spinal muscular atrophy (SMA) is a group of inherited diseases that cause progressive muscle degeneration and weakness, eventually leading to death. In last week's issue of Cell, Dr. Gideon Dreyfuss and his colleagues from the University of Pennsylvania School of Medicine reported that the effect of a deficiency in the SMN protein is not limited to motor neurons, indicating that SMA is a more general disorder. The SMN protein is essential for all cells, but reduced levels cause SMA. The reason for this cell-specific reduction remains to be elucidated. The role of SMN is to allow the assembly of small RNAs with specific proteins to form snRNPs (small nuclear ribonucleoprotein), which cooperate in most RNS splicing. When SMN levels are reduced, the biochemical balance needed to make the snRNP complexes for splicing RNA is impaired. The authors examined reduced SMN levels in vitro and in vivo and found that changes in levels of the snRNPs, as well as their spliced products, the mRNAs, were affected and produced abnormal mRNAs. These effects varied from tissue to tissue, suggesting that spinal muscular atrophy is a general disease of splicing. Based on the results of this study, a potential therapeutic approach for SMA would be the body-wide restoration of SMN levels. This study was partly funded by the Association Francaise contre les Myopathies.> Read the News ReleaseMon, 02 Jun 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_4016.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3912.phpIn studies with Drosophila (a strain of fruit fly), Dr. Nancy Bonini and her colleagues from the University of Pennsylvania discovered that a mutant RNA may be partially responsible for the neurodegeneration associated with Spinocerebellar ataxia type 3 (SCA3). SCA3 and the other polyglutamine diseases, like Huntington's disease and SCA1, are caused by genetic mutations consisting of an abnormally long number of triplet repeats. They are progressive diseases, with a correlation between the number of tripet repeats within the gene, the severity of disease and age at onset. For this set of diseases, the repeated nucleotide triplet is CAG, which encodes glutamine. The mutant version associated with human disease thus leads to a protein with an abnormally long glutamine string. The malformed protein is toxic to cells and causes neurological regeneration. Dr. Bonini and her team previously demonstrated that the gene that codes for the ataxin-3 protein, responsible for SCA3, can cause the disease in Drosophila. Previous studies had suggested that the disease is caused largely by the toxic polyglutamine protein encoded by the gene. In the present study reported in Nature, the researchers used Drosophila that had a mutation in the gene that is altered in human patients with SCA3. Drosophila exhibits neural degeneration and is a useful laboratory model for human SCA3. During these studies, the researchers discovered that activating the muscleblind (mbl) gene in the flies dramatically increased neural degeneration. Further analyses suggested that the mbl gene exacerbated the disease by interacting with RNA. When the human version of the mbl gene was inserted into the fly, neurodegeneration also deteriorated, providing a hint that mbl might also play a role in human polyglutamine diseases. To further implicate the RNA in disease progression, genetically engineered mutant flies that produced only the repetitive RNA but no aberrant protein were analyzed. This also caused significant neural degeneration, suggesting that the RNA on its own contributes to the pathology. These new results reveal that polyglutamine diseases like SCA3 and Huntington's disease may share the property of RNA toxicity with a different class of triplet repeat diseases, which includes myotonic dystrophy type 1 and fragile X-associated ataxia. Although the new studies suggest that the two classes of triplet repeat diseases are caused in part by RNA toxicity, these analyses indicate that the mechanism of RNA toxicity appears to be different for each class of disease. These findings suggest that treatments that target the abnormal RNA might offer double benefits by alleviating both the protein as well as RNA toxicity.Mon, 26 May 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3912.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3911.phpDr. Isabelle Richards and her colleagues have discovered a promising protein link to Limb-girdle muscular dystrophy (LGMD). They determined that individuals with LGMD are missing the c-FLIP protein that prevents muscle tissue loss. By targeting the cellular and molecular mechanisms responsible for producing this protein, scientists could develop new drugs to stop muscle wasting from LGMD and other conditions. To identify c-FLIP as a cause of LGMD, they used tissue from human biopsies to analyze the molecular pathways involved at each step of the disease progression. The authors found that the c-FLIP protein, which is responsible for blocking the death of muscle cells, is not produced as it should in patients with LGMD, and that the production of the c-FLIP protein is controlled by another protein called calpain-3. These data will provide more insight into the causes of LGMD and it is hoped that the findings of this research will lead to the development of new treatments to stop disease related muscle wasting. This discovery could also have implications for other types of muscular dystrophy and other situations involving the death of muscle tissue, such as long-term immobilization, denervation, aging, or cachexia. This work was funded by the AFM.Mon, 26 May 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3911.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3907.php A team of researchers led by Dr. Christine Des Rosiers from the Université de Montreal and the Montreal Heart Institute has recently shown that the administration of sildenafil (Viagra) protects the heart in mice with Duchenne muscular dystrophy. Sildenafil, a drug that has helped treat millions of impotent men, is known to inhibit the breakdown of cGMP (cyclic guanosine monophosphate), an enzyme that plays a key role in the dilation of blood vessels and is involved in the signaling pathways that help maintain a healthy heart. The choice of sildenafil was based on previous studies, which indicated that the hearts of dystrophic mice do not function as effectively and are more susceptible to stress-induced cell death. These studies suggested that this may be due to a decrease in the formation of cGMP. In the present study, two different approaches to increase cGMP production in the heart were employed, with the result that the hearts were able to function more effectively and were less susceptible to cell death. The mice were given doses of sildenafil equivalent to those administered to treat erectile dysfunction in men. The results showed that sildenafil significantly reduced the levels of damage to contracting heart muscle cells, compared to mice that were not administered the drug. The researchers also inserted a gene that increased cGMP production in the mice's heart cells, and found that this helped the animals to maintain normal cardiac function. Echocardiography and other assays showed that the heart function was better, suggesting that sildenafil had protected the heart muscle. The findings support existing theories that defects in the cGMP signaling pathway play an important role in the development of muscular dystrophy-related heart muscle problems. The authors believe their research suggests that the evolution of heart problems in muscular dystrophy patients could be prevented by partially restoring this pathway. Therefore, medications that increase cGMP signaling, such as sildenafil, may prove to be a novel therapeutic approach for the treatment of muscular dystrophy-related cardiomyopathies in the future. Future studies are warranted to determine whether these drugs could delay, prevent, or even reverse the onset of heart injury and loss of function in patients with Duchenne and Becker muscular dystrophies. The study findings are published in the online edition of the Proceedings of the National Academy of Sciences. > Read the press releaseTue, 20 May 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3907.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3902.phpThis MYORES Workshop will confront the latest models provided by a Multi-Organismic approache of muscle regeneration. We will discuss how this basic knowledge can support improvement of clinical trials in human.Thu, 15 May 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3902.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3899.phpDutch researchers from University Medical Centre Utrecht and the Hubrecht Institute have made a breakthrough in stem cell research by successfully growing stem cells from adult human hearts into new heart muscle cells. For a long time, researchers thought that the adult heart contained no stem cells. However, recent studies have revealed the existence of a small pool of potential stem cells in the adult heart. In this latest study, principal investigator Professor Doevendans and his team succeeded in isolating some of these stem cells from the material left over from open-heart surgery. Until now, scientists have relied on human embryonic stem cells to create heart stem cells. However, this method is not very productive, as many of the cells do not develop into muscle cells. Furthermore, isolating stem cells from embryos remains a controversial issue. The researchers cultured these cells in the laboratory and allowed them to develop. Almost all the cells developed spontaneously into mature heart muscle cells that contract rhythmically and respond to both electrical activity and adrenaline. These cultured heart muscle cells will enable scientists to study heart defects and test new medicines, and could one day be used to repair heart tissue which has been damaged during a heart attack. The findings are published in the latest issue of the journal Stem Cell Research.Sun, 27 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3899.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3897.phpPTC Therapeutics has started an international pivotal trial of PTC124 in patients with Duchenne or Becker muscular dystrophy due to a nonsense mutation. The primary objective of this registration-directed Phase IIb trial is to demonstrate the efficacy of PTC124 as measured by improvements in the walking ability of patients with this progressive genetic disease. In this double-blind study, patients will be randomized to receive placebo, or one of two dose levels of PTC124, three times per day. Eligible patients will be boys with nonsense-mutation-mediated Duchenne or Becker muscular dystrophy (DMD/BMD) who are at least five years of age and are able to walk at least 75 meters or approximately 80 yards in six minutes. PTC expects to enroll a total of 165 patients at approximately 35 investigational sites; all study subjects will undergo 48 weeks of blinded treatment. Thereafter, all participants, including those who have been receiving placebo, will be eligible to enroll in an open-label PTC124 extension study. The primary outcome measure is the total distance walked during a 6-minute walk test, a test of ambulation that has now been standardized for boys with DMD/BMD. Other outcome measures in the will evaluate activity at home, muscle and heart function, strength, cognitive ability, muscle integrity, and muscle dystrophin expression. Safety parameters, compliance, and PTC124 blood levels will also be monitored. Future plans for PTC124 include the initiation of longer-term studies in cystic fibrosis, as well as additional proof-of-concept studies in other indications.Sun, 27 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3897.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3896.phpResearchers at Cold Spring Harbor Laboratory (CSHL) and Isis Pharmaceuticals have devised a potential approach to treat the neuromuscular disease spinal muscular atrophy (SMA) caused by a deficiency in the survival of motor neuron protein (SMN) caused by a single gene mutation. SMA is a neurodegenerative disease of the motor neurons and results in progressive muscle weakness. It is also the leading hereditary cause of infant mortality. CSHL professor Dr. Adrian Krainer and his team have devised a method to stimulate cells to replenish the SMN protein by activating an existing, slightly modified copy of the mutant gene, survival of motor neuron 1, centromeric (SMN1). The researchers injected antisense oligonucleotides (ASO) into mice that had an added, human version of the SMN2 gene. As expected, the gene produced significantly more SMN RNA, including the section that is usually omitted, in tissues where the ASOs accumulate. These results highlight the therapeutic potential of some of these ASOs in the context of SMA. However, before this approach can be applied to human patients, several additional issues must be addressed-such as whether the ASOs really benefit growing animals with SMA and how and when they should be administered to affect the nervous system.Sun, 27 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3896.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3895.phpDuchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder currently lacking a curative treatment. Palliative treatment for DMD can prolong the lifespan of patients, but the prognosis is limited, and a progressive reduction in quality of life and early death in adulthood cannot be prevented using currently available treatment regimens. The best hopes for a cure lies with cellular and gene therapy approaches that target the underlying genetic defect. The helper-dependent adenovirus (HDAdv) is the only viral vector that can accommodate the large size of the full-length dystrophin complementary DNA. This study carried out by a team of Japanese scientists aimed to investigate whether gene transfer by HDAdv to multiple proximal skeletal muscles of utrophin/dystrophin double knockout (dko) mice was effective as a therapy for muscular dystrophy. Examination of the muscle pathology 8 weeks post-injection clearly showed that dystrophin was expressed beneath the sarcolemmal in wild-type and injected dko mice. The dystrophin associated proteins, β-dystroglycan, and α-sarcoglycan as well as neuronal nitric oxide (nNOS) were also expressed in the dystrophin positive fibres of both groups, whereas myc-tag (confirms that the dystrophin was derived from the transferred gene) was expressed only in the injected dko mice. There was a significant reduction in the number of centrally nucleated fibres in the injected dko mice compared with uninjected dko mice. There were much fewer immune cells in the injected dko muscles than in the uninjected dko muscles. Furthermore, vector-injected dko mice showed an increase in body weight, improved motor performance and lived longer. These results may have a potential use in the establishment of an effective therapy for muscular dystrophy. Sun, 27 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3895.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3894.phpMcArdle disease (Glycogen Storage Disease type V) is caused by the absence of the glycolytic enzyme, muscle phosphorylase. People present with exercise-induced pain, cramps, fatigue, and myoglobinuria, which can result in acute renal failure if it is severe. When muscle injury occurs, cytokines are released at the site of inflammation, initiating a systemic inflammatory response. To date, no study has investigated the circulating levels of cytokines in McArdle patients at rest and after an acute exercise bout. The present study was designed to determine CK, white blood cell count and circulating inflammatory factors involved in the process of inflammation and/or tissue repair in a group of 31 McArdle patients at baseline. The response of inflammatory factors to acute exercise was also evaluated in these patients. The results were compared with those of healthy controls. The authors observed a resting CK activity that was significantly elevated in McArdle patients, reflecting a constant, ongoing state of muscle breakdown even when following a sedentary lifestyle. The resting neutrophil count was significantly higher in patients than in controls whereas no significant difference was seen for lymphocyte and monocyte counts. The cytokine response to exercise was comparable in both groups and the myokine, interleukin-6, significantly increased in patients and controls. The data from this study suggest an association between systemic low-level inflammation and McArdle disease and could help improve the understanding of the pathophysiology of McArdle disease and provide the rationale for potential therapeutic interventions. Sun, 27 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3894.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3876.phpDuchenne Muscular Dystrophy (DMD) is the most common fatal heritable disease worldwide, caused by mutations in the gene encoding dystrophin. The majority of DMD mutations encode early termination signals, or deletions and insertions that produce out of frame mRNA transcripts. The loss of functional dystrophin results in progressive muscle weakness throughout the body. Antisense oligonucleotides (AOs) with 2-O-methyl substitutions (2OMeAOs) function by modulating dystrophin pre-mRNA splicing, and are broadly regarded as promising drugs for potential treatment of DMD. Specifically, 2OMeAOs have been shown to facilitate targeted "skipping" of dystrophin exons, enabling the removal of early termination codons or restoration of the correct reading frame, thereby restoring production of a functional protein. However, the main obstacle that has limited the usefulness of 2OMeAOs in treatment of DMD is a lack of adequate carriers to facilitate their delivery to myonuclei. The group of Dr. Gordon Lutz at the Drexel University College of Medicine, Philadelphia, is focused on the development of effective novel nanopolymer-oligonucleotide drugs for the treatment of DMD. Recently they synthesized a family of cationic nanopolymers comprised of poly(ethylene-glycol) (PEG)-poly(ethylene imine) (PEI), that represent a flexible AO delivery system with controllable size and surface charge, adjustable unpackaging properties, and flexibility for addition of moieties that target specific entities on cell membranes. In this study, they examined the capacity of various PEG-PEI copolymers to enhance AO transfection efficiency and facilitate dystrophin expression in skeletal muscle of mdx mice. Single intramuscular injections of AO complexed with low Mw PEG-PEI copolymers into TA muscles of mdx mice resulted in widespread distribution of dystrophin-positive fibers at 3 weeks after injection, with no evidence of cytotoxicity. The data from this study demonstrate that low Mw PEG-PEI copolymers function as high-capacity, non-toxic AO carriers suitable for in vivo transfection of skeletal muscle, and are promising compounds for potential use in non-viral molecular therapy of DMD.Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3876.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3875.phpThe new website “Duchenne Community”, online since March 2008, allows contacts with families and Duchenne organizations worldwide. It offers the possibility to find updated information on research and medical care, to be informed of important events, and to start a blog. The website has a multilingual design. Become an active member of the Duchenne community by participating (learn, discuss, exchange, etc.) to make it lively and attractive. Simply register, it's free! Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3875.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3874.phpOn Tuesday May 6 2008, the NIH will host a one-day symposium entitled “Challenges and Promise of Cell-Based Therapies". The purpose of the symposium is to determine productive new directions for research in regenerative medicine using stem cells and to help NIH prioritize research with the greatest potential for clinical benefit. The opening plenary session will feature an overview of hematopoietic stem cell therapy. This will be followed by four plenary sessions that will highlight cell-based therapies for the treatment of neurological, cardiac, musculoskeletal, and metabolic diseases and disorders. It will close with a presentation on induced pluripotent stem cells (iPSCs) and the issues that need to be addressed to enable their potential use in cell-based therapies.Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3874.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3873.phpThe Muscular Dystrophy Association has produced a special report detailing the ground-breaking research and other important events taking place in the quest to treat and cure Duchenne and Becker muscular dystrophies.Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3873.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3872.phpThe Muscular Dystrophy Association has produced a special report detailing the ground-breaking research and other important events taking place in the quest to treat and cure Duchenne and Becker muscular dystrophies.Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3872.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3871.phpThe National Organization for Rare Disorders (NORD) has announced funding opportunities for 2008 through its clinical research program. Grants are available through this international program for the study of five rare diseases. The deadline for submitting abstracts and letters of intent to NORD is May 9, 2008. The NORD Research Grant Program provides seed-money grants to academic scientists for clinical research. The hope is that these studies will ultimately lead to new diagnostics or treatments for rare diseases. NORD's program provides grants for the study of diseases for which there are few other sources of funding. In all, six grants are available at this time for the study of the following five diseases:Alveolar capillary dysplasia APECED/APS type 1 Olivopontocerebellar atrophy (OPCA) and closely related diseasesTarlov cyst Tyrosinemia type 1 Sun, 06 Apr 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3871.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3850.phpDysferlin deficiency results in defective membrane repair mechanisms. Although dysferlin is expressed in human skeletal and cardiac muscles, mutations in the encoding gene (DYSF) lead only to skeletal muscle phenotypes without myocardial involvement, namely limb girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. The consequences of DYSF mutations on protein structure are poorly understood. In this article, Dr. Simone Spuler and her colleagues in Germany, the UK and the USA, investigated whether there is a relationship between amyloid in skeletal muscle and mutations in DYSF. In patients with suspected dysferlin-deficient muscular dystrophy, the gene encoding dysferlin was sequenced. Antibodies against N-terminal dysferlin-peptides were raised and muscle biopsy specimens were analyzed by histochemistry, immunohistochemistry and electron microscopy. Three families were identified with muscular dystrophy due to homozygous or compound heterozygous DYSF mutations featuring sarcolemmal and interstitial amyloid deposits. These mutations were all located in the N-terminal region of the protein and dysferlin was a major constituent of the amyloid deposits. Mutations in other regions of the dysferlin gene did not lead to muscle amyloidosis. The data from this study demonstrate the first association of a muscular dystrophy with amyloidosis. For patients with amyloidogenic mutations, treatment strategies that interfere with amyloid formation could be a promising.Sun, 30 Mar 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3850.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3849.phpLaminopathies are the collective term for diseases caused by mutations in the lamin genes. The LMNA gene, and as recently discovered also the LMNB1 and LMNB2 genes, give rise to the most phenotypically diverse group of diseases of all the intermediate filament-induced pathologies. LMNA- and LMNB-encoded proteins are expressed in nearly all cell types and yet only some tissues are susceptible to pathogenic damage. Seven autosomal-dominant and four autosomal-recessive distinct laminopathies have been reported. The diversity appears to be unrelated to the location of mutations in the protein as pathogenic mutations have been found in many positions and the reasons for this extreme phenotypic diversity of disorders are not yet understood. In this clinical report, the authors describe a 7-year-old girl with an atypical phenotype combining mandibuloacral dysplasia (MAD), progeroid features and congenital muscular dystrophy. Genetic analysis allowed the identification of a homozygous LMNA mutation predicting p. R471C. The consanguineous parents and brother were normal and heterozygous for the mutation. It was therefore concluded that the inheritance of the phenotype is autosomal-recessive. This is the first description of the homozygous LMNA R471C LMNA mutation resulting in a very severe phenotype of the MAD spectrum. Sun, 30 Mar 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3849.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3848.phpThe process of drawing up a comprehensive set of recommendations for standards of care in DMD on the basis of true international consensus is ongoing, under the auspices of the CDC Care Considerations project, and is likely to be complete in 2008. In the intervening period, TREAT-NMD is working to get as much useful information as possible summarized and out into the public domain. A group of experts, primarily co-authors of existing DMD management guidelines, has been invited to collaborate with the TREAT-NMD activity leaders with the aim of first collecting and comparing existing management recommendations and reaching consensus from these documents and updates of present knowledge, and subsequently presenting these consensus recommendations at a "DMD standards of care" meeting in 2008. The aim of these brief recommendations is to achieve the rapid dissemination of existing knowledge in this area while awaiting the more detailed recommendations presently being drawn up by the US Center for Disease Control in collaboration with TREAT-NMD. The present guidelines are to be considered as expert opinion, and are not based on systematic review processes, although an evidence-based approach has guided the work. Sun, 30 Mar 2008 12:00:00 +0200http://www.institut-myologie.org/anglais/ewb_pages/n/news_3848.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3839.phpIn a study led by Dr. Jeff Molkentin at Cincinnati Children's Hospital Medical Centre, it was found that an investigational antiviral drug, Debio-025, currently undergoing human trials in Europe for treating Hepatitis C infections, may act as a potential treatment strategy to reduce muscle cell damage in Duchenne and other forms of muscular dystrophy (MD). Debio-025 is a known inhibitor of the protein cyclophilin D, which regulates the swelling of mitochondria in response to cellular injury. It is manufactured by DebioPharm S.A. of Lausanne, Switzerland. In earlier laboratory tests, the researchers saw that when a gene encoding cyclophilin D is deleted, it reduced swelling and reversed or prevented the disease's muscle-damaging characteristics. This led them to test the drug in mice with forms of MD caused by a deficiency of two structural proteins, delta-sarcoglycan and laminin alpha2. Treatment with Debio-025 reduced mitochondrial swelling and necrotic manifestations in mice with MD, comparable to deleting the gene encoding cyclophilin D. Debio-025 has already passed Phase II clinical trials in Europe and is considered safe in people. Therefore, inhibiting cyclophilin D could be a potential new treatment strategy in patients with Duchenne MD. During the onset of muscular dystrophy, the loss of certain proteins critical to muscle function, such as dystrophin, can lead to an influx of calcium around muscle tissue. When this occurs, cyclophilin D renders the membranes of mitochondria more permeable, causing mitochondria to be flooded by calcium, reorganize, swell and eventually rupture. This triggers cell death in muscle fibres and leads to the progressive muscle weakness, wasting and often early death associated with muscular dystrophy. Mice lacking the protein delta-sarcoglycan exhibited severe dystrophy and swelling in both skeletal and heart muscle. When the gene encoding cyclophilin D was deleted in these mice, the muscle cells returned to near normal and did not show appreciable signs of swelling and cell death. The experiments were then repeated in mice lacking a gene encoding laminin alpha2, which causes a more severe dystrophy, swollen skeletal muscle cells and premature death before two months of age. In contrast, mice lacking both laminin alpha2 and cyclophilin D showed much healthier muscle cells, increased body weight and walked more. Furthermore, 75% of the mice lacking laminin alpha2 and cyclophilin D lived more than three times longer than mice lacking only laminin alpha2. They thus embarked on finding pharmacological treatments that could also inhibit cyclophilin D. Cyclosporine is a known inhibitor of cyclophilin D. However its use is problematic as it also inhibits calcineurin, a protein that is vital to skeletal muscle cell repair after injury and to skeletal muscle cell development. Debio-025 has the advantage in that it inhibits cyclophilin D and blocks cell death in a number of situations but it does not suppress the immune system or block calcineurin. This study is published online in the recent issue of Nature MedicineTue, 18 Mar 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3839.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3838.phpMyostatin, a member of the TGF-beta superfamily, is an endogenous inhibitor of muscle growth. Its structure and function are highly conserved across species including in humans. In the absence of myostatin, muscle growth is stimulated, at least partially, through the disinhibition of muscle progenitor cells. Myostatin has shown promising results as a potential therapeutic target for treating muscular dystrophy in animal studies, where its inhibition led to increased muscle mass and strength. In a new study led by Dr. Kathryn Wagner at the John Hopkins School of Medicine, the safety of MYO-029, a myostatin inhibitor produced by Wyeth Pharmaceuticals, in patients with muscular dystrophy has been investigated for the first time. The study had a double-blind, randomized design including 116 patients with muscular dystrophy and was conducted by researchers from 10 centres in the United States and United Kingdom. Patients with multiple different types of muscular dystrophy were given sequentially higher doses of MYO-029. Different groups were randomized to receive the test drug or a placebo in a 3:1 ratio. The drug or placebo was administered intravenously every two weeks for six months, after which the patients were followed for three months. Although the purpose of the study was to test for safety, muscle strength and mass were also assessed. The results showed that safety assessments, including vital signs, laboratory tests and physical examination showed no significant differences between treatment and placebo groups. There were no side effects to skeletal, smooth or cardiac muscle, and the most significant side effects related to the treatment were hypersensitivity skin reactions. No increase in muscle strength or improvement in function was seen during the nine months of the study, although muscle mass did increase in some of the patients. Larger studies over longer periods of time would be necessary to properly evaluate the efficacy of this new treatment. Nevertheless, the trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies, and these inhibitors should be evaluated for stimulating muscle growth in muscular dystrophy. Inhibiting myostatin will not address the underlying pathophysiology of various muscular dystrophies, and the authors anticipate that ultimately, such agents will be used in conjunction with therapies such as gene therapy or stem cell transplantation to reduce fibrosis and increase efficacy.Tue, 18 Mar 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3838.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3835.phpThe February 20, 2008 issue of the New York Times featured a front-page article entitled, “Lacking Cure, a New Tack on a Muscle Disease”. The article provides an overview of the status of various approaches to the treatment of Duchenne muscular dystrophy and the work towards establishing a consistent standard of care for the disease. It highlights that without a cure for Duchenne muscular dystrophy (DMD), doctors are now focusing on managing the disease by "making better use of available therapies to eke out longer lives for their patients." Rather than concentrate only on a cure, some researchers are now intent on developing drugs that may alleviate the effects of the disease.Wed, 05 Mar 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3835.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3824.phpMyotonic dystrophy is a disorder that affects multiple body systems. It is characterized by progressive muscle weakness, cardiomyopathy and arrhythmias, cataracts, and abnormalities in brain and endocrine function, including mental retardation. There is a wide variation in the severity of symptoms between patients, although the condition is generally more severe and/or appears at an earlier age in later generations of a family that is affected. In a report in the current online issue of the Proceedings of the National Academy of Science, Professor Thomas Cooper and his colleagues from Baylor College of Medicine and France have shed further light on the molecular complexities of type 1 myotonic dystrophy (MMD1) and hinted at a possible reason for some of the differences between this disease and type 2 MMD (MMD2). The investigators describe how mice with expanded CUG repeats in the MMD1-associated gene on chromosome 19 (DMPK) have elevated levels of a protein called CUGBP1 in muscle cells and exhibit severe muscle wasting, as observed in humans with type 1 MMD. The increase in CUGBP1 levels, which has deleterious effects on muscle tissue and correlates with the severe muscle atrophy, appears to occur only when the expanded DNA sections are in the DMPK gene and not when they're in other genes. People with MMD2, which involves an expansion of repeated DNA sequences in a gene other than DMPK, don't have high levels of CUGBP1 and typically have milder muscle wasting than people with MMD1. The study challenges a widely held view that the location of the expanded DNA repeat isn't important in either type of MMD and that its existence in any location would cause roughly the same problems.Unlike previous mouse models of the disease, these mice mimic the human disease better than any other mouse model of MMD1 created and have a genetic mutation that causes the muscle wasting that is the most devastating element of this inherited disorder. Thu, 28 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3824.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3821.phpThe 29 February 2008 will be the first celebration of the European Rare Disease Day, which is being co-ordinated by the European patient group Eurordis and by National Alliances at the national level. “A Rare Day for Very Special People”, is the chosen motto for the 2008 Rare Disease Day. “Rare Diseases: A Public Health Priority,” is the theme, because it is broad enough to be applicable all across Europe, and it will further promote the concept of rare diseases as a public health priority. The issue of rare diseases is a hot topic currently at EU level and many member states are also beginning to put into place national Rare Disease Plans. Events will be taking place throughout the EU to help raise awareness of rare diseases to policy makers, health professionals and the wider public. The Rare Disease Day will take place every year from 2008 onward. Mon, 18 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3821.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3820.phpInflammation in Duchenne Muscular Dystrophy (DMD) increases the production of connective tissue fibrosis. No current treatment has been effective in eliminating or reducing the build up of collagen fibers. A newly discovered anti-fibrotic drug, halofuginone, promotes recovery and prevents fibrosis. The current study examines the effectiveness of halofuginone in treating and preventing fibrosis in mdx mice. It was hypothesized that halofuginone treatment would resolve pre-established fibrosis and prevent collagen deposits, improving muscle and cardio-respiratory function. Mice (8-9 months old) were treated with saline or halofuginone for 5, 10 and 12 weeks. Muscle strength and endurance, respiration and muscle susceptibility to damage were assessed. Northern blots, Sirius red stains, immunofluorescence, and in-situ hybridization were used to evaluate histochemical and molecular pathologies of the diaphragm, heart, quadriceps and tibialis anterior. Echocardiography was performed at 0, 5, and 10 weeks. Halofuginone prevented and reduced fibrosis in mdx mice, leading to functional recovery and delayed disease progression. If halofuginone proves successful in mice, this treatment has the potential to improve quality of life and lengthen the lifespan of DMD patients.Mon, 18 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3820.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3819.phpResearchers from the University of California, San Diego (UCSD) School of Medicine, led by Pr. Don Cleveland have found a way to slow the progression of amyotrophic lateral sclerosis (ALS) in mice, offering hope to those with ALS or Lou Gehrig's disease. ALS is a progressive disease that slowly attacks the body's motor neurons. Degeneration of the motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death. Typically, ALS patients live only one to five years after initial diagnosis. Currently, no one cause has been singled out for the most common form of the disease. Even though researchers have found genes for a variety of inherited types, including the mutated SOD1 gene in the most common familial ALS, exactly how they cause or advance the disease isn't clear. Accumulating evidence shows that cells other than motor neurons play an active role in their ultimate decline and death. In findings published in Science in June 2006, Pr. Cleveland and his colleagues showed that in early stages of inherited ALS, microglia are damaged by mutations in the SOD1 protein, and that these cells then act to significantly accelerate the degeneration of the motor neurons. The present study demonstrates a similar process with astrocytes, key components in balancing the neurotransmitter signals that neurons use to communicate. It is speculated that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment. As with microglia, the helper role of astrocytes is altered due to mutations in the SOD1 protein. Specifically targeting the mutated SOD1 gene in astrocytes did not slow disease onset or early disease, but late disease progression was sharply delayed. Overall, the mice survived an average of 60 days longer, nearly doubling the life expectancy of ALS mice. Silencing SOD1 in astrocytes not only helps protect the motor neuron, but delays activation of mutant microglia that act to accelerate the progression of ALS. These promising findings show that mutant astrocytes are likely to be viable targets to slow disease progression and extend the life of patients with ALS. The study appears in the online publication on Nature Neuroscience's web site.Sun, 10 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3819.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3818.phpWalker-Warburg syndrome (WWS) is the most severe of a group of congenital disorders, characterized by congenital muscular dystrophy coupled with severe ocular and brain malformations. In at least 1/5 of reported cases, mutations in the protein O-mannosyltransferase 1 (POMT1) gene are associated with this disease, suggesting that the dysfunction of other genes might give rise to WWS. Mutations in the fukutin, fukutin related protein (FKRP), the protein O-mannosyltransferase 2 (POMT2) and very recently in LARGE genes have also been shown to result in WWS. However, mutations in any of these five genes only account for about 25% of WWS patients. Numerous recent studies have demonstrated that the clinical spectrum of the diseases associated with mutations in the fukutin gene is expanding, depending on the type of mutation that arises. In this short report, the authors describe two new mutations in the fukutin gene that cause WWS. The first patient harboured two novel mutations; a point mutation affecting glycine and a deletion in the 3'UTR that affects the polyadenylation signal of the fukutin gene, which could lead to a complete loss of fukutin protein function. These mutations have not been described previously in Fukuyama congenital muscular dystrophy (FCMD), WWS or limb girdle muscular dystrophy (LGMD) patients. The second patient carries a homozygous-single nucleotide insertion that produces a frameshift. This is the first time that this mutation has been detected in a homozygous form in a patient, and appears to give rise to a more severe phenotype compatible with WWS.Sun, 10 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3818.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3817.phpThe most common form of congenital muscular dystrophy (CMD), caused by mutations in the LAMA2 gene encoding the α2 chain of laminin-211, is characterized by clinical manifestations mainly affecting skeletal muscle. Numerous nonsense mutations identified in the LAMA2 gene lead to premature termination codons (PTCs). The ability of aminoglycoside antibiotics to promote read-through of nonsense mutations has attracted interest in these drugs as potential therapeutic agents in genetic diseases. However, the toxicity of aminoglycoside antibiotics such as gentamicin may result in severe side effects during long-term treatment. In this paper, Dr. Valérie Allamand and colleagues analyzed the effect of two other compounds with antibiotic activities, negamycin, a dipeptide antibiotic and amikacin, another member of the aminoglycoside family, on a PTC in the LAMA2 gene in vitro and ex vivo using a dual reporter assay. Their results show that in NIH3T3 cells, amikacin leads to a 2.5-fold increase in readthrough whereas negamycin readthrough was increased up to 19-fold. Similar results were obtained for negamycin in vivo. Furthermore, negamycin treatment strongly sustained the stabilization of the LAMA2 transcripts in patient-derived myotubes up to 77% of control levels. However, neither gentamicin nor negamycin enabled re-expression of the laminin α2 chain in the patients' myotubes at the protein level. This study demonstrates that negamycin, a compound less toxic and more efficient for premature termination readthrough than gentamicin, appears to be an alternative for treatment of patients carrying a PTC mutation.Sun, 10 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3817.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3816.phpMyoblast transplantation is limited by the massive and early death of the majority of transplanted cells. This massive death may be partly due to the reduction of the arterial blood supply within the injection zone generally due to damage, constriction or blocking of blood vessels contributing to hypoxia. Vascular endothelial growth factor (VEGF) is secreted by endothelial cells to promote neo-vascularization. VEGF acts on endothelial progenitor cells by encouraging their proliferation, migration and survival. VEGF is also produced in cells that have a limited oxygen supply. These oxygen deficient cells produce the hypoxia inducible factor (HIF) that stimulates the release of VEGF. In light of recent studies demonstrating that VEGF transient over-expression prolongs islet survival after transplantation, this study led by Dr. Jacques Tremblay aimed to evaluate the implication of hypoxia in the early death of transplanted myoblasts. They also verified whether VEGF could improve the survival and/or proliferation. Pimonidazole hydrochloride labeling showed that the majority of transplanted myoblasts were hypoxic, indicating that the injection procedure restricts oxygen supply to the cells. To investigate whether VEGF could enhance cell survival in vivo, female SCID mouse TA muscles were electroporated with the VEGF plasmid and radioactive human male myoblasts were transplanted several days later. The results demonstrated that VEGF reduced myoblast hypoxia and promoted angiogenesis. VEGF enhanced transplanted human myoblast survival and their engraftment but did not improve their proliferation. Elevated levels of human VEGF enhanced by 1.4-fold 4 days following their transplantation. Furthermore, graft success was 1.3-fold higher in mice electroporated with the plasmid coding for VEGF than in control mice electroporated with the empty vector. The data from this study imply that hypoxia is partially involved in the death of transplanted myoblasts and that VEGF treatment is a potential method to improve their survival.This work was partly funded by the AFM.Sun, 10 Feb 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3816.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3814.phpThe discovery of an unexpected protein-protein interaction has led investigators at the University of Iowa, led by Dr. John Engelhardt, to identify a drug that slows the progression of Amyotrophic Lateral Sclerosis (ALS) in mice and nearly doubles the animals' lifespan. These findings may lead to a treatment for some forms of ALS, and the research also reveals a biological mechanism that might represent a new drug target for ALS and other neurological diseases. ALS, also known as Lou Gehrig's disease is a fatal, progressive neurodegenerative disease that affects the motor nerve cells of the brain and spinal cord. Degeneration of motor neurons impairs muscle control and movement and eventually leads to paralysis and death. While studying the basic biology of cell signaling, the researchers made the unexpected discovery that superoxide dismutase-1 (SOD1), a protein that is mutated in inherited forms of ALS, interacts with Rac1, a protein that regulates the production of reactive oxygen species (ROS) by the Nox2 protein complex. ROS are short-lived, highly reactive molecules that are essential for normal cell function, but abnormal ROS production is a suspected cause of ALS and other neurodegenerative diseases. The unexpected interaction between a protein that is mutated in familial ALS and the cell machinery that produces ROS, which are implicated in ALS progression, prompted the scientists to investigate further. Recently, they found that deletion of the Nox2 protein almost doubles the lifespan of mice with an inherited form of ALS, strengthening the notion that Nox2-generated ROS play a role in ALS progression. In their latest study, the researchers have shown that the drug called apocynin, which blocks Nox2, similarly slows progression and increases lifespan of ALS-affected mice. The new finding is the first to directly connect mutated SOD1 genes with the overproduction of toxic levels of ROS molecules and, therefore, with oxidative stress and inflammation. Although the apocynin results are quite dramatic in mice, and the drug does not appear to be toxic to the animals, rigorous safety and efficacy testing in pre-clinical and clinical trials will be required to determine if the drug may also be useful in humans.Sun, 27 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3814.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3813.phpMyotonic dystrophy type1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. In this month's Nature Genetics Dr. Mani Mahadevan and colleagues report unanticipated data showing that mice and individuals with DM1 actually overproduce NKX2-5, yet experience the same kind of heart problems associated with too little of it. The protein, NKX2-5, is a biomarker for heart stem cells. It is also very important for the normal development of the heart. Too little of it causes major cardiac problems including slow and irregular heartbeats. Excessive NKX2-5 may explain why as many as 60 to 70 percent of individuals with DM1 develop heart problems which cause their heartbeats to become slow and irregular, often necessitating the need for pacemakers. If these irregular heartbeats are not detected, sudden death can occur. By using the mouse model of DM1 and mice genetically engineered to produce less NKX2-5, the authors showed that reducing the excessive levels of NKX2-5 seemed to protect the mice from the heart problems. Surprisingly, they also observed NKX2-5 in the skeletal muscle of mice and DM1 patients. Usually, NKX2-5 is found only in the heart of adults. This discovery could prove beneficial and lead to development of a simple diagnostic test to follow a patient's response to potential therapies. The data from this study demonstrate a new effect of RNA toxicity and how this may cause cardiac conduction abnormalities.Sun, 27 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3813.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3812.phpResearchers at the University of Texas Southwestern Medical Center (UT Southwestern) have used embryonic stem cells from mice to grow healthy and functioning muscle cells in dystrophic mice. The study represents a major step in the field, as it is the first to demonstrate that transplanted embryonic stem cells restore function to defective muscles in a mouse model of muscular dystrophy. A cell population from differentiating ES cell cultures that has substantial muscle regeneration potential was derived via a newly developed sorting technique, which avoids the risk of tumor formation while improving the overall muscle strength and coordination of the mice. Intramuscular and systemic transplantation of these cells into dystrophic mice results in extensive engraftment of adult myofibres with enhanced contractile function without the formation of teratomas. Dr. Rita Perlingeiro and her colleagues focused on manipulating genes that are active in the very early stages as embryonic stem cells start to develop into more specialized cells. They genetically manipulated mouse-derived embryonic stem cells to over-express Pax-3, which is essential in pointing stem cells down the path of muscle formation, before transplantation into mouse muscles. Those cells caused tumors containing many different cell types, indicating that there were still residual undifferentiated embryonic stem cells in the cultures at the time of implantation. Fluorescence Activated Cell Sorting (FACS) was used to sort cells depending on whether some surface markers were activated while others were turned off. The final selection contained only one cell type, which was again injected into the hind-limb muscles of dystrophic mice. After a month, the fluorescent dyes showed that the cells had penetrated the muscle and many of the muscle fibers also contained dystrophin. Furthermore, three months post-transplantation, the mice showed no signs of tumors. Tests of isolated muscles showed that the treated muscles were significantly stronger than untreated dystrophic mice, although not quite as strong as those of normal mice. Coordination analyses, which are important to assess quality of life benefits, demonstrated that the performance of treated dystrophic mice was better than that of untreated dystrophic mice, but not as good as that of normal mice. While still in its early stages, the researchers ultimately hope to develop a cell-based therapy for patients with muscular dystrophy and other muscle related diseases. These proof of principal data demonstrate the therapeutic potential of ES cells in muscular dystrophy.Sun, 27 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3812.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3794.phpMcArdle's disease is a common metabolic disorder characterized by marked exercise intolerance, premature fatigue during exertion, myalgia, and cramps. The pathophysiology involves a deficiency of myophosphorylase enzyme resulting in an inability to degrade glycogen stores. The insertion/deletion (I/D) trait in the angiotensin-converting enzyme (ACE) has been suggested to be a strong modulator of severity in McArdle's disease. Dr. Andrea Martinuzzi and colleagues have previously observed that a common polymorphism insertion/deletion (I/D) in the ACE gene is associated with disease severity. The severity of symptoms may vary from case to case, and this variability may be in relation to the activity levels of ACE, with patients carrying one or two D alleles being the most severely affected.In the present collaborative study coordinated by Dr. Andrea Martinuzzi, the authors hypothesized that modulating ACE activity through the use of inhibitors may reproduce the condition of those patients with a milder phenotype and may result in an alleviation of the symptoms of the disease such as exercise intolerance. In this double-blind, randomized, placebo-controlled clinical trial the efficacy of the ACE inhibitor ramipril, a drug commonly used to treat hypertension and congestive heart failure, was examined in 8 patients with McArdle's disease. This hypothesis is further supported by studies showing that patients treated with ramipril for cardiovascular problems had increased strength and resistance exercise. Patients were evaluated in terms of their muscular strength and their perceived quality of life. Besides the fact that ling-term low treatment with low-dose ramipril is safe and well tolerated, this study failed to show any treatment effect in the objective measures of exercise performance and muscle metabolism.Wed, 23 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3794.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3762.php Leiden University Medical Center (LUMC) and Biotech Company Prosensa have announced positive results from the first clinical study with RNA-based therapeutic PRO051 in four patients with Duchenne Muscular Dystrophy (DMD). In the study, DMD patients between 10 and 13 years of age received a single injection of PRO051 (a 2-'O-methyl antisense oligonucleotide) in a small area of a muscle in the lower leg. In a biopsy taken four weeks later, novel dystrophin expression was observed in the vast majority of muscle fibers with protein levels that are expected to be clinically relevant. This study demonstrates clinical proof-of-mechanism that PRO051, based on Prosensa's proprietary exon skipping technology, was able to correct this genetic error in locally injected muscle tissue of DMD patients. PRO051 will now enter systemic Phase I/II trials in order to investigate the effects and safety of PRO051 after repeated systemic injections and assess the broader benefits available to patients. These extremely promising results of the first human exon-skipping trial have raised much excitement and enthusiasm amongst the patient community. RNA-based therapeutics hold great promise as an approach to create a whole new class of innovative medicines. Tue, 01 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3762.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3760.phpMuscular dystrophies are a group of neuromuscular disorders characterized by muscle weakness, atrophy and reduced muscle tone. Patients with certain neuromuscular disorders may also exhibit muscle pain, tenderness, stiffness, cramps, fasciculations, hypotonia, and myoglobinuria. Myoglobinuria is a metabolic condition seen in the glycogen storage and lipid storage disorders characterized by the presence of myoglobin protein in the urine often accompanied by transient muscle weakness, pain, and sometimes swelling of the affected muscle, usually after exercise. In this case study led by Professor Volker Straub, myoglobinuria in three prednisolone-treated Duchenne muscular dystrophy (DMD) patients is described. Two of the patients had repeated episodes of myoglobinuria, but they were short-lived and did not require treatment. All three boys showed a significant improvement in motor ability on prednisolone therapy. These cases underline the need to increase awareness of myoglobinuria in corticosteroid-treated boys therapy and its appropriate clinical monitoring.Tue, 01 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3760.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3759.phpThe U.S. Food and Drug Administration has granted fast-track status to AVI BioPharma's product candidate, AVI-4658, for the treatment of Duchenne muscular dystrophy (DMD), a devastating disease that currently has no viable treatment or cure. Fast-track designation of a product candidate is intended to facilitate the development and to expedite the review of drugs for serious and life-threatening conditions so that an approved product can reach the market expeditiously. This designation provides for priority interactions with the FDA. AVI-4658 uses AVI's ESPRIT technology (Exon Skipping Pre-RNA Interference Technology) and is designed to benefit patients with certain mutations in the dystrophin gene. In animal models, ESPRIT technology restored near-normal levels of dystrophin production. By skipping exon 51, the proper RNA reading frame can be restored in suitable patients, resulting in the production of functional dystrophin. AVI plans to initiate a clinical trial with systemically delivered AVI-4658 by mid-2008, to evaluate the safety and potential efficacy of the drug in ambulatory DMD patients. Clinical researchers at the Imperial College of London received approval to begin enrollment for a proof-of-principle study evaluating AVI-4658 in a single-dose, intramuscular administration study. This study is being conducted in collaboration with the United Kingdom-based MDEX Consortium. Tue, 01 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3759.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3758.phpThe biopharmaceutical company Insmed Inc. recently reported that the Food and Drug Administration (FDA) has granted orphan drug designation for Iplex™ for the treatment of Myotonic Muscular Dystrophy (MMD), guaranteeing market exclusivity for seven years. Orphan status is granted by the FDA to promote the development of products that demonstrate promise for the treatment of rare diseases. Insmed is currently conducting a 24-week Phase III enabling trial for Iplex™ in MMD, and recently was awarded a grant of approximately $2.1 million from the Muscular Dystrophy Association (MDA), which is expected to cover a substantial portion of the external costs associated with the trial. There is currently no cure for MMD, and no specific treatment has been developed to satisfactorily reverse or ameliorate the common symptoms associated with the disease. Tue, 01 Jan 2008 11:00:00 +0100http://www.institut-myologie.org/anglais/ewb_pages/n/news_3758.phphttp://www.institut-myologie.org/anglais/ewb_pages/n/news_3757.phpCharcot-Marie-Tooth disease (CMT) is the most frequently inherited neuropathy. The most common form of CMT is type 1A (CMT1 A) is associated with a duplication of the peripheral myelin protein 22 (