Scientists at the University of Rochester Medical Centre have identified a critical first step toward development of a long-sought drug to treat myotonic muscular dystrophy (MMD), the most common form of muscular dystrophy in adults. The disease is marked by progressive muscle weakness, and eventually many patients have difficulty walking, swallowing, and breathing. The disease also affects the eyes, the heart, and the brain. Currently there is no treatment. Earlier this decade, the research team discovered that faulty messenger RNA has a toxic effect on muscle and heart tissue. The toxic RNA binds tightly to a crucial protein known as muscle blind (MBNL1). The genetic error involves a repeated sequence of three chemical bases. Healthy people have anywhere from 5 to 30 copies of the CUG triplet repeat, but people with muscular dystrophy typically have hundreds or thousands of copies. These extra copies become part of large, faulty messenger RNA molecules that can mistakenly delete the normal function of proteins. The objective is to release MBNL1 in cells so that it can perform its normal activities, which include building proper chloride channels that are central to normal muscle function. The research team therefore worked to free MBNL1 by designing an experiment to search for a small molecule that would absorb extra CUG copies. Using a drug discovery technique known as dynamic combinatorial chemistry, the researchers mixed two sets of 150 compounds, one on polymer beads and the other in solution, and let the components link up with each other amid CUG triplet repeat RNA strands. The technique allowed investigators to simultaneously analyze how effectively more than 11,000 molecular combinations could bind to the target CUG RNA strand. The investigators then sorted out which combinations muscled out the others for access to RNA strands and held most tightly to them. The team then took the best performers and put them in a solution containing both CUG triplet repeat RNA strands and MBNL1. The chosen molecules were able to break up the interaction between the two, with the best molecules freeing up to half the MBNL1. The team is now continuing its work, further refining the molecules in an attempt to find one that frees MBNL1 even more effectively. Drugs more commonly target DNA or proteins, with the RNA approach offering a different and potentially valuable route to developing new medications for certain diseases. This is the first description of a molecule that targets the errant RNA at the origin of myotonic muscular dystrophy.

Spinal Muscular Atrophy (SMA), a neurodegenerative disorder, is caused by the loss of survival motor neuron 1 (SMN1) and is the leading genetic cause of infantile death. In humans two copies of the SMN gene exist, SMN1 and SMN2. The critical distinction between the two genes occurs at the RNA processing level: SMN1 produces full-length transcripts, while SMN2 primarily produces an alternatively spliced transcript lacking the final coding exon. Thus SMN2 alone cannot compensate for the loss of SMN1. SMN2 is retained in essentially all SMA patients and is a primary target for SMA therapeutic development such as trans-splicing. Trans-splicing therapy relies on splicing of mutant RNA and therapeutic RNA in order to correct RNA sequence. As a therapeutic approach, trans-splicing offers the advantage over gene replacement in that the endogenous promoter intrinsically controls expression. Consequently, temporal and spatial constraints on gene expression are retained. While this form of molecular therapy has had impressive results as a treatment for spinal muscular atrophy in cell-based models of disease, scientists have been unable to translate the therapy to humans.  In this article, researcher from the University of Missouri have developed a strategy that will enhance trans-splicing activity and bring it closer to being used in the clinical setting. To improve efficiency, a series of antisense RNAs were screened to identify a sequence that would disable SMN exon 8 and promote trans-splicing. Inactivating the gene reduces competition at splice sites and improves the likelihood of achieving the desired results. In vitro assays identified an enhancing antisense RNA and were constructed into a novel single vector system individually expressing the trans-splicing RNA and the antisense RNA. Cell-based assays identified a highly efficient vector system that resulted in high levels of trans-splicing and correspondingly high SMN protein levels and increased SMN activity in SMA-derived extracts. This strategy provides insight into the trans-splicing mechanism and significantly improves trans-splicing activity in a mouse model of spinal muscular atrophy, demonstrating a platform that can significantly elevate SMN levels in vivo and in a relevant disease context.

Mutations in the nuclear intermediate filament lamin A/C (LMNA) gene are associated with a variety of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy, which affects skeletal and cardiac muscle. However, mutations in LMNA cause the disease by unknown mechanisms. In this study, a team of international scientists, including researchers from The Institute of Myology, has demonstrated that one such mechanism involves the disruption of neuromuscular junctions. In normal muscle fibres, several nuclei cluster together under the cell membrane at sites of neuronal contact. These postsynaptic nuclei synthesize the components of the neuromuscular junction that specify the overlying membrane as the target site for innervation. The authors found that LMNA-deficient animals (including those with a point mutation in LMNA that in humans can cause Emery-Dreifuss disease) failed to position nuclei into these postsynaptic clusters. This prevented the proper organization of the neuromuscular junction and disrupted muscle fibre innervation. The authors showed that either loss or mutation of LMNA disrupted nuclear positioning by causing the mislocalisation of two other proteins: Nesprin-1, which spans the outer nuclear membrane and anchors nuclei to the actin cytoskeleton, and SUN2, which spans the inner nuclear membrane, linking Nesprin to lamin A/C. Although lamin A/C is ubiquitously expressed, LMNA defects specifically affected striated and skeletal muscle because Nesprin-1 and SUN2 are highly expressed in these tissues. Emery-Dreifuss muscular dystrophy patients exhibit similar hallmarks of skeletal muscle functional denervation.  These results suggest that lamin A/C–mediated NMJ defects contribute to the autosomal dominant Emery-Dreifuss disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD.

In the presence of its president, Laurence Tiennot-Herment, the AFM, received today the gold medal of the National Academy of Medicine. This great institution has honoured the Association for its role in “the fight against neuromuscular diseases and the disability they cause, and, more generally, the fight against diseases of genetic origin and its research support, culminating in the creation of Généthon.”
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On behalf of Thomas, Aleyna, Florian, Jessie, Mickael, Myriam, Marina, the children and families, the AFM would like to express its thanks and gratitude to all its supporters in France who rallied round so splendidly. Despite the economic difficulties encountered daily, our supporters reached out and took up the challenge, thus proving that the only way to shape the future is through solidarity. 
“During these thirty hours, the people of France have shown unfailing solidarity. And this gives us the strength and means to pursue our combat towards other victories, like that of Aleyna’s cure. Thank you all so much. This evening more than ever, you are our strength!” declared Laurence Tiennot-Herment, President of the AFM.
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In work published on 24 November in the journal Nature biotechnology, Anselme Perrier and his team at I-stem identified a recurrent anomaly in the genome of human embryonic stem cells left in culture for too long. Whether or not by chance, this same anomaly is found in a certain number of cancers. This discovery leaves open the possibility that the same process could be at the origin of stem cell and cancer cell proliferation.
This work has been supported by the AFM (French Muscular Dystrophy Association) thanks to Téléthon donations.
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Using a gene surgery technique, a team of Swiss researchers led by Prof Daniel Schümperli of the University of Berne has succeeded in restoring production of the SMN (Survival MotoNeuron) protein in mouse models of spinal amyotrophy, one of the most frequent neuromuscular diseases in children. To obtain this result they used antisense U7 RNAs which specifically recognise one part of the gene (the exon), thus avoiding its “elimination” by the cell machinery. Disease symptoms were considerably improved in the treated mice and – for a number of them – even disappeared.
This work was in part financed by the AFM thanks to Téléthon donations and has been published in Human Molecular Genetics. It can be consulted online on the Internet site of the review.
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The first Euro-Latinoamerican School of Myology (known as EVELAM for its acronym in Spanish) was held in Santiago, Chile, from December 11th to 13th. This initiative, designed as an “overseas” extension of the Summer School of Myology of Paris, was conceived by Dr. J. Andoni Urtizberea (Hendaye, France), Dr. Alberto L. Rosa (Cordoba, Argentina), Norma B. Romero (Paris, France) and Prof. Jorge A. Bevilacqua (University of Chile).

Experts from Europe and Latin America lectured on the wide spectrum of neuromuscular disorders ranging from basic knowledge to diagnosis and therapy of inherited myopathies, neuropathies and motor neuron diseases, including presentation and discussion of selected clinical cases and and histopathological workshops. About 120 participants from all over Latin America including Mexico, Brazil, Uruguay, Ecuador, Venezuela, Argentina and Chile joined in the enthusiastic and friendly atmosphere in Santiago.

> Access the complete conference report on TREAT-NMD website

This book is an impressive compilation of contributions on the hot topic of cardiac stem cell therapy from leading groups all over the world. In the assembly of chapters, a structured approach is adopted; starting from the clinician's perspective, all developments in both the experimental and clinical research areas are covered. This journey will take the reader from the bench-top to the bedside, with all chapters written by leading authorities in their respective fields, including data still in press with medical journals. So, beyond being excellent as an overall update for scientists in the field of cardiac stem cell therapy, this book will likely prove an indispensable tool for every budding scientist considering a research project within this field.

Tissue engineering can be seen in both scientific and sociological contexts and successes in the field are leading to clinical reality. This book attempts to define the path from basic science to practical application. It is a unique volume and the first of its kind to bring together leading names in the field of tissue engineering and stem cell research. A relatively young science, tissue engineering can be seen in both scientific and sociological contexts and successes in the field are now leading to clinical reality. This book attempts to define the path from basic science to practical application. A contribution from the UK Stem Cell Bank and opinions of venture capitalists offer a variety of viewpoints, and exciting new areas of stem cell biology are highlighted. With over fifty stellar contributors, this book presents the most up-to-date information in this very topical and exciting field.
> Advances in Tissue Engineering

The bimonthly Newsletter of the Institute of Myology keeps you up to date with developments in myology research, and presents a summary of the latest scientific, medical, political and associative news concerning neuromuscular diseases.

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