What was the aim of your study?
I wanted to clarify the unknown role of selenoprotein N (SelN) and the pathophysiological mechanisms of this myopathy to identify potential therapeutic targets. This muscle disease is caused by mutations in the SEPN1 gene, which induces a deficiency or loss of function of this selenoprotein. Affected children have muscle weakness, scoliosis and respiratory failure that can be fatal. I have demonstrated for the first time that oxidative stress plays a key role in selenoproteinopathy. I performed ex vivo studies of cultures of myoblasts and myotubes from patients deficient in SelN and found that these cells have an increased production of free radicals that induce an oxidation process (carbonylation) of specific proteins.

Charcot-Marie-Tooth disease (CMT) is a chronic and progressively degenerative, inherited disorder of the nervous system. CMT is classified into 5 groups, CMT type 1 (CMT1), being by far the most common form. The symptoms include muscle weakness, tremor and sensory loss. Approximately 70%-80 % of CMT1 patients have the type called CMT1A, which is caused by a genetic defect of the PMP22 gene that is thought to function in the formation and maintenance of myelin in the peripheral nervous system.  It has been suggested that the use of high doses of ascorbic acid (AA) could be a treatment for Charcot-Marie-Tooth type 1A disease. The rationale for this proposition is based on the reversion of a CMT mouse model obtained after treatment by high doses of AA. Ascorbic acid is thought to reduce the levels of PMP22 protein through its actions on the PMP22 gene and cyclic adenosine monophosphate (cAMP), thus improving the symptoms of the disease. Ascorbic acid was designated by the EMEA as an orphan drug for CMT1A in April 2008.

In light of this knowledge, the authors of the present study aimed to test the safety and efficacy of ascorbic acid in adult patients with CMT1A. Patients were randomized to receive daily 1 g ascorbic acid, 3 g ascorbic acid, or placebo for 12 months. The primary outcome was the Charcot–Marie–Tooth disease neuropathy score (CMTNS) at 12 months. Treatment with ascorbic acid for 12 months was safe and well tolerated but there were no significant differences between the groups and the efficacy of ascorbic acid was not demonstrated.
This study was partly funded by the AFM.
Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

Duchenne muscular dystrophy (DMD) is a relentlessly progressive and incurable muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of functional protein. There is currently no effective treatment for DMD, but for the first time in decades, there is a range of promising therapies under development. Antisense-mediated exon skipping is one of the most promising approaches for the treatment of DMD because of its capacity to correct the reading frame and restore dystrophin expression. In particular, peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have recently been shown to induce widespread high levels of dystrophin expression in the mdx mouse model. An international research team (The University of Oxford, The University of Western Australia and biotech company AVI BioPharma) has published breakthrough data that support the promise of this therapeutic approach for the treatment of Duchenne muscular dystrophy (DMD). The researchers have demonstrated that an exon skipping PPMO has dramatic effects in the prevention and treatment of severely affected, dystrophin/utrophin double knock out mice (dKO), preventing severe deterioration of the treated animals and extending their lifespan. Treatment of affected mice from 10 days of age for six weeks with the mouse-specific PPMO at a dosage of 25 mg/kg/week resulted in a nearly complete skipping of exon 23 in all of the muscles examined except cardiac muscle. Skipping of exon 23 restored the reading frame of dystrophin mRNA and led to widespread continued translation of dystrophin protein. Treated dKO mice showed near normal measures for most of the examined parameters, including striking prevention of kyphosis and maintaining of near normal mobility. This study demonstrates for the first time the efficiency of such an exon-skipping approach in the dKO mouse, which is a much more severe and progressive mouse model of DMD. If these findings are reproducible in human studies, they suggest great potential for the systemic treatment of DMD patients with a PPMO.

Prosensa and GlaxoSmithKline (GSK) have entered into an exclusive worldwide collaboration for the development and commercialization of RNA based therapeutics for Duchenne Muscular Dystrophy. The scope of the alliance includes four RNA-based products intended to treat specific subpopulations of patients suffering from DMD. Under the terms of the agreement, GSK will obtain an exclusive worldwide license to develop and commercialize Prosensa’s lead compound, PRO051, which targets the skipping of exon 51 on the dystrophin gene. In September 2009, the company reported positive results from a Phase I/IIa study, which was conducted in patients with DMD. Results showed that the systemic delivery of PRO051 in patients with DMD was well tolerated and induced novel expression of dystrophin. GSK will continue to progress the further development of PRO051 in collaboration with Prosensa. Both parties have begun preparations for a double blind placebo controlled Phase III study, which is scheduled to start in early 2010. GSK will fund all costs associated with the further clinical development of PRO051. In addition, GSK has exclusive options to license three more RNA-based compounds targeting additional DMD exons. One such option includes Prosensa’s second lead compound, PRO044, which targets the skipping of exon 44 and for which Prosensa expects to initiate a Phase I/II study before the end of 2009. The alliance is in-line with GSK’s strategy of collaborating with biotech companies that have cutting edge technologies and platforms for drug discovery and development. Currently, there is no known cure for DMD. As such, PRO051 could carve a niche for itself on successful development and approval. The candidate could target approximately 13% of all DMD patients.
> Read the Press Release

December 10th, 2009 - Paris, France

The 2nd Latino American School of Myology (known as EVELAM for its acronym in Spanish) will be held in Montevideo, Uruguay from December 3rd to 5th. Nearly one hundred participants from all over Latin America are expected, mainly students from the Southern Cone (Argentina, Chile, Uruguay). Amongst the speakers, six were from Europe (Switzerland, Spain and Italy) three from France (S. Quijano-Roy and N. Romero from the Institute of Myology and JA Urtizberea from the marine Hospital in Hendaye). Partners included the AFM, TREAT-NMD and the Uruguayan Telethon, also heavily involved in the organization. Last year, the 1st EVELAM, held in Santiago, Chile, trained over a hundred medical or paramedical professionals. Beyond this training aspect, EVELAM aims to attract the attention of authorities on the importance of developing research and improve local patient care, particularly by setting up multidisciplinary consultations.

 > Read ‘Myology in Latin America’, J. Belavicqua and A. Rosa in ‘Les Cahiers de Myologie’, Oct. 2009, p.42-44 (in french).

The French team led by Prof. Aubourg and Dr Cartier (Saint-Vincent de Paul Hospital, Inserm), long supported by the AFM through Telethon donations, announced that it has successfully treated two children suffering from a rare genetic brain disease – adenoleukodystrophy – in the journal Science on 6 November 2009. The treatment has halted this progressive disease in these children. This represents a major advance for all rare disease sufferers and also for all those who have rallied to support them over the years, especially during the annual Telethon campaigns.
> Access the complete press release

Action Duchenne’s annual conference, which took place on 23 & 24 October in central London, was the largest and most successful to date. Over 300 people attended the conference, which boasted renowned speakers from around the world, an increase of 25% on the previous year. Delegates heard about the very latest developments in the race to find treatments for Duchenne, including information from three different teams working on Exon Skipping technology, and the very latest clinical trial results were announced by AVI BioPharma for AVI 4658.
> For more information:
http://www.treat-nmd.eu/about/news/news/698/
http://www.actionduchenne.org/viewarticle?news=35

The Department of Cardiovascular Medicine at the University of Oxford is looking for a highly motivated individual to join its research group studying disease mechanisms in hypertrophic cardiomyopathy. The post, starting in January 2010, is funded for three years by a European Commission FP7 award, which will fund research into hypertrophic cardiomyopathy in five centres. This collaborative project is co-ordinated in Oxford and the successful applicant will assume the role of project manager as well as being involved in the characterisation of disease models. Applicants should have a PhD in a relevant subject and have a strong background in cardiac muscle biology. The successful candidate will possess good organisational and presentational skills.
Further particulars, which detail the application procedure, should be obtained from http://www.cardiov.ox.ac.uk/vacancies
Informal enquiries may be made to cvm_recruitment(a)cardiov.ox.ac.uk or Dr. Charles Redwood (credwood(a)well.ox.ac.uk). Please quote vacancy reference HS/09/021.

The European Neuro Muscular Centre (ENMC) is a platform of international neuromuscular patient organisations, whose main scope is to facilitate communication among scientists, clinicians and persons affected by neuromuscular diseases, through the organisation of international workshops.
To guide and develop ENMC´s scientific activities, ENMC is seeking candidates for the position of ENMC Research Director.
Qualified candidates interested in this position should submit their curriculum vitae together with a letter of motivation to enmc(a)enmc.org by December 15, 2009.
> For more information: http://www.treat-nmd.eu/about/jobs/jobs/

This advanced manual includes evolving methods for studying dynamic changes in living cells and organisms, presenting techniques as well as background material, and serving also as a text in advanced courses. The first section covers principles and fundamental issues of detection and imaging; the second provides detailed protocols for imaging live systems. Unique to this edition are advances in 3-D microscopy: atomic force microscopy and structured illumination microscopy (using OMX). New analytical options are also described: live high-throughput/content screening and computational analysis of live cell data.
> Live Cell Imaging: A Laboratory Manual, Second Edition

This handbook is a convenient bench companion for biologists, designed as a handy reference guide for elementary and intermediate statistical analyses. Statistical methods most frequently used in publications and reports, as well as guidelines for the interpretation of results, are explained using simple examples with complete instructions for Excel.
> Statistics at the Bench: A Step-By-Step Handbook for Biologists

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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