Developing standard procedures for murine and canine efficacy studies of DMD therapeutics: report of two expert workshops on "Pre-clinical testing for Duchenne dystrophy": Washington DC, October 27th-28th 2007 and Zürich, June 30th-July 1st 2008.

Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA.
Neuromuscular Disorders (Impact Factor: 3.13). 07/2009; 19(7):502-6. DOI: 10.1016/j.nmd.2009.05.003
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    ABSTRACT: The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
    Brain 12/2014; DOI:10.1093/brain/awu368 · 10.23 Impact Factor
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    ABSTRACT: It has recently been proposed that a set of standard operating procedures be established for evaluating pre-clinical testing data in mdx mice Through the universal adoption of standardized laboratory assays, the results of multiple pre-clinical trials performed in independent laboratories could be evaulated. The laboratory assays that we have employed in designing our new scaling system have been identified as robust tests for evaluating endpoints in the mdx mouse.
    Muscular Dystrophy, Edited by Dr. Madhuri Hegde, 05/2012: chapter From Basic Research to Clinical Trials: Preclinical Trial Evaluation in Mouse Models, Muscular Dystrophy: pages 463-474; In Tech., ISBN: 978-953-51-0603-6
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    Neuromuscular Disorders 09/2014; DOI:10.1016/j.nmd.2014.09.003 · 3.13 Impact Factor

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