The influence of low dystrophin levels on disease pathology in mouse models for Duchenne Muscular Dystrophy

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The influence of low dystrophin levels on disease pathology in mouse models for Duchenne Muscular Dystrophy

Title: The influence of low dystrophin levels on disease pathology in mouse models for Duchenne Muscular Dystrophy
Author: Putten, Maaike van
Publisher: Department of Human Genetics, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Issue Date: 2013-02-26
Keywords: Dystrophin
Duchenne muscular dystrophy
Mouse models
Utrophin
Pathology
Muscle
Gene therapy
Biomarkers
Skewed X-inactivation
Cardiomyopathy
Abstract: Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive to exercise-induced damage, resulting in progressive muscle wasting, loss of ambulation and premature death. There is no cure, but several therapeutic approaches are clinically tested. At best, these clinical interventions result in the expression of low dystrophin levels. Fortunately, expression of wild type levels is not needed, as both humans and mice expressing ~50% of dystrophin do not show pathology. Detailed studies on which dystrophin levels are needed to prevent pathology and improve muscle function have been performed in this thesis. After the set-up of good outcome measures and serum biomarkers to monitor disease progression, two new innovative mouse models expressing low levels of dystrophin based on skewed X-inactivation were generated. In the mdx-Xist∆hs model we observed that <15% dystrophin already improved muscle performance, while histopathology was largely with >15% dystrophin. To protect muscles from exercise-induced damage >22% dystrophin was needed. Dystrophin levels between 3-21% prevent the development of dilated cardiomyopathy in 10 months old mice. Mice lacking both dystrophin and its homologue utrophin, mimic the human phenotype and die before the age of 12 weeks. In these mice, <10% dystrophin improved life expectancy and muscle function while >10% dystrophin was needed to improve histopathology. These findings are encouraging for ongoing and future clinical trails.
Description: Promotor: G.J.B. van Ommen, Co-Promotor: A.M. Aartsma-Rus
With Summary in Dutch
Faculty: LUMC
Citation: Putten, M. van, 2013, Doctoral Thesis, Leiden University
ISBN: 9789461822390
Sponsor: Prosensa Therapeutics B.V. Columbus Instruments
Handle: http://hdl.handle.net/1887/20555
 

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