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Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-α2 deficiency

Erb, M. and Meinen, S. and Barzaghi, P. and Sumanovski, L. T. and Courdier-Fruh, I. and Ruegg, M. A. and Meier, T.. (2009) Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-α2 deficiency. Journal of pharmacology and experimental therapeutics, 331 (3). pp. 787-795.

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Abstract

Laminin alpha2-deficient Congenital Muscular Dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the pro-apoptotic Bax gene in a mouse model for MDC1A prolong survival and mitigate pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the pro-apoptotic glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1 mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Williams and Wilkins
ISSN:0022-3565
Note:Variant title: Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency -- Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:21 Sep 2017 14:30
Deposited On:22 Mar 2012 13:31

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