Omigapil in MDC1A

Omigapil ameliorates the pathology in MDC1A

J Pharmacol Exp Ther. 2009 Sep 16. [Epub ahead of print]

Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-{alpha}2 deficiency.

Erb M, Meinen S, Barzaghi P, Sumanovski LT, Courdier-Fruh I, Ruegg MA, Meier T.

1 Santhera Pharmaceuticals;

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.

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  • Congenital Muscular Dystrophy

    A group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. A child with CMD may have various neurological or physical impairments. Some children never gain the ability to walk, while others lose the ability as they grow older. Learn more...

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