Odanacatib as a Potential Drug to Reduce the Risk of Stroke in the Context of Sickle Cell Disease

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Anbazhakan, Suhaas
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Sickle cell disease is a genetic mutation of hemoglobin in red blood cells that causes them to become more rigid, aggregate and block blood vessels, and also to prematurely lyse and die releasing inflammatory contents into the blood. Unfortunately, 11% of children with sickle cell disease suffer a stroke before the age of 20, with children between the ages of 2-5 being the most vulnerable. Upon clinical examination of these stroke lesions, there are signs of arterial remodeling through enzymatic degradation of the elastic lamina. Our lab has shown previously that TNFα stimulation or peripheral blood mononuclear cells from people with sickle cell disease can induce the expression and activity of the potent elastase and collagenase cathepsin K in human aortic endothelial cells. Given these promising results, here we present data on cathepsin K inhibition as a novel therapeutic target for the reduction of the elastic lamina degradation in arteries in a mouse model of sickle cell disease. Three week old AS and SS mice were given 6mg/kg intraperitoneal injections of odanacatib daily for 10 weeks. The carotid arteries were used for histological studies of elastin by Van Giesen staining, and immunostaining for cathepsin K. Elastin staining showed that cathepsin K inhibition significantly reduced the number of fragmentations in the elastin within the arterial wall. This suggests that odanacatib is effectively reducing cathepsin K activity in the arterial wall, and this is correlated with a significant reduction in elastic lamina fragmentation in these mice. Proteolytic degradation of elastic lamina is a key signal for smooth muscle cell migration and luminal narrowing, and our demonstration here that elevated cathepsin K in sickle cell transgenic mice can be reduced by cathepsin K inhibition presents a novel mechanism to target accelerated arterial remodeling in children with sickle cell disease at high risk for strokes at such early ages.
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