Use of pi3kc2b inhibitors for the preservation of vascular endothelial cell barrier integrity

Abstract

Ischemic conditions are a leading cause of death for both men and women. Ischemia, a condition characterized by reduced blood flow and oxygen to an organ. Re-establishment of blood flow, or reperfusion, and re-oxygenation of the affected area following an ischemic episode is critical to limit irreversible damage. However, reperfusion also associates potentially damaging consequences. For instance, increased vascular permeability is an important contributor to edema and tissue damage following ischemic events. Here the inventors shows that genetic inhibition of PI3K-C2β reduces cerebral infarction in two ischemia/reperfusion (I/R) models and improves neurological outcome. The genetic inhibition stabilizes the blood—brain barrier (BBB) after ischemic stroke and reduces inflammation. Accordingly, the present invention relates to a method for the preservation of vascular endothelial cell barrier integrity in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a PI3KC2β inhibitor.

1 . A method for the preservation of vascular endothelial cell barrier integrity in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a PI3KC2β inhibitor. 
     
     
         2 . The method of  claim 1  wherein the patient suffers from sepsis. 
     
     
         3 . The method of  claim 1  wherein the patient suffers from an ischemic condition. 
     
     
         4 . The method of  claim 1  wherein the patient suffers from an acute ischemic stroke. 
     
     
         5 . The method of  claim 1  wherein the PI3KC2β inhibitor is suitable for reducing infarct size, preventing or reducing edema, preventing hemorrhage and preventing no-reflow. 
     
     
         6 . The method of  claim 1  wherein the PI3KC2β inhibitor is suitable for preventing ischemia-reperfusion injuries. 
     
     
         7 . The method of  claim 1  which is performed sequentially or concomitantly with angioplasty, thrombolysis, or surgical thrombectomy. 
     
     
         8 . The method of  claim 7  wherein the thrombolysis is performed with t-PA. 
     
     
         9 . The method of  claim 1  which comprises the steps consisting of i) restoring blood supply in the ischemic tissue, and preserving the vascular endothelial cell barrier integrity of said ischemic tissue by administering to said patient a therapeutically effective amount of PI3KC2β inhibitor. 
     
     
         10 . The method of  claim 1  wherein the PI3KC2β inhibitor is a small organic molecule. 
     
     
         11 . The method of  claim 1  wherein the PI3KC2β inhibitor is an inhibitor of PI3KC2β expression.