Figure 6.

Potential pleiotrophic effects of AKB-9778 mediated Tie2 activation on restoring normal structure/function of SC. Tie2 and VE-PTP, the molecular target of AKB-9778 and a critical negative regulator of Tie2 activation, are expressed in Schlemm's canal (SC) endothelial cells (ECs). In the normal SC, Tie2 activation is maintained principally by Angpt-1 produced by cells adjacent to SC endothelial cells including trabecular meshwork cells. Reduced Tie2 signaling has been implicated in the development of congenital glaucoma, ocular hypertension and open angle glaucoma. Tie2 signaling may be important for maintaining both the structural integrity of SC and the normal structure/function relationship between the anterior wall of SC and TM. Tie2 activation with AKB-9778 appears to have both short-term functional effects mediated by eNOS activation and Rho kinase pathway inhibition and longer term anatomic remodeling effects on lumen size of SC, with potential secondary effects on TM. Thus, restoring Tie2 signaling with AKB-9778 represents a novel SC targeted approach to the treatment of OHT/OAG.