A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure

• Published in: Investigative ophthalmology & visual science 2020-12, Vol.61 (14), p.12
• Main Authors: Li, Guorong, Nottebaum, Astrid F, Brigell, Mitchell, Navarro, Iris D, Ipe, Ute, Mishra, Sarthak, Gomez-Caraballo, Maria, Schmitt, Heather, Soldo, Brandi, Pakola, Steve, Withers, Barbara, Peters, Kevin G, Vestweber, Dietmar, Stamer, W Daniel
• Format: Article
• Language: English
• Subjects: Aniline Compounds - pharmacology; Animals; Diabetic Retinopathy - drug therapy; Double-Blind Method; Female; Fluorescent Antibody Technique; Glaucoma - drug therapy; Glaucoma - pathology; Humans; Intraocular Pressure - drug effects; Male; Mice; Mice, Inbred C57BL; Middle Aged; Physiology and Pharmacology; Receptor, TIE-2 - metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 3 - antagonists & inhibitors; Sulfonic Acids - pharmacology; Trabecular Meshwork - drug effects; Trabecular Meshwork - metabolism; Trabecular Meshwork - pathology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.61.14.12

Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) activation in Schlemm's canal (SC) endothelium is required for the maintenance of IOP, making the angiopoietin/Tie2 pathway a target for new and potentially disease modifying glaucoma therapies. The goal of the present study was to examine the effects of a Tie2 activator, AKB-9778, on IOP and outflow function. AKB-9778 effects on IOP was evaluated in humans, rabbits, and mice. Localization studies of vascular endothelial protein tyrosine phosphatase (VE-PTP), the target of AKB-9778 and a negative regulator of Tie2, were performed in human and mouse eyes. Mechanistic studies were carried out in mice, monitoring AKB-9778 effects on outflow facility, Tie2 phosphorylation, and filtration area of SC. AKB-9778 lowered IOP in patients treated subcutaneously for diabetic eye disease. In addition to efficacious, dose-dependent IOP lowering in rabbit eyes, topical ocular AKB-9778 increased Tie2 activation in SC endothelium, reduced IOP, and increased outflow facility in mouse eyes. VE-PTP was localized to SC endothelial cells in human and mouse eyes. Mechanistically, AKB-9778 increased the filtration area of SC for aqueous humor efflux in both wild type and in Tie2+/- mice. This is the first report of IOP lowering in humans with a Tie2 activator and functional demonstration of its action in remodeling SC to increase outflow facility and lower IOP in fully developed mice. Based on these studies, a phase II clinical trial is in progress to advance topical ocular AKB-9778 as a first in class, Tie2 activator for treatment for ocular hypertension and glaucoma.