A small molecule inhibitor of VE-PTP activates Tie2 in Schlemm’s canal increasing outflow facility and reducing intraocular pressure

Guorong Li, Astrid F. Nottebaum, Mitchell Brigell, Iris D. Navarro, Ute Ipe, Sarthak Mishra, Maria Gomez-Caraballo, Heather Schmitt, Brandi Soldo, Steve Pakola, Barbara Withers, Kevin G. Peters, Dietmar Vestweber, W. Daniel Stamer

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish (US)
Article number2772060
JournalInvestigative Ophthalmology and Visual Science
Volume61
Issue number14
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • Glaucoma pharmacology
  • Intraocular pressure
  • Schlemm’s canal
  • Tie-2
  • Trabecular meshwork

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'A small molecule inhibitor of VE-PTP activates Tie2 in Schlemm’s canal increasing outflow facility and reducing intraocular pressure'. Together they form a unique fingerprint.

Cite this