July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
By targeting Tie2/VE-PTP in Schlemm’s canal, AKB-9778 lowers intraocular pressure via increasing outflow facility in mice
Author Affiliations & Notes
  • W Daniel Stamer
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Guorong Li
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Iris D Navarro
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Astrid Nottebaum
    Max Planck Institute, Germany
  • Dietmar Vestweber
    Max Planck Institute, Germany
  • Kevin G Peters
    Aerpio Pharmaceuticals, Ohio, United States
  • Footnotes
    Commercial Relationships   W Daniel Stamer, Aerpio Pharmaceuticals (F), Aerpio Pharmaceuticals (C); Guorong Li, None; Iris Navarro, None; Astrid Nottebaum, None; Dietmar Vestweber, Aerpio Pharmaceuticals (F), Aerpio Pharmaceuticals (C); Kevin Peters, Aerpio Pharmaceuticals (E)
  • Footnotes
    Support  Research contract-Aerpio Pharmaceuticals
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2186. doi:
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      W Daniel Stamer, Guorong Li, Iris D Navarro, Astrid Nottebaum, Dietmar Vestweber, Kevin G Peters; By targeting Tie2/VE-PTP in Schlemm’s canal, AKB-9778 lowers intraocular pressure via increasing outflow facility in mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2186.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Tie2 dysfunction in the conventional outflow pathway has been implicated in the pathogenesis of congenital glaucoma and post-natal open- angle glaucoma. Vascular endothelial protein tyrosine phosphatase (VE-PTP) is a negative regulator of Tie2 and VE-PTP inhibition activates Tie2 in vascular endothelial cells. The purpose of the present study was to assess the expression of VE-PTP in the conventional outflow pathway and to test the effect of AKB-9778, a potent VE-PTP inhibitor, on intraocular pressure (IOP) and outflow facility after topical ocular administration in normotensive mice.

Methods : Using mice heterozygous for a nuclear localizing beta galactosidase VE-PTP knock-in allele, X-gal staining and Tie2 immunohistochemistry were employed to assess VE-PTP and Tie2 expression in conventional outflow tissues. Overlapping expression of CD31 and Prox-1 were used to positively identify location of Schlemm’s canal (SC) in confocal microscopic projections. In C57BL6J mice, topical AKB-9778 (40 mg/ml) to one eye or vehicle (to contralateral eye) were administered once daily 4 days. IOP was measured daily prior to dosing, and at 2 and 4 hours post dose on Day 3. Outflow facility was assessed by iPerfusion in a separate group of animals (AKB-9778 to one eye; vehicle to contralateral eye) after three days of topical dosing.

Results : Confocal microscopy demonstrated co-expression of VE-PTP and Tie2 in SC endothelium and in the endothelium of collector channels originating from SC, but not in the trabecular meshwork. Tie2 appeared in every SC cell, while VE-PTP displayed a heterogeneous distribution. Topically administered AKB-9778 was well tolerated and resulted in significantly reduced pre-dose IOP (p<0.05, n=5) with maximal reduction (~6 mmHg) at 2 hours post-dose on Day 3 of dosing. Outflow facility was significantly increased in AKB-9778-treated versus vehicle-treated eyes (3.4±0.4 vs. 2.53±0.2 nl/min/mmHg, p=0.047, n=9).

Conclusions : Tie2 and VE-PTP were co-expressed in endothelium of SC and collector channels, and VE-PTP inhibition significantly reduce IOP and enhanced outflow facility in normotensive mice. These findings support evaluation of Tie2 activation by AKB-9778 as the first SC-targeted approach for IOP reduction in patients with open angle glaucoma or ocular hypertension.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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