# Activation of the Angiopoietin-Tie2/TEK Pathway to Treat Ocular Hypertension and Glaucoma

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $617,955

## Abstract

SUMMARY - Glaucoma is a leading cause of blindness affecting more than 60 million people worldwide.
Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma and
results from increased resistance to aqueous humor outflow. IOP reduction has been shown to reduce the risk
of conversion to glaucoma in eyes with ocular hypertension and reduce the risk of disease worsening in eyes
with existing glaucoma damage. While IOP-lowering therapies capable of restoring structure and function of the
diseased tissues that increase outflow resistance are particularly desirable, few such therapies currently exist.
These diseased tissues reside in the conventional outflow tract that is comprised of the trabecular meshwork
(TM) and Schlemm’s canal (SC). In 2013, our group discovered that reduced activity of the Angiopoietin (Angpt)-
TEK vascular signaling pathway results in a severe form of primary congenital glaucoma (PCG) in mice due to
failure of the SC to form. During the last grant cycle, we showed that the Angiopoietin1 ligand is expressed in
the TM and is required to activate the Tie2/TEK receptor in the SC and that severity of glaucoma disease
phenotype correlates tightly with the dose of Angpt/TEK signal strength. We were able to rescue the PCG
disease phenotype in mice, by inhibiting the vascular-specific phosphatase PTPRB, thereby boosting TEK signal
strength in a ligand-independent manner. In collaboration with an international team, we have now identified 20
unique loss-of-function mutations in the TEK and ANGPT1 genes in 20 individuals, providing a new genetic
cause of PCG and confirming the importance of this pathway in human disease. In adult patients with primary
open angle glaucoma (POAG), risk variants in the Angpt/TEK pathway have been identified and a pepti-body
targeting Angiopioetin ligands causes rapid onset of high pressure OAG in adult monkeys by reducing outflow
facility, extending importance of this pathway beyond childhood glaucoma. Altogether, our findings, largely
funded by the first cycle of this grant, have led to major new insights into the pathogenesis of glaucoma and
development of the outflow tract and have led directly to the identification of a new genetic cause of glaucoma.
In this competitive renewal, we propose to leverage these seminal discoveries to:1) fully characterize the cellular
basis of Angpt-TEK signaling in development of the outflow tract and pathogenesis of glaucoma through single
cell analysis 2) functionally annotate 2 new disease genes identified in patients with PCG and POAG and
determine how they modulate Angpt/TEK signal strength and 3) test the ability of a novel ANGPT1-mimetic to
repair defective SC and TM in glaucoma models and enhance outflow facility. By the end of the next cycle, we
will have characterized specific cell populations in the TM and SC, identified new genes responsible for glaucoma
and provide lead compounds to take forward to clinical devel...

## Key facts

- **NIH application ID:** 10051981
- **Project number:** 2R01EY025799-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** SUSAN E. QUAGGIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,955
- **Award type:** 2
- **Project period:** 2016-05-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051981

## Citation

> US National Institutes of Health, RePORTER application 10051981, Activation of the Angiopoietin-Tie2/TEK Pathway to Treat Ocular Hypertension and Glaucoma (2R01EY025799-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051981. Licensed CC0.

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