# Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $368,658

## Abstract

Project Summary:
Optic nerve damage is a primary contributor to debilitating vision loss in glaucoma. The prevalence of
glaucoma is increasing in the USA and worldwide and there is an urgent need for new, accessible treatments
to improve visual outcomes in glaucoma patients. To date, lowering of intraocular pressure (IOP) remains the
only treatment strategy with proven efficacy in preserving vision in glaucoma. However, IOP-lowering drugs
and surgeries are not effective in all patients, and many patients with seemingly controlled IOP still experience
progressive loss of vision. Transforming growth factor-beta (TGF-β) has emerged as playing a key role in
progression of optic nerve damage, promoting glial cell activation, extracellular matrix remodeling and,
ultimately, formation of glial scar in the optic nerve head (ONH). The overall goal of this application is to
provide insight into the effects of blocking angiotensin II type1 receptor (AT1) on glaucoma progression. Our
central hypothesis is that AT1 blockade will down-regulate TGF-β expression and pro-fibrotic pathways to
ameliorate optic nerve axon loss and glial scarring in glaucoma. In Aim 1: To determine the clinical efficacy of
AT1 blocker therapy on the progression of glaucomatous optic neuropathy in vivo, a pre-clinical study will be
conducted in a spontaneous glaucoma model. To test the working hypothesis that AT1 blocker therapy will
preserve axons and limit scarring in the optic nerve in glaucoma, functional (electrophysiological) and structural
(OCT-derived) measures of glaucoma progression in vivo and axon counts in situ will be compared between
eyes receiving IOP-lowering therapy alone and in combination with AT1 blocker and untreated eyes, in adult
subjects with established glaucoma. In Aim 2: To determine if AT1-blockade affects pathways associated with
gliosis and fibrosis in the ONH in this model, gene expression profiling will complement studies that focus on
quantifying and localizing mediators of fibrosis in the TGF-β signaling pathway in ONHs in situ in treated
subjects relative to untreated controls. These studies will utilize an existing, FDA-approved AT1 blocker with
favorable pharmacokinetics, safety profile and unique properties likely to enhance its anti-fibrotic and neuro-
protective effects. Significant innovation and strengths of this proposal include the lack of exogenous
experimental manipulations to induce glaucoma in a unique, spontaneous model of glaucoma that
recapitulates many important features of glaucoma in human patients. The research proposed will enhance
mechanistic insight and provide proof of concept that treatment strategies that mitigate the effects of TGF-β
signaling limit loss of visual function in spontaneous glaucoma, lending support to a new paradigm for the
adjunctive therapy of glaucoma patients.

## Key facts

- **NIH application ID:** 9968408
- **Project number:** 5R01EY027396-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Gillian Jane McLellan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,658
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968408

## Citation

> US National Institutes of Health, RePORTER application 9968408, Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma (5R01EY027396-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9968408. Licensed CC0.

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