# Phosphoinositide signaling in glaucoma: rescue strategies for Lowe syndrome

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $398,145

## Abstract

ABSTRACT
Glaucoma is a leading cause of irreversible blindness. Lowering intraocular pressure (IOP) is the 
only modifiable target for intervention, but the mechanisms causing elevated IOP remain poorly 
understood. This proposal builds on our studies of oculocerebrorenal syndrome of Lowe, a rare 
X-linked disease that presents with congenital glaucoma, the major cause of blindness in these 
children. OCRL is an inositol phosphatase mutated in Lowe syndrome. This application seeks to 
restore the phosphoinositide imbalance that underlies Lowe syndrome by targeting inositol-signaling 
pathways. We have found evidence that restoring phosphoinositide levels in trabecular meshwork 
cells can rescue the disease in a Lowe mouse model. We have identified patients with Lowe syndrome 
who are born with congenital glaucoma and have characterized their mutations. We also discovered 
mTOR signaling defects in these patients. Thus, we hypothesize that modulation of phosphoinositide 
signaling in the trabecular meshwork will restore aqueous outflow. Our aims are to (1) restore 
aqueous outflow by viral delivery of OCRL, (2) balance excess PI(4,5)P2 by inhibiting upstream 
kinase, (3) modulate mTOR signaling in both the mouse model and a human iPSC model of Lowe 
syndrome. Our work should help determine the role of OCRL in aqueous outflow regulation. Since 
phosphoinositide signaling is a novel area of IOP control, the experiments should facilitate 
discovery of new glaucoma therapies that can reduce the burden of blindness.

## Key facts

- **NIH application ID:** 10101360
- **Project number:** 1R01EY032159-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yang Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,145
- **Award type:** 1
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101360

## Citation

> US National Institutes of Health, RePORTER application 10101360, Phosphoinositide signaling in glaucoma: rescue strategies for Lowe syndrome (1R01EY032159-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10101360. Licensed CC0.

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