# Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma

> **NIH NIH U24** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $145,254

## Abstract

Project Summary / Abstract
 Retinal ganglion cells (RGCs) are the output neurons of the retina responsible for transmitting information
about the visual world from the eye to the brain. Thus, RGC damage and loss, a characteristic of many disorders
of the visual system, has the direct consequence of vision impairment, or blindness when RGC loss is more
severe. Our translation-enabling approach builds on a very well-established, thoroughly characterized and
validated experimental glaucoma (EG) model. This affords our study the distinct advantage of conducting each
of the proposed hypothesis-driven experiments within the framework of a reliable model of RGC degeneration
that closely recapitulates the anatomical changes and pathophysiological processes observed in human
glaucoma. Moreover, our preliminary results establish the feasibility of our approach, demonstrating that we have
already achieved successful transplantation of human induced pluripotent stem cell (iPSC)-derived RGCs into
the EG retina, while also characterizing major barriers that require targeted solutions. Hence, we propose to
employ a series of manipulations to both donor RGCs and the recipient EG retina in order to overcome the
existing barriers to RGC replacement and thus make a giant leap forward toward realization of the audacious
goal to restore vision in persons blinded by glaucoma or other optic neuropathies. Each of our Aims is soundly
based on existing knowledge of the relevant biology and will lead to meaningful enhancement of donor RGC
survival, integration, and function in the glaucomatous EG retina. We will utilize rigorous quantitative
electrophysiological and anatomical assessments for testing the hypothesis at the core of each Aim. Aim 1 will
target neuroinflammation to improve the long-term survival of transplanted RGCs. We will create
hypoimmunogenic iPSCs and manipulate the host retinal environment using systemic immunosuppressive
agents or inhibition of microglial activation. Aim 2 will augment donor cell survival and integration through
modulation of cellular age, with host retinal glia experimentally induced to an immature state through cellular
rejuvenation. Aim 3 will enhance the connectivity and axon outgrowth of donor RGCs in the retina. Donor RGCs
will be edited to express hM3Dq DREADD receptors for chemogenetic stimulation and mTOR activators.
Thrombospondin will be overexpressed in host retinal astrocytes and donor RGCs, leveraging astrocyte-derived
factors that promote axonal outgrowth and synaptogenesis. Together, these Aims will generate a wealth of
knowledge and resources for the scientific community and bring us significantly closer to the reality of vision
restoration through RGC replacement.

## Key facts

- **NIH application ID:** 11100041
- **Project number:** 3U24EY033269-04S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** BRAD FORTUNE
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $145,254
- **Award type:** 3
- **Project period:** 2021-09-30 → 2026-05-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100041

## Citation

> US National Institutes of Health, RePORTER application 11100041, Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma (3U24EY033269-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11100041. Licensed CC0.

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