# Testing Gene Therapy in Models of Geographic Atrophy

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $523,020

## Abstract

Chronic inflammation is a characteristic, and possibly a cause, of the retinal damage associated with age
related macular degeneration (AMD), a leading cause of blindness among the elderly. Inflammation may be a
consequence of age related oxidative stress or accumulation of toxins within the RPE and retina. This is a
project to develop gene therapy for AMD by preventing inflammatory processes signaled by potent cytokines
such as IL-1β. It is our hypothesis that, by reducing inflammation associated with these signaling molecules,
we can halt the progression of AMD in patients diagnosed with early stage disease. There are two forms of the
advanced disease, wet (exudative) AMD and geographic atrophy, both of which lead to loss of central vision.
While there are effective treatments for wet AMD, there is no treatment for geographic atrophy, which leads to
death of the retinal pigment epithelium and photoreceptor cells in the macula. Furthermore, atrophic processes
may persist in wet AMD, even when choroidal neovascularization is under control.
This project is a collaboration between two groups that have generated distinct mouse models for geographic
atrophy. One of the models increases oxidative stress in the retinal pigment epithelium (RPE) by deleting the
gene for a protective enzyme, manganese superoxide dismutase. The second model deletes the gene for the
aryl hydrocarbon receptor (AhR), causing ocular dysregulation of several pathways relevant to AMD including
cholesterol homeostasis and clearance of oxidative stress-inducing toxins such as those found in cigarette
smoke. Both models result in key features of dry AMD including accumulation of basal deposits in the RPE,
damage to Bruch's membrane, RPE atrophy and dysfunction and death of photoreceptors.
We propose to develop gene therapy in these models using adeno-associated virus (AAV) which has been
demonstrated to be safe for gene transfer to the retina. Importantly, this virus does not provoke a severe
inflammatory response. Our approach to therapy in the two models is to deliver genes for secreted, cell
penetrating proteins that increase protection from oxidative stress or that reduce the production of
inflammatory cytokines by stimulating synthesis of anti-oxidant enzymes or blocking the activity of the NLRP3
inflammasome and preventing the activation of caspase-1. We will validate that delivery of the secreted anti-
inflammatory proteins to the vitreous produces peptides that permeate the retina and RPE. In the final
component of the project, we will use cell-type specific viral vectors that produce non-secreted peptides in
order to identify the cells that are major producers of inflammatory cytokines in our mouse models. Our goal is
to develop gene therapy vectors that could be tested in patients, and we believe that one-time delivery of a
therapeutic vector to the vitreous will be translatable to human gene therapy.

## Key facts

- **NIH application ID:** 10011817
- **Project number:** 5R01EY026268-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Alfred S Lewin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,020
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011817

## Citation

> US National Institutes of Health, RePORTER application 10011817, Testing Gene Therapy in Models of Geographic Atrophy (5R01EY026268-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10011817. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*