# Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

> **NIH NIH R42** · ONL THERAPEUTICS, INC. · 2020 · $618,183

## Abstract

PROJECT SUMMARY / ABSTRACT
Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause
of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke
(CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II
antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not
effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced
disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of
health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function,
and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and
thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal
pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell
death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no
therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas-
mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology
company developing innovative therapies that prevent retinal cell death to improve visual outcomes for
patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model
of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and
chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the
role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal
will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. Phase I of this Fast-
track STTR proposal will i) determine the feasibility of using Fas inhibition to protect against acute CS-induced
retinal damage, and ii) demonstrate that the duration of inhibition is clinically meaningful. Phase II will test the
ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitor. In addition, we
will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single
intravitreal injection of a Fas inhibitor vector in a novel, peer-reviewed chronic model of atrophic AMD in which
apoB100 mice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles
human disease. This proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas
inhibitors in models of atrophic AMD. Successful execution of the project will support the continued pre-clinical
development of...

## Key facts

- **NIH application ID:** 10093659
- **Project number:** 4R42EY029625-02
- **Recipient organization:** ONL THERAPEUTICS, INC.
- **Principal Investigator:** James T Handa
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $618,183
- **Award type:** 4N
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093659

## Citation

> US National Institutes of Health, RePORTER application 10093659, Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD (4R42EY029625-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10093659. Licensed CC0.

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