# Epigenetic-guided studies of AMD pathology and iPSC-RPE transplantation therapy

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2020 · —

## Abstract

Age-related macular degeneration (AMD) affects nearly 5% of aging veterans, and millions of civilian Americans.
AMD is caused by genetic and environmental factors, which lead to central vision loss initially, and can lead to
rapid degeneration of remaining vision in a few years. While this is a prevalent disease with costs to both the
affected individuals and society as a whole, few treatments, and no cures, currently exist. Contributing to the
lack of treatments for AMD, is the fact the underlying genetic factors resulting in pathogenesis remain unsolved.
While variants in, or around, 34 genes have been identified as risk factors for disease, none have been
demonstrated to be a causative agent. Epigenetics is an area yet to be fully explored in AMD pathogenesis. In
collaboration with Dr. Margaret DeAngelis, we have performed DNA methylation studies on RPE from 140 dry
AMD donors, identifying over 400 differentially methylated regions. Combining this data with RNA-Seq data from
iPSC-RPE under oxidative stress, we have identified 81 genes to be both differentially methylated and
differentially expressed. At the top of this list is Thymine DNA Glycosylase, an enzyme that performs the last
step of DNA demethylation. We hypothesize that TDG repression results in perturbation of the natural
methylation/demethylation cycle that the cell uses to regulate gene expression in response to environmental
stimuli, such as oxidative stress. In Aim 1, we will test this hypothesis using CRISPR/Cas9-based knockdown of
TDG in induced pluripotent stem cell-derived RPE (iPSC-RPE) under normal and oxidative stress conditions. A
second contributing factor to the lack of treatments for AMD is the limited progress observed in clinical trials
using cell replacement therapy, a form of regenerative medicine. One hurdle to overcome in regenerative
medicine for the eye is the difficulty in producing retinal tissues with high similarity to native tissue. The retinal
pigment epithelium (RPE) is a pigmented monolayer at the back of the eye, which has the most regenerative
medicine potential, since it can be readily derived from patient-specific iPSCs. Multiple animal and human studies
using these iPSC-RPE cells, however, fail to produce lasting results, as the cells either die, produce an immune
response, or yield no functional improvement, likely because these iPSC-RPE are only RPE-like and not exact
replicas of native RPE. Our group, and others, have shown significant differences in the transcriptional landscape
of iPSC-RPE, relative to native RPE. Many of the protein-coding genes that define the RPE are expressed, but
at significantly lower levels in iPSC-RPE when compared to native RPE. It has been well documented that
reprogramming somatic tissue to iPSCs removes most of the epigenetic memory, but some remains. This
memory is passed along during the differentiation process to the target cell type, and can promote
dedifferentiation to the original cell type. The exact epigen...

## Key facts

- **NIH application ID:** 9892385
- **Project number:** 1I01BX004695-01A1
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** Michael Farkas
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892385

## Citation

> US National Institutes of Health, RePORTER application 9892385, Epigenetic-guided studies of AMD pathology and iPSC-RPE transplantation therapy (1I01BX004695-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892385. Licensed CC0.

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