# Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $132,609

## Abstract

PROJECT SUMMARY/ABSTRACT
Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed
world. Recent studies provide strong evidence supporting the hypothesis that mitochondrial (Mt) defects in the
retinal pigmented epithelium (RPE) contribute to the pathogenesis of AMD. This study will focus on samples
from eyebank donors and AMD patients harboring the AMD risk SNP (rs1061170; T to C conversion; amino acid
change Y402H) for complement factor H (CFH) since members of this group have significantly more RPE MtDNA
damage and display genotype-specific Mt defects in the RPE. Therefore, this genetically defined group may
benefit from treatments that protect the mitochondria. Studies in this application will use our primary RPE and
induced pluripotent stem cell (iPSC)-derived RPE cultured from individuals with AMD harboring the CFH CC risk
alleles, to investigate disease mechanisms and response to drugs that protect or enhance Mt function. Our
experimental system is unique in that all donors are phenotyped for disease severity and also genotyped for the
AMD CFH risk allele. Aim 1 will test the hypothesis that Mt dysfunction and susceptibility to oxidative stress in
primary and iPSC-derived RPE harboring the CC risk alleles are genotype-specific. Aim 2 will test the hypothesis
that compounds that enhance Mt activity will preserve RPE cell function and prevent cell death. We will use
iPSC-RPE to test the prediction that cells harboring the CC risk allele require different, allele-specific drug
combinations to preserve Mt function and prevent RPE cell death compared with cells lacking the risk allele. We
will utilize iPSC-RPE from CFH CC and CFH TT donors to determine the optimal cell-protective drug
combinations and then test these in the RPE-specific sod2 conditional KO that has Mt and RPE defects. If our
prediction is correct, the optimum combination of drugs from the in vitro experiments will protect the retina in the
RPE-specific sod2 conditional KO mouse and maintain RPE cell integrity. Aim 3 is translational. We will test the
response of iPSC-RPE generated from conjunctival biopsies from living AMD patients harboring the CFH CC
risk allele to the optimal drug combinations that improve Mt function. In summary, these studies will define
differences in RPE Mt defects, response to oxidative stress and to drugs that improve Mt function, between cells
from patients with the CFH CC AMD risk allele and from patients with the TT protective allele. Results from these
studies may lead to development of therapies to prevent AMD by targeting the primary defect in a genetically
defined population of AMD patients and may also lead to “personalized medicine” for treating AMD since our
method for producing patient-specific iPSC-RPE can be readily translated to patients with AMD.

## Key facts

- **NIH application ID:** 10322504
- **Project number:** 3R01EY028554-03S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** James R. Dutton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $132,609
- **Award type:** 3
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322504

## Citation

> US National Institutes of Health, RePORTER application 10322504, Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration (3R01EY028554-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322504. Licensed CC0.

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