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

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $452,969

## 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:** 9893873
- **Project number:** 5R01EY028554-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** James R. Dutton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $452,969
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893873

## Citation

> US National Institutes of Health, RePORTER application 9893873, Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration (5R01EY028554-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893873. Licensed CC0.

---

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