# Laying a Foundation for Precision Medicine for Fuchs' Dystrophy

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $381,341

## Abstract

PROJECT SUMMARY
Fuchs’ endothelial corneal dystrophy (FECD) is an age-related degenerative disorder resulting in corneal edema
and loss of vision. FECD occurs in 4% of whites over the age of 40 years and is the leading indication for corneal
transplantation in the U.S. Over 70% of cases are caused by a CTG triplet repeat expansion in the TCF4 gene.
Expanded CUG repeat RNA (CUGexp) transcripts expressed from this gene locus accumulate as nuclear foci in
the corneal endothelium of patients. The CUGexp foci bind and functionally sequester the splicing factors MBNL1
and MBNL2 to trigger mis-splicing in FECD endothelial tissue. To examine the endothelial cell-type specificity
for FECD, we will determine if somatic mutations in the post-mitotic corneal endothelium of FECD patients results
in a larger triplet repeat expansion than in their blood. We will examine if other anterior segment cell-types
including corneal epithelium, stromal keratocytes, and trabecular meshwork cells are prone to accumulation of
CUGexp foci and associated molecular defects. To test the MBNL sequestration hypothesis, we will examine if
the knockdown of MBNLs in healthy donor endothelial tissue is sufficient to recapitulate the mis-splicing and
upregulation of extracellular matrix (ECM) genes found early in the disease course. In early and late FECD, we
observed a marked overexpression of the cochlin gene that produces a secreted ECM protein also capable of
recruiting immune cells. The cochlin protein was previously detected in the trabecular meshwork of patients with
primary open angle glaucoma (POAG), and our preliminary data indicate that the protein is present in the
aqueous humor and trabecular meshwork of FECD subjects. We will examine levels of the cochlin protein in
corneal tissue, aqueous humor samples, and trabecular meshwork tissue of FECD patients for its possible
contribution to corneal disease findings and the increased risk for glaucoma in these patients. Additionally, we
will examine the prevalence of POAG in our large UTSW FECD cohort and determine if there is a correlation
with the triplet repeat length. We will use single-cell RNA sequencing combined with IHC to identify the immune
cells and their contribution to late-stage FECD. We have characterized the efficacy of 45 antisense
oligonucleotides (ASOs) and duplex RNAs that block disease-causing CUGexp foci. Using patient-derived cells
and tissue, we will examine their potency based on their ability to block foci formation and their specificity based
on transcriptome-wide assessment of on- and off-target events. We will examine delivery, length of action, and
safety using wild-type mice. To enable studies of disease biology and in vivo drug testing, we have generated
what we believe is the first mouse model with a knock-in of expanded CTG repeats. In preliminary studies, we
show that our knock-in strategy successfully recapitulates CUGexp foci formation in corneal endothelium. We will
further characterize thi...

## Key facts

- **NIH application ID:** 10487580
- **Project number:** 5R01EY022161-11
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Venkateswara Vinod Mootha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,341
- **Award type:** 5
- **Project period:** 2012-05-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487580

## Citation

> US National Institutes of Health, RePORTER application 10487580, Laying a Foundation for Precision Medicine for Fuchs' Dystrophy (5R01EY022161-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487580. Licensed CC0.

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