# Gene therapy for GERD-associated esophageal epithelial barrier dysfunction

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $530,161

## Abstract

Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders worldwide and
is one of the greatest risk factors in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.
GERD is characterized by a broad spectrum of typical symptoms, such as heartburn and acid regurgitation,
and extra-esophageal manifestations, such as asthma, chronic cough and laryngitis. Although proton pump
inhibitors (PPIs) are currently the most effective treatment for GERD and its complications, up to 45% of
patients with GERD remain symptomatic on standard therapy. Long term use of PPIs can cause severe side
effects including chronic kidney disease and myocardial infarction. Thus, there is an urgent need to develop
new methods to treat PPI refractory GERD. Dilated intercellular space (DIS) in the esophageal squamous
epithelium is one of the important early pathological features in GERD. In reflux disease, gastro-duodenal
contents, the most important of which are stomach acid and bile acids, regurgitate into the distal esophagus
and cause DIS formation and loss of barrier function through epithelial injury and disruption of tight and
adherens junctions in the human esophagus as well as in animal models of the disease. Molecular analysis
has shown in patients and animal models of GERD that levels of a number of tight junction and adherens
junction proteins are reduced in this disease. Using a 3-D transwell culture of human EPC1 esophageal
squamous cells as a GERD model, we have shown that bile acid at pH 5 damaged cell junctions and causes
DIS. We have recently found that overexpression of the Na+,K+-ATPase β1 subunit by electroporation of
plasmids into healthy and injured lungs of mice and pigs protected them from subsequent lung injury and
partially reversed existing lung injury through upregulation of tight junction proteins and barrier function. We
have found similar upregulation of tight junction proteins in esophageal squamous epithelial cells following
gene transfer of the Na+,K+-ATPase β1 subunit. We hypothesize that by enhancing the levels of tight and
adherens junction complexes in the esophageal squamous epithelium by gene transfer of the Na+,K+-ATPase
β1 subunit, we may be able to prevent or reverse the appearance and consequences of DIS during
progression of GERD. Aim 1 will test whether gene transfer of the Na+,K+-ATPase β1 subunit increases,
protects, and/or restores apical junctional complexes in an in vitro stratified 3-D model of human esophageal
squamous cells and in murine esophageal organoids. Aim 2 will determine whether electroporation-mediated
gene delivery of the Na+,K+-ATPase β1 subunit to the lower esophagus in living animals can increase apical
junctional complexes. Aim 3 will determine whether electroporation-mediated gene delivery of the Na+,K+-
ATPase β1 subunit to the lower esophagus can prevent and/or treat cell junction damage and DIS in a rabbit
GERD model. These studies will provide proof of ...

## Key facts

- **NIH application ID:** 9970948
- **Project number:** 1R01DK120680-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** David A Dean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,161
- **Award type:** 1
- **Project period:** 2020-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970948

## Citation

> US National Institutes of Health, RePORTER application 9970948, Gene therapy for GERD-associated esophageal epithelial barrier dysfunction (1R01DK120680-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970948. Licensed CC0.

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