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A gene therapy approach to prevent dilated intercellular space, a hallmark of gastroesophageal reflux disease
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DOI：10.1038/s41434-026-00634-0.png)
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Abstract
En 中文
The incidence of esophageal disease ranging from gastroesophageal reflux disease (GERD) to cancer has dramatically risen over the last 10 years. However, there have been limited descriptions of effective gene delivery methods for the esophagus. We developed a simple and effective electroporation-based gene delivery procedure to target the distal esophagus in living animals. We have used this approach to prevent formation of dilated intercellular space (DIS), a pathological feature of GERD, which is characterized by disruption of tight junctions and loss of epithelial barrier function. We found that tight junction proteins and the Na+,K+-ATPase β1 subunit were decreased in biopsies from patients with GERD. Transfection of esophageal epithelial cells with plasmids expressing the Na+,K+-ATPase β1 subunit increased levels of tight junction proteins and transepithelial electrical resistance. Electroporation-mediated gene delivery to the distal esophagus resulted in no injury in either rat or rabbit models. Gene expression was detected within 2 days in the esophageal mucosa and persisted for at least 12 weeks. DIS developed by 12 weeks in a rabbit GERD model and was reduced by 70% when the Na+,K+-ATPase β1 subunit was delivered. These results are encouraging for future development of gene-based treatments for GERD and its downstream consequences.
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