Prevention of esophageal stricture after endoscopic submucosal dissection using RNA-based silencing of carbohydrate sulfotransferase 15 in a porcine model

Abstract

Endoscopic submucosal dissection (ESD) for esophageal carcinoma frequently causes fibrotic strictures that require treatment. A possible preventive effect of small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) on esophageal stricture formation after ESD was investigated in 3 pigs. Two half-circumferential ESD ulcers were created in the oral and anal ends of the esophagus. CHST15 siRNA was injected submucosally in one of the two ESD ulcers. Endoscopic, macroscopic, histological, and polymerase chain reaction analyses were performed.On post-operative day 14, the non-treated ulcers were found to show histological fibrosis and increased expression of the CHST15 messenger RNA. A single endoscopic injection of CHST15 siRNA alleviated stricture development in post-ESD ulcers with significant reduction in the mucosal contraction rate. The deposition of collagen and accumulation of fibroblasts and myofibroblasts were diminished in ulcers treated with CHST15 siRNA, where significant suppression of CHST15, transforming growth factor-beta (TGF-β), and collagen-1 messenger RNAs was also seen. CHST15 siRNA alleviated esophageal post-ESD stricture formation via repression of fibrosis, revealing a novel therapeutic role for antifibrotic agents in the prevention of post-ESD strictures.

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

“…Major activity of STNM01 is on activated fibroblasts but not on normal fibroblasts that do not show higher level of CHST15. Important information was achieved from pig model of esophageal stricture after ESD which is characterized by both fibrosis and atrophic change of muscularis proper (27). STNM01 showed no muscle layer defect, supporting the low risk of perforation or fistula.…”

“…STNM01 (or experimental grade of CHST15 siRNA with the same sequence; hereafter we refer both as "STNM01") suppressed CHST15 mRNA in human colon and lung fibroblast cell lines in vitro and reduced the expression of CHST15 mRNA in the colon of mouse DSS colitis (25), the esophagus of pig esophageal stricture post ESD (27), the lung of mouse pulmonary fibrosis (28) and the heart of rat myocarditis (29). CHST15 protein was also reduced by STNM01 in in vivo disease models.…”

“…Considering anti-fibrotic actions of CHST inhibition in other organs like heart and lung (27,28), further modification to systemically applicable formulation including oral or systemic siRNA or screening of small molecule inhibitors is of great interest in the future.…”

Prevention of esophageal stricture after endoscopic resection

“…(iv) Carbohydrate sulfotransferase 15 (CHST15) is a type II transmembrane Golgi protein that biosynthesizes highly sulfated disaccharide units of chondroitin sulfate into ECM. Blockade of CHST15 by small interfering RNA (siRNA) reportedly repressed fibrosis . These materials showed promising effects to prevent stricture in animal models.…”

“…Blockade of CHST15 by small interfering RNA (siRNA) reportedly repressed fibrosis. 73 These materials showed promising effects to prevent stricture in animal models. Further evaluation in humans is needed before its clinical use.…”