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

Abstract

Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue-specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target-and tissue-specific findings-based strategy would be a key to translation in developing anti-fibrosis therapy.

Association of genetic variants of CircCHST15 with oral squamous cell carcinoma in the Chinese Han population

“…Using the endoscopic ultrasound‐guided intratumoral injection of oligonucleotide STNM01 to inhibit CHST15 prolongs the overall survival in patients with pancreatic cancer 20 . CHST15 is associated with fibrosis in diseases, such as inflammatory bowel disease, 21 colitis, 22 and esophageal stricture, 23 and can inhibit cardiac remodeling 24 . A few studies have explored circCHST15.…”

Oligonucleotides—A Novel Promising Therapeutic Option for IBD

“…IBD pathogenesis is not only connected to an active acute and chronic inflammatory response but also to structural damage, with matrix remodeling and tissue fibrosis, which can take place independently of the inflammatory activity (Suzuki and Yoneyama, 2017). Approximately one third of patients with CD and 5% of those with UC are diagnosed with fibrotic stenosis in the clinical course (Rieder et al, 2013; de Bruyn et al, 2015).…”

Biochemical and crystallographic assessments of the effect of 4,6‐O‐disulfated disaccharide moieties in chondroitin sulfate E on chondroitinase ABC I activity

“…The interaction between CSE and bioactive proteins has become clear, suggesting that CSE has a crucial role in physiological activities and diseases [4][5][6][7][8][9][10][11]. CSE has attracted attention as a target molecule for disease treatment because lots of literature have demonstrated that CSE is associated with cancer, inflammatory bowel disease and spinal cord injury [12][13][14][15].…”