title: Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions.
abstract: OBJECTIVE
  Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated.
  
  
  RESULTS
  STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis.
  
  
  CONCLUSIONS
  Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan kjsuzuki@med.niigata-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yokoyama
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawauchi
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyagi
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Terai
authors.affiliation: Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.affiliation: Internal Medicine, Toho University, Sakura Medical Center, Sakura, Chiba, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Sameshima Hospital, Kagoshima, Kagoshima, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Sameshima
authors.affiliation: Matsushima Hospital, Yokohama city, Kanagawa, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University, Sapporo, Hokkaido, and Department of Pathobiochemistry, Meijo University, Nagoya, Aichi, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.affiliation: Department of Medicine a, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.affiliation: Department of Medicine a, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Science, Niigata, Niigata, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Stelic Institute & Co., Inc., Minato, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Asakura
mesh_terms: D001706:Biopsy / Q000379:methods; D002809:Chondroitin Sulfates / Q000096:biosynthesis / Q000378:metabolism; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D000069916:Endoscopic Mucosal Resection / Q000379:methods; D005260:Female; D005355:Fibrosis; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006801:Humans; D015552:Injections, Intralesional; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D062072:Patient Acuity; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C411874:CHST15 protein, human; D005765:Gastrointestinal Agents; D008562:Membrane Glycoproteins; D020320:Oligoribonucleotides, Antisense; D034741:RNA, Small Interfering; D002809:Chondroitin Sulfates; D015238:Sulfotransferases
keywords: CHST15; Crohn’s disease; mucosal healing