title: A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn’s disease.
abstract: BACKGROUND
  In Crohn's disease (CD), knockdown of Smad7, an inhibitor of Transforming Growth Factor (TGF)-β1 activity, with a specific antisense oligonucleotide (GED0301) seems to be safe and tolerable and associates with TGF-β1-mediated suppression of inflammatory pathways.
  
  
  OBJECTIVE
  Since TGF-β1 has pro-fibrogenic effects in many organs, we evaluated whether GED0301 treatment associates with the formation of small bowel strictures.
  
  
  METHODS
  Fifteen patients with active, inflammatory CD, receiving oral GED0301 once daily for 7 days, were monitored for the formation of small bowel strictures by Small Intestine Contrast Ultrasonography (SICUS). Serum basic fibroblast growth factor (bFGF) and human chitinase 3-like 1 (also known as YKL-40), two markers of CD-related intestinal strictures, and matrix metalloproteinases (MMP) and tissue inhibitor 1 of MMPs (TIMP1) were analysed at day 0 and day 180 by ELISA. Crohn's disease activity index (CDAI) changes were also monitored.
  
  
  RESULTS
  Fourteen patients completed the 6-month study; the remaining underwent intestinal resection for a severe relapse not responsive to medical treatment. No patient developed small bowel stricture and none experienced obstructive symptoms during the study period. GED0301 treatment induced no significant change in the circulating levels of bFGF, YKL-40, MMPs and TIMP1. Seven of 12 patients who reached clinical remission following GED0301 treatment maintained a CDAI < 150 at day 180.
  
  
  CONCLUSIONS
  Short-term treatment of patients with Crohn's disease using GED0301 is not associated with the development of small bowel stricture, thus reinforcing the concept that this drug is safe at least at early time points.
authors.affiliation: Department of Systems Medicine, University of Rome ‘Tor Vergata’, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Zorzi
authors.forename: E
authors.initials: E
authors.lastname: Calabrese
authors.forename: I
authors.initials: I
authors.lastname: Monteleone
authors.forename: M
authors.initials: M
authors.lastname: Fantini
authors.forename: S
authors.initials: S
authors.lastname: Onali
authors.forename: L
authors.initials: L
authors.lastname: Biancone
authors.forename: F
authors.initials: F
authors.lastname: Pallone
authors.forename: G
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000328:Adult; D003251:Constriction, Pathologic; D003424:Crohn Disease / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000201:enzymology; D007421:Intestine, Small / Q000000981:diagnostic imaging* / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D012307:Risk Factors; D051906:Smad7 Protein / Q000235:genetics*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D016376:Oligonucleotides, Antisense; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D020782:Matrix Metalloproteinases