title: TGF-Beta signaling manipulation as potential therapy for IBD.
abstract: Crohn's disease (CD) and ulcerative colitis (UC), two chronic and relapsing inflammatory bowel diseases (IBD), are supposed to develop in genetically-predisposed individuals as a result of an excessive immune mucosal response directed against normal components of the gut microbiota. There is also evidence that defects in counter-regulatory mechanisms play a major role in the pathogenesis of IBD. One such a defect involves TGF-β1, a cytokine produced by multiple cells types and able to inhibit pathogenic responses in the gut. In both CD and UC, TGF-β1 is highly produced but unable to signal through the TGF-β receptor-associated Smad pathway and suppress production of inflammatory molecules. Abrogation of TGF-β1 activity has been related to Smad7, an intracellular protein that binds to TGF-β receptor and inhibits TGF-β1-driven Smad-dependent signalling. Indeed, silencing of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad signalling, thereby down-regulating inflammatory cytokine production and ameliorating experimental colitis in mice. Altogether these observations led to the development of an oral pharmaceutical compound containing the specific Smad7 antisense oligonucleotide (herein termed GED0301), which seems to be safe and well tolerated in CD patients. In this article we summarize the data supporting the pathogenic role of Smad7 in IBD and discuss the recent results of the use of GED0301 in CD.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy. Gi.Monteleone@Med.uniroma2.it.
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.forename: Francesca
authors.initials: F
authors.lastname: Zorzi
authors.forename: Sefora
authors.initials: S
authors.lastname: Codazza
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000276:immunology; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051906:Smad7 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C000588548:GED0301