Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases.

Abstract

The aetiology of both Crohn's disease and ulcerative colitis, the major forms of inflammatory bowel diseases in human beings, remains unknown. However, compelling evidence suggests that the associated pathological process in inflammatory bowel disease is driven by an excessive immune response directed against normal components of the bacterial microflora and marked by defects in counter-regulatory mechanisms, such as those involving transforming growth factor-β1. Indeed, a diminished activity of transforming growth factor-β1, as indicated by a reduced phosphorylation of Smad3, a signalling molecule associated with the activated transforming growth factor-β receptor, is evident in the inflamed gut of inflammatory bowel disease patients and this alteration is due to high Smad7, an intracellular inhibitor of Smad3 phosphorylation. Consistently, silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-β1/Smad3 signalling, thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice. These findings together with the demonstration that Smad7 antisense oligonucleotide is safe and well-tolerated in patients with Crohn's disease indicate that Smad7 antisense oligonucleotide-based pharmaceutical compounds could enter the therapeutic armamentarium of these disorders. In this article we review the available data supporting the pathogenic role of Smad7 in the gut and discuss why Smad7 antisense therapy could help dampen the mucosal inflammation in inflammatory bowel disease.

• Authors: Francesca Zorzi, Erika Angelucci, Silvia Sedda, Francesco Pallone, Giovanni Monteleone
• Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (Dig Liver Dis) Vol. 45 Issue 7 Pg. 552-5 (Jul 2013) ISSN: 1878-3562 [Electronic] Netherlands
• PMID: 23287011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Oligonucleotides, Antisense
• SMAD3 protein, human
• SMAD7 protein, human
• Smad3 Protein
• Smad7 Protein
• Transforming Growth Factor beta1

Topics

• Animals
• Humans
• Inflammatory Bowel Diseases (drug therapy, immunology)
• Mice
• Oligonucleotides, Antisense (therapeutic use)
• Signal Transduction (immunology)
• Smad3 Protein (immunology)
• Smad7 Protein (antagonists & inhibitors, genetics, immunology)
• Transforming Growth Factor beta1 (immunology)