Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases.

Abstract

The etiology of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD) in humans, is still unknown, but evidence suggests that genetic and environmental factors interact to promote an excessive immune response that leads to tissue damage. Defects in the counter-regulatory mechanisms are also supposed to make a major contribution to the amplification and maintenance of the IBD-related inflammatory response. One such a mechanism involves TGF-β1, a cytokine synthesized by both immune and non-immune cells in the gut, which is essential in the maintenance of immune homeostasis. In both CD and UC, active inflammation occurs in areas characterized by enhanced production of TGF-β1 and reduced ability of this cytokine to activate Smad-associated signaling and suppress inflammatory pathways. The defective TGF-β1 activity is due to elevated levels of Smad7, an intracellular protein that inhibits TGF-β1-associated Smad signaling. Data from original studies and reviews were selected through an accurate research of the literature using the terms "IBD", "colitis", "Crohn's disease", "Smad7", "TGF-β1", "antisense oligonucleotide" and "Mongersen". Twenty-fours studies describing the most accredited hypothesis about IBD pathogenesis and the role of Smad7 in the negative control of TGF-β1 were discussed in the review. Additionally, we reported data from original work illustrating the generation and the in vitro and in vivo effect of a specific Smad7 antisense oligonucleotide on intestinal inflammatory signals. We also discussed the results of phase 1 and phase 2 studies assessing the safety profile and clinical efficacy of Mongersen, an oral Smad7 antisense oligonucleotidecontaining drug, in patients with active CD. Data indicate that, in IBD, high Smad7 contributes to sustain detrimental immune responses and knockdown of this molecule can help attenuate the ongoing mucosal inflammation in patients with such disorders.