Smad7 as a Target for Immunomodulation Strategy in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBD) are chronic inflammatory pathologies of the gut, characterized by a relapsingremitting course. Although IBD pathogenesis is not fully understood, epidemiological and experimental data suggest that multiple environmental factors can, in genetically predisposed individuals, trigger an excessive immune response directed against the antigens of the normal intestinal microflora, which eventually leads to the tissue damage. Defects in the physiological mechanisms/factors of counter-regulation contribute to amplify and sustain such a detrimental response. For instance, in inflamed tissue of IBD patients there is diminished activity of the immunesuppressive cytokine transforming growth factor (TGF)-β1, due to elevated levels of Smad7, an intracellular inhibitor of TGF-β1 signaling. Consistently, knockdown of Smad7 with a specific antisense oligonucleotide suppresses inflammatory signals in cultured intestinal cells of IBD patients and in the gut of mice with IBD-like experimental colitis. Moreover, treatment of patients with active Crohn's disease, one of the two major IBD in human beings, with Mongersen, an oral compound containing Smad7 antisense oligonucleotide, is accompanied by induction of clinical remission. Altogether these data indicate that targeting Smad7 represents a promising approach to modulate the ongoing mucosal inflammation in IBD.

Smad7 in psoriasis vulgaris patients: A clinical and immunohistochemical study

“…Smad7 inflammatory role in immune‐mediated inflammatory diseases can be confirmed by reviewing previous studies. Sedda et al 26 demonstrated the inflammatory role of Smad7 in inflammatory bowel disease. In addition, they support the concept that knockdown of Smad7 with Mongersen as targeted therapy can be a promising therapeutic approach to modulate the ongoing mucosal inflammation in inflammatory bowel disease.…”