Mongersen, an oral Smad7 antisense oligonucleotide, in patients with active Crohn's disease

Abstract

In Crohn's disease (CD), the tissue-damaging inflammation is sustained by defects of counter-regulatory mechanisms, which normally inhibit immune-inflammatory signals and promote repair of mucosal injury. In particular, in inflamed gut of CD patients there are elevated levels of Smad7, an intracellular protein that inhibits the function of transforming growth factor (TGF)-β1. Knockdown of Smad7 with a specific antisense oligonucleotide, named mongersen, restores TGF-β1 activity thus leading to suppression of inflammatory pathways and resolution of colitis in mice. Consistently, oral administration of mongersen to patients with active CD induces clinical remission. In this article, we review the available data supporting the pathogenic role of Smad7 in CD and discuss the results of recent phase I and II trials assessing the efficacy and safety of mongersen in CD patients.

Keywords: IBD; Smad7; TGF-β; colitis; mucosal immunity.

Figure 1.

Schematic illustration showing the TGF-β1-associated Smad pathway in normal (a) and inflamed (b) intestine. Physiologically active TGF-β1 binds to the TGF-β receptor subunit II (RII) and promotes phosphorylation (p) and activation of TGF-β receptor subunit I (RI), thus leading to phosphorylation of Smad2 and Smad3. Once phosphorylated, Smad2 and Smad3 interact with Smad4 and the complex translocates to the nucleus, where it controls the transcriptional activity of multiple genes, including those encoding for inflammatory molecules (a). In the gut of patients with inflammatory bowel diseases (b) there is a defective TGF-β1-associated Smad pathway, because cells express elevated levels of Smad7, an intracellular protein whose expression is regulated by molecules that enhance its acetylation status (i.e. p300). Smad7 binds to TGF-βRI and prevents phosphorylation of Smad2 and Smad3, with the downstream effect of suppressing TGF-β1-driven counter-regulatory properties, thus amplifying inflammatory gene expression. TGF, transforming growth factor.