Lay Summary

Proposal No. IBD-0301R
Principal Investigator:  Giovanni Monteleone, M.D., Ph.D.
Applicant Organization:  University Tor Vergata of Rome (Italy)
Project Title:  Effect of Smad7 antisense oligonucleotide on clinical, laboratory and immunological variables in patients with active Crohn's disease: the first human experience
Period of Award:  July 1, 2010 - June 30, 2012

In recent years, biologics have transformed the management of difficult-to-treat Crohn’s disease (CD) patients. However these novel therapies do not work in all patients, efficacy may wane with time, and such treatment can associate with serious side-effects. Therefore, the identification of new pathways that cause inflammation in the gut could help develop novel therapies. In this context, we have recently shown that in CD there is a diminished activity of TGF-beta1, an anti-inflammatory molecule, and that this defect relies on the enhanced expression of Smad7, a protein that blocks the TGF-beta1 immunoregulatory function. Indeed, abrogation of Smad7 restores TGF-beta1 activity with the downstream effect of reducing inflammation in the gut. Such observations prompted us to develop a pharmaceutical compound containing an antisense oligonucleotide that is able to inhibit Smad7. Therefore, a Phase 1 study has been designed to assess the safety profile of this compound, termed GED0301, in patients with active CD. The proposed project is aimed at monitoring the clinical course of such patients and assessing whether GED0301 is therapeutically effective. Data from the proposed experiments will help to understand if inhibition of Smad7 may be a novel therapeutic approach for CD.