Scientific Abstract
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
Crohn’s disease (CD) is a serious and chronic illness that primarily affects the small intestine and colon, and is characterized by segmental, transmural inflammation and tissue damage. Since the cause of CD is unknown, medical management of CD is largely symptom-based. Imunosuppressive drugs and anti-TNFα antibodies promote mucosal healing, but more than one third of patients do not respond to these therapies, and efficacy may wane with time. Therefore, there is great interest in identifying new molecules/pathways that can be therapeutically targeted in CD. Novel therapeutic compounds have been predicated on the hypothesis that CD results from an exaggerated immune response, occurring in genetically susceptible individuals, and directed against components of the bacterial flora. Such hyper-immune reactivity is in part dependent on the inability of the mucosal immune system to mount a vigorous and effective counter-regulatory response. For example, studies conducted in our laboratory have previously shown that, in CD, there is a defective activity of the suppressive cytokine TGF-beta1, due to high levels of Smad7, an intracellular protein that binds to the TGF-beta1 receptor and prevents TGF-beta1-driven signalling. Consistently, treatment of CD mucosal cells with a specific Smad7 antisense oligonucleotide restored TGF-β1 activity, with the down-stream effect of inhibiting inflammatory cytokine production. Moreover, in vivo in mice, oral administration of Smad7 antisense oligonucleotide attenuated experimental colitis, thus suggesting that Smad7 constitutes a potential molecular target for direct therapeutic interventions in CD.
To inhibit gut mucosal expression of Smad7, we developed a Smad7 antisense oligonucleotide-containing pharmaceutical compound, herein termed GED0301. GED0301 is an oral gastro-resistant formulation with a pH-dependent, delayed-release of the oligonucleotide in the terminal ileum and right colon. Pre-clinical studies showed that oral GED0301 limited experimental colitis in mice and that such a treatment was not toxic in mice and cynomologus monkeys. Therefore, we have designed a Phase 1 clinical trial to assess the tolerability, pharmacokinetics, and safety of GED0301. In this non-randomized, open-label study, GED0301 will be administered to active CD patients once daily for 7 days. We aim also at obtaining preliminary evidence for the therapeutic benefits of GED0301 in CD and ascertaining whether GED0301 administration leads to a reduced expression of surrogate markers of inflammation and/or changes in the peripheral blood fractions of effector and regulatory T cells.
Results of this study will advance our understanding of Smad7 in the pathogenesis of IBD, and provide useful information about the mechanism responsible for the efficacy of GED0301, thus opening up new avenues of research and therapy.