Phase i clinical trial of smad7 knockdown using antisense oligonucleotide in patients with active crohn's disease

Giovanni Monteleone, Massimo C. Fantini, Sara Onali, Francesca Zorzi, Giulia Sancesario, Sergio Bernardini, Emma Calabrese, Francesca Viti, Ivan Monteleone, Livia Biancone, Francesco Pallone

Research output: Contribution to journalArticle

Abstract

In the gut of patients with Crohn's disease (CD), high Smad7 blocks the immune-suppressive activity of transforming growth factor (TGF)-Β1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/ resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD.

Original languageEnglish
Pages (from-to)870-876
Number of pages7
JournalMolecular Therapy
Volume20
Issue number4
DOIs
Publication statusPublished - Apr 2012

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Monteleone, G., Fantini, M. C., Onali, S., Zorzi, F., Sancesario, G., Bernardini, S., Calabrese, E., Viti, F., Monteleone, I., Biancone, L., & Pallone, F. (2012). Phase i clinical trial of smad7 knockdown using antisense oligonucleotide in patients with active crohn's disease. Molecular Therapy, 20(4), 870-876. https://doi.org/10.1038/mt.2011.290