title: Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease.
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.
authors.affiliation: Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.forename: Sara
authors.initials: S
authors.lastname: Onali
authors.forename: Francesca
authors.initials: F
authors.lastname: Zorzi
authors.forename: Giulia
authors.initials: G
authors.lastname: Sancesario
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.forename: Emma
authors.initials: E
authors.lastname: Calabrese
authors.forename: Francesca
authors.initials: F
authors.lastname: Viti
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.forename: Livia
authors.initials: L
authors.lastname: Biancone
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
mesh_terms: D000328:Adult; D003424:Crohn Disease / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D010599:Pharmacokinetics; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016376:Oligonucleotides, Antisense; C497806:SMAD7 protein, human; D051906:Smad7 Protein