Clinical Studies of Inflammatory Bowel Diseases

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This program is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD) AND to using basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include: 1. Completing a pilot study of the safety and efficacy of a novel oral agent targeting IL-12p40 in the inflammatory enteropathy affecting a subset of common variable immunodeficiency patients (we reported on this IBD in Gastroenterology 131:748-756, 2006). We enrolled four patients and observed at least one subject who had significant reversal of symptoms including steatorrhea, d-xylose absorption, weight gain, and improvement in cytopenias. 2. Collaborating with Biogen-Idec on a Phase II study using Avonex (Interferon beta 1a) in ulcerative colitis. Using the results of our NIH-based open-label trial in UC, we are moving forward with plans for a multi-center proof-of-concept placebo-controlled trial to further test the safety and efficacy of this type-I interferon in UC. 3. Initiating a protocol to study the immune abnormalities and response to conventional IBD therapy for Hermansky-Pudlak syndrome patients who develop idiopathic colitis. Hermansky-Pudlak syndrome (HPS) is a model inherited disease for study of IBD etiology because it is caused by a defect in interacting proteins due to single gene mutations on different chromosomes. Patients with HPS have loss of pigment in the skin and eye (oculocutaneous albinism) with reduced vision, a platelet disorder leading to easy bleeding, and may develop pulmonary fibrosis. Patients with HPS also have a risk of IBD over ten-fold greater than the general population; the colitis may be granulomatous and we have shown that it is associated with only two of the known HPS gene defects. Active NIH protocols included in this program during this past year (Dr. Mannon as PI): 82-I-0183 Studies of the Immune Regulation of Idiopathic Inflammatory Bowel Diseases: Crohns Disease, Ulcerative Colitis, and Undefined Inflammatory Conditions of the Gut (including 02-I-0153 The Immune Basis for the Gastrointestinal Complications of Common Variable Immunodeficiency 02-I-0019 Granulocyte-Colony Stimulatiing Factor Treatment for Crohns Disease:A Pilot Study Assessing Immune and Clinical Response 03-I-0019 An Open-label, Pilot Study of Type I Interferon Treatment of Ulcerative Colitis 04-I-0231 Procurement of Clinical Specimens for Immunologic or Genetic Studies in Inflammatory Bowel Diseases 06-I-0021 A Randomized, Double-blind, Pilot Study of the Oral IL-12/23 Inhibitor, STA-5326 mesylate, to Investigate Peripheral Blood and Mucosal Mononuclear Cell Phenotype and Cytokine Responses in Patients with Crohns Disease 06-I-0037 A Pilot Study of Safety and Efficacy of the Oral IL-12/23 Inhibitor, STA-5326 Mesylate, for Symptomatic Gastrointestinal Inflammation Associated with Common Variable Immunodeficiency 07-I-0205 An Observational Study of the Immunopathogenesis of and Response to Step-Up Inflammatory Bowel Disease Therapy for Hermansky-Pudlak Syndrome-Associated Colitis