Scientific Abstract

Proposal No. IBD-0171R
Principal Investigator:  Laura P. Hale, M.D., Ph.D.
Applicant Organization:  Duke University (Durham, North Carolina, U.S.A.)
Project Title: Therapy of inflammatory bowel disease using LMP-420
Period of Award:  March 1, 2006 – February 28, 2007

The recent introduction of the tumor necrosis factor (TNF) antibody – infliximab has revolutionized the treatment of inflammatory bowel disease (IBD).  However, use of infliximab has significant disadvantages, including high cost, need for administration by injection, stimulation of antibodies that limit drug effectiveness, and long-lasting immunosuppression that can lead to life-threatening opportunistic infections. LMP-420 is a novel purine-based small molecule containing boronic acid that inhibits production of TNF at the transcriptional level. Our preliminary data show that LMP-420 also decreases production of the chemokine MCP-1 that contributes to leukocyte accumulation within IBD mucosa. Furthermore, LMP-420 enhances production of G-CSF, a cytokine currently being evaluated in clinical trials to decrease Th1-mediated inflammation in IBD. Thus far, LMP-420 has primarily been administered by injection for preliminary in vivo studies.  However, it is topically active and poorly absorbed when given orally, suggesting that it has potential for local therapy within the intestine following oral administration. Delivery methods that target drug activity to the colon have previously been shown to both maximize the efficacy and minimize the side effects of IBD drugs such as corticosteroids and 5-aminosalicylic acid. Based on its activity profile in vitro, we hypothesize that in vivo therapy with LMP-420 will decrease intestinal production of pro-inflammatory cytokines such as TNF and MCP-1 and thus decrease intestinal inflammation in IBD. The specific aims of this proposal are: 1) To establish non-toxic doses of LMP-420 that inhibit gastrointestinal production of pro-inflammatory cytokines and chemokines in vivo; and 2) To determine how LMP-420 affects colon inflammation and production of pro-inflammatory cytokines and chemokines in the dextran sulfate sodium (DSS) and IL-10 knockout murine models of colitis. If results of this initial study appear promising, a follow-up proposal will be submitted to address issues related to oral administration as well as the efficacy of LMP-420 in the T cell transfer model of colitis and in treatment of human colon biopsies. This novel drug that could represent a major advance in the therapy of patients with IBD. Furthermore, the additional insight into mechanisms underlying anti-inflammatory efficacy in IBD that will be provided by these studies will be broadly applicable toward development of a variety of improved IBD therapies.