The disorders collectively known as inflammatory bowel disease (IBD) including Crohn?s disease (CD) and ulcerative colitis (UC) affect up to one and a half million Americans. Both result from uncontrolled chronic inflammatory activity in the GI tract. Most therapeutic agents act by down-regulating inflammation, are not curative and suffer from significant side-effects. Forty to 60% of patients do not obtain benefit long-term from available treatments and have a two-fold greater risk of developing colorectal cancer. Thus, there is an unmet need for new therapeutic modalities. Numerous groups, including our own, have reported promising results with the anti-inflammatory cytokine interlukin-10 (IL-10). However, clinical trials with systemic IL-10 in IBD patients have been disappointing. Rapid clearance, dose limiting toxicities and lack of oral bioavailability have precluded use. We have developed a proprietary sustained-release formulation of IL-10, which upon oral administration is preferentially taken up and retained in the immune structures of the gut and restores immune homeostasis in the inflamed colon. Preliminary studies in IL-10-/- murine model of colitis demonstrated that oral IL-10 ameliorated both early and established disease without overt toxicity or systemic exposure. In light of these findings, this application will test the therapeutic efficacy of oral IL-10 in two commonly utilized acute and chronic models of murine colitis.
In Aim 1 treatment will be evaluated in the acute dextran sulphate sodium (DSS) model; dose and schedule will be optimized; and finally the effect of IL-10 on the phenotype and functional properties of colonic lamina propria and mesenteric lymph node mononuclear cells will be examined.
Aim 2 will test efficacy in the CD4+CD25- T-cell reconstituted SCID mouse model of chronic colitis, monitor potential side effects and determine how chronic treatment affects inflammatory mononuclear cell activity in the long-term. Local and sustained release of IL-10 directly to the disease microenvironment from orally- administered IL-10 loaded microspheres is expected to provide several advantages, including: a) the ability to directly target the gut leading to increased efficacy, b) the requirement for significantly lower doses, thus reducing the toxic side-effects associated with systemic administration and c) sustained-release, reducing the need for frequent administration.
-PUBLIC HEALH RELEVANCE Inflammatory bowel diseases (IBD) classified as Crohn?s disease (CD) and ulcerative colitis (UC) are chronic disorders of the gastrointestinal tract affecting 1.4 million Americans. Symptoms include diarrhea, nausea, abdominal pain, weight loss and increased risk for colorectal cancer. In extreme cases, they can be fatal. Therapies fall into three groups: anti-inflammatory agents, antibiotics and ?biologics?, macromolecules that target pro-inflammatory lymphocytes or the cytokines they produce. While initial response rates are high, most patients relapse. 80% and 45% of CD and UC patients (respectively) will require surgery. All therapies are associated with potentially serious side effects. An urgent unmet medical need exists for a deeper understanding of pathogenesis and novel, targeted therapies. This proposal seeks to develop an orally administered, immune based therapy for IBD using proprietary methods for the microencapsulation of macromolecules that can safely, sustainably and conveniently deliver a potent immune regulatory signal directly to the gut.
