Oral sustained-release IL-10 microspheres for therapy of IBD

Abstract 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 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 IL However clinical trials with systemic IL 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 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 murine model of colitis demonstrated that oral IL 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 in two commonly utilized acute and chronic models of murine colitis In Aim treatment will be evaluated in the acute dextran sulphate sodium DSS model dose and schedule will be optimized and finally the effect of IL on the phenotype and functional properties of colonic lamina propria and mesenteric lymph node mononuclear cells will be examined Aim will test efficacy in the CD CD 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 directly to the disease microenvironment from orally administered IL 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 NARRATIVE 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 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 and 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