UBC Theses and Dissertations
Evaluating the effects of GlycoCaged dexamethasone in SHIP-deficient mice Luzentales-Simpson, Matthew
Inflammatory bowel disease (IBD), encompassing Crohn’s Disease (CD) and ulcerative colitis, is characterized by gastrointestinal inflammation. Inflammation can be chronic, relapsing and remitting, or progressive, and accompanied by symptoms of pain, nausea, and diarrhea. Treatment in children or people with mild-to-moderate IBD follows a step-up approach to therapy, beginning with NSAIDs before moving to steroids, immunomodulators, and finally biologics. Though corticosteroids reduce inflammation, their use is limited by adverse dose-dependent systemic effects which include, but are not limited to immunosuppression, mood changes, and, in children, negative effects on growth and development. We present the use of a drug delivery system, termed “GlycoCage” in a SHIP-deficient (SHIP-/-) mouse model of CD-like ileitis, conjugated to the corticosteroid, dexamethasone (DEX). The GlycoCage renders active corticosteroids inactive until they are released from the GlycoCage. “De-caging” relies on commensal bacteria which produce enzymes, called xyloglucanases, to digest the GlycoCage and release active corticosteroid near the site of disease. I found that xyloglucanase activity along the gastrointestinal tract of SHIP-/- mice is inducible with 2% xyloglucan supplementation in the diet essentially priming the microbiome to release GlycoCaged therapies. I also found that the CD-like ileitis in SHIP-/- mice can be treated with GlycoCaged DEX at a minimum effective dose 10-fold lower than free DEX. Specifically, I observed doses of GlycoCaged DEX 10-fold lower than that of free DEX resulted in a reduction of gross ileal pathology, histopathology, and inflammatory cytokine production in the distal ileum of SHIP-/- mice. Additionally, I observed off-target effects on the lungs and mesenteric lymph nodes when mice were treated with free DEX. These off-target effects were eliminated when mice were treated with GlycoCaged DEX. Together my data suggests GlycoCaged DEX is more efficacious and has reduced off-target effects when compared to free DEX, supporting its potential to improve current corticosteroid treatments for IBD. This work provides the foundation for analyzing the GlycoCage in murine models of intestinal inflammation and supports further research to explore its applications for human use.
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