SuperGAGs for Intravesicular Treatment of Interstitial Cystitis

ABSTRACT The goal of this PhaseSTTR project is to demonstrate the efficacy of a novel class of proteoglycanmimic biopolymers for the treatment of interstitial cystitis bladder pain syndromeIC BPSIC BPS is a chronic disease characterized by lower pelvic painurinary urgency and frequencyand urge incontinenceChronic pain results from a disruption of the protective glycosaminoglycanGAGlayer of the luminal bladder wall urotheliumcausing permeability and urinary leakageThere are few therapeutic options and approved treatments have met with limited successHencethemillion Americans suffering with IC BPS face a lifetime of chronic debilitating abdominal painOne promising treatment option to restore bladder impermeability is GAG replenishment therapyHoweverthe single chainlow molecular weightMWGAGs currently used do not properly mimic the proteoglycan bound GAG layer of the normal urotheliumand response rates are lowProteoglycans display multiple sulfated GAG chains in clusterscreating zones of high anionic charge and osmotic hydrationThereforeGlycologix has developed a novel and innovative family of high MWbranched biopolymers known as superGAGs that mimic the structure of proteoglycansSuperGAGs display clustered arrays of sulfated GAG chainsand have been designed to improve adherence to the urothelium due to their greater sizedendritic structureand affinity for the bladder surfaceSynthesis of first generation superGAGs has demonstrated the feasibility of this novel synthetic chemistryThe next technical challenge is to exploit the modular nature of superGAG chemistry to provide second generation compounds bearing targeting ligands with even greater affinity for the bladder wallAimis to synthesize and characterize novel superGAG biopolymers for use in treating IC BPSSuperGAGs bearing targeting ligands will be prepared to bind with lectins known to reside on the bladder wallThese biopolymers will preferentially adhere to the urothelium and more effectively restore impermeabilityTargeted and untargeted superGAGs will be characterized by analytical size exclusion chromatography coupled with multi angle laser light scatteringAimis to compare the effectiveness of superGAG biopolymers in a wellestablished clinically validated rat model of induced IC BPS in which bladder permeability is induced by protamine sulfateStudy rats will be treated with superGAG biopolymers and comparators by intravesicular instillationQuantitative contrast enhanced magnetic resonance imaging will be used to measure restoration of bladder impermeability and prevention of colitis due to organ crosstalkAimis to confirm superGAG efficacy by measuring the permeability of bladder and colon tissue by transepithelial electrical resistance in a Ussing chamberIn another set of study ratsthe ability of superGAG treatment to reduce pelvic pain will be assessed by quantifying pain responses to the application of von Frey filaments to the suprapubic area PROJECT NARRATIVE Interstitial cystitis bladder pain syndromeIC BPSis a chronic disease characterized by lower pelvic painurinary urgency and frequencyand urge incontinenceIt is a disease with high prevalencemillion Americansand morbidityand the few available therapeutic options are not highly effectiveThis project will test a novel class of therapeutic biopolymers designed to be more effective in repairing the damaged bladder liningrestoring normal bladder function and preventing chronic abdominal pain