Research Project
9556144
ABSTRACT The goal of this Phase 1 STTR project is to demonstrate the efficacy of a novel class of proteoglycan- mimic biopolymers for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). IC/BPS is a chronic disease characterized by lower pelvic pain, urinary urgency and frequency, and urge incontinence. Chronic pain results from a disruption of the protective glycosaminoglycan (GAG) layer of the luminal bladder wall urothelium, causing permeability and urinary leakage. There are few therapeutic options and approved treatments have met with limited success. Hence, the 4-12 million Americans suffering with IC/BPS face a lifetime of chronic debilitating abdominal pain. One promising treatment option to restore bladder impermeability is GAG replenishment therapy. However, the single chain, low molecular weight (MW) GAGs currently used do not properly mimic the proteoglycan-bound GAG layer of the normal urothelium, and response rates are low. Proteoglycans display multiple sulfated GAG chains in clusters, creating zones of high anionic charge and osmotic hydration. Therefore, Glycologix has developed a novel and innovative family of high MW, branched biopolymers known as superGAGs that mimic the structure of proteoglycans. SuperGAGs display clustered arrays of sulfated GAG chains, and have been designed to improve adherence to the urothelium due to their greater size, dendritic structure, and affinity for the bladder surface. Synthesis of first-generation superGAGs has demonstrated the feasibility of this novel synthetic chemistry. The 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 wall. Aim 1 is to synthesize and characterize novel superGAG biopolymers for use in treating IC/BPS. SuperGAGs bearing targeting ligands will be prepared to bind with lectins known to reside on the bladder wall. These biopolymers will preferentially adhere to the urothelium and more effectively restore impermeability. Targeted and untargeted superGAGs will be characterized by analytical size exclusion chromatography coupled with multi-angle laser light scattering. Aim 2 is to compare the effectiveness of superGAG biopolymers in a well- established clinically validated rat model of induced IC/BPS in which bladder permeability is induced by protamine sulfate. Study rats will be treated with superGAG biopolymers and comparators by intravesicular instillation. Quantitative contrast-enhanced magnetic resonance imaging will be used to measure restoration of bladder impermeability and prevention of colitis due to organ crosstalk. Aim 3 is to confirm superGAG efficacy by measuring the permeability of bladder and colon tissue by transepithelial electrical resistance in a Ussing chamber. In another set of study rats, the 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.
