Novel Glycosaminoglycan Derivatives for Treatment of Bladder Inflammation

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DESCRIPTION (provided by applicant): Painful bladder syndrome/interstitial cystitis (PBS/IC) is an indolent bladder disorder that has continued to be a debilitating disease with few truly effective treatment options. Inflammatory conditions that afflict the urinary bladder can lead to pelvic pain, debilitating urinary symptoms, bladder fibrosis, recurring urinary infection, and renal failure. We have developed a murine model of bladder inflammation extrapolated from the pathophysiology of skin lesions in rosacea, which express high levels of the antimicrobial cathelicidin peptide LL-37. This highly cationic defensin is both correlated with, and causative for, the profound inflammatory responses in rosacea. Importantly, LL-37 is naturally produced in the urinary system, is significantly upregulated during urinary tract infection episodes, and appears to trigger profound bladder inflammation. Two anti-inflammatory sulfated polysaccharides are currently used for therapy, but neither is particularly effective. First, heparin is administered intravesically, but the anti-coagulant properties and expense limit its regular usage. Second, Elmiron (pentosan polysulfate) is administered orally, has a long lead time for onset of efficacy, is only effective in <50% of women, and is poorly bioavailable. The unsulfated glycosaminoglycan (GAG), hyaluronan (HA), is available outside the US as Cystistat but has low efficacy. A better treatment is needed. In this Phase I project, GlycoMira will test the feasibility of using novel anti-inflammatory GAG derivatives to mitigate LL-37-mediated bladder inflammation. GlycoMira is developing a new class of non-anticoagulant, anti-inflammatory sulfated polysaccharides as safe and effective inflammation-modulating agents, the semi-synthetic glycosaminoglycan ethers (SAGEs). SAGEs also inhibit numerous pathways that exacerbate inflammation, including P- and L-selectin binding, cationic protease activity, and activation of the receptor for advanced glycation end-products (RAGE). Specifically, in this Phase I SBIR project, GlycoMira will explore the feasibility of using the SAGE GM-1111 to coat bladder uroepithelium and to reduce LL-37-mediated bladder inflammation in two Specific Aims. First, the localization, binding, and penetration of the bladder tissues by SAGEs will be examined by intravesical instillation of a fluorescent bioconjugate, AlexaFluor-GM-1111 and compared with AlexaFluor-labeled heparin and HA. Second, we will test the therapeutic potential of GM-1111 by pre-treatment or post-treatment with GM-1111, heparin, or HA in the model of bladder inflammation by intravesical instillation of LL-37. Tissues will be analyzed histologically for myeloperoxidase activity to quantify neutrophil infiltration. Preliminary data suggest that GM-1111 coats the uroepithelium and reduces bladder inflammation. GlycoMira's collaborating urologists at the University of Utah recognize the potential of GM-1111 for clinical treatment of bladder inflammation. PUBLIC HEALTH RELEVANCE: Inflammatory conditions that afflict the urinary bladder are a significant urologic health concern to many in the United States. Specifically in women afflicted with a debilitating condition known as painful bladder syndrome/interstitial cystitis (PBS/IC), these inflammatory processes can lead to severe symptoms characterized by urinary frequency, bladder pain, nocturia, urgency, and pelvic pain. The proposed studies are innovative and aim to understand the cause of bladder inflammation and to develop a new treatment. A physiologically relevant method to create bladder inflammation will be developed to unravel novel pathways that perpetuate the disease process. In addition, novel therapeutic sulfated polysaccharides will be examined for their efficacy in successfully treating inflammation in this model. The ultimate goal of this proposal is to both gain a better understanding of bladder inflammatory pathogenesis, and to provide a safe and effective new treatment for the many patients who suffer from PBS/IC.