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.
Thesaurus Terms: 1-(Aminomethyl)Cyclohexaneacetic Acid;1-Propanamine, 3-(10,11-Dihydro-5h-Dibenzo(A,D)Cyclohepten-5-Ylidene)-N,N-Dimethyl-;2-(2-(4-((4-Chlorophenyl)Phenylmethyl)-1-Piperazinyl)Ethoxy)Ethanol;4h-1-Benzopyran-4-One, 2-(3,4-Dihydroxyphenyl)-3,5,7-Trihydroxy-;Acne Rosacea;Acute;Advanced Glycation End Products;Advanced Glycosylation End Products;After Care;After-Treatment;Aftercare;Amitriptyline;Anti-Inflammatories;Anti-Inflammatory Agents;Anti-Inflammatory;Antiinflammatories;Antiinflammatory Agents;Atarax;Behavior;Binding;Binding (Molecular Function);Bioavailable;Bladder;Bladder Diseases;Bladder Disorder;Bladder Instillations;Bladder Tissue;Bladder Urinary System;Body Tissues;Botox;Cd62l Antigens;Cramp Protein;Chondroitin Sulfates;Chronic;Clinic;Clinical Treatment;Cnlp;Coagulants;Combined Modality Therapy;Cutaneous Disorder;Dmso;Data;Data Collection;Defensins;Demasorb;Demeso;Dermatoses;Dimethyl Sulfoxide;Dimethylsulphinyl;Dimethylsulphoxide;Disease;Disorder;Domoso;Dose;Dromisol;Drugs;Dysfunction;Esteroproteases;Ethers;Experimental Models;Female;Fibrosis;Functional Disorder;Glycans;Glycosaminoglycans;Goals;Health;Hemi-Myeloperoxidase;Heparin;Heparinic Acid;Histologic;Histologically;Hyaluronan;Hyaluronic Acid;Hydroxyzine;Increased Frequency Of Micturition;Indolent;Infection;Inflammation;Inflammatory;Inflammatory Response;Inorganic Sulfates;Interstitial Cystitis;Intravesical Instillation;Investigational New Drug Application;Kidney Failure;Kidney Insufficiency;L-Selectin;Lam-1;Lam-1 Leukocyte Adhesion Molecule;Lecam-1;Loinc Axis 2 Property;Label;Lead;Leu-8 Antigen;Life;Location;Lymphocyte Adhesion Molecule 1;Mediating;Medication;Mel-14 Antigen;Methods;Mice;Mice Mammals;Modeling;Molecular Interaction;Mucopolysaccharides;Multimodal Therapy;Multimodal Treatment;Multimodality Treatment;Murine;Mus;Myeloperoxidase;Narcotics;Neurontin;Neutrophil Infiltration;Neutrophil Recruitment;Nocturia;Nycturia;Oral;Pain;Painful;Pathogenesis;Pathway Interactions;Patients;Pb Element;Pelvic Pain;Penetration;Pentosan Polysulfate;Peptidases;Peptide Hydrolases;Peroxidases;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Physicians;Physiopathology;Polysaccharides;Prevention Measures;Process;Property;Prophylactic Treatment;Prophylaxis;Proteases;Proteinases;Proteolytic Enzymes;Protocol;Protocols Documentation;Quercetin;Receptor Activation;Receptor Protein;Renal Failure;Renal Insufficiency;Renal/Urologic Organ System;Resiniferatoxin;Rosacea;Sbir;Sbirs (R43/44);Skin Diseases;Skin Diseases And Manifestations;Small Business Innovation Research;Small Business Innovation Research Grant;Sulfates;Sulfinylbis(Methane);Symptoms;Tq1 Antigen;Testing;Therapeutic;Time;Tissues;United States;Universities;Unspecified Or Sulfate Ion Sulfates;Urinary Frequency;Urinary System;Urinary Tract (All Sites);Urinary Tract Infection;Urinary Tract Infectious Disease;Urologic/Renal Body System;Urologist;Utah;Vistaril;Woman;Xylan Hydrogen Sulfate;Xylan Polysulfate;Advanced Glycation Endproduct;Amitryptiline;Cathelicidin Antimicrobial Peptide;Cathelin-Like Protein;Cathelin-Related Antimicrobial Peptide;Combination Therapy;Combined Modality Treatment;Combined Treatment;Disease/Disorder;Drug/Agent;Effective Therapy;Effective Treatment;Experience;Gabapentin;Heavy Metal Pb;Heavy Metal Lead;Hydrogen Sulfate Chondroitin;In Vivo;Innovate;Innovation;Innovative;Intravesical;Mouse Model;Multimodality Therapy;New Therapeutics;Next Generation Therapeutics;Novel;Novel Therapeutics;Painful Bladder Syndrome;Pathophysiology;Pathway;Post Treatment;Pre-Clinical;Preclinical;Receptor;Response;Skin Disorder;Skin Lesion;Sulfate;Trial Regimen;Trial Treatment;Urinary;Urinary Bladder;Urinary Bladder Disorder;Urologic;Urological
