Novel Glycosaminoglycan Derivatives for Treatment of Bladder Inflammation

用于治疗膀胱炎症的新型糖胺聚糖衍生物

• 批准号: 8198976
• 负责人: THOMAS PRESTON KENNEDY
• 金额: $ 20万
• 依托单位: GLYCOMIRA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198976
• 关键词: Acute; Advanced Glycosylation End Products; Aftercare; Amitriptyline; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Binding; Bioavailable; Bladder; Bladder Diseases; Bladder Tissue; Botox; Chondroitin Sulfates; Chronic; Clinic; Clinical Treatment; Coagulants; Combined Modality Therapy; Data; Data Collection; Defensins; Dimethyl Sulfoxide; Disease; Dose; Ethers; Experimental Models; Female; Fibrosis; Functional disorder; Glycosaminoglycans; Goals; Health; Heparin; Histologic; 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; L-Selectin; Label; Lead; Life; Location; Mediating; Methods; Modeling; Mus; Narcotics; Neutrophil Infiltration; Nocturia; Oral; Pain; Pathogenesis; Pathway interactions; Patients; Pelvic Pain; Penetration; Pentosan Polysulfate; Peptide Hydrolases; Peroxidases; Pharmaceutical Preparations; Phase; Physicians; Polysaccharides; Process; Property; Prophylactic treatment; Protocols documentation; Quercetin; Receptor Activation; Resiniferatoxin; Rosacea; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Time; Tissues; United States; Universities; Unspecified or Sulfate Ion Sulfates; Urinary system; Urinary tract infection; Urologist; Utah; Woman; cathelicidin antimicrobial peptide; effective therapy; experience; gabapentin; in vivo; innovation; intravesical; mouse model; novel; novel therapeutics; painful bladder syndrome; pre-clinical; receptor; response; skin disorder; skin lesion; urinary; urologic

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.

描述（由申请方提供）：膀胱疼痛综合征/间质性膀胱炎（PBS/IC）是一种惰性膀胱疾病，一直是一种使人衰弱的疾病，几乎没有真正有效的治疗选择。影响膀胱的炎性病症可导致骨盆疼痛、使人衰弱的泌尿系统症状、膀胱纤维化、复发性泌尿系统感染和肾衰竭。我们已经开发了一种膀胱炎症的小鼠模型，该模型从酒渣鼻皮肤病变的病理生理学推断，其表达高水平的抗微生物凯萨林菌素肽LL-37。这种高度阳离子防御素与酒渣鼻中的严重炎症反应相关，并且是酒渣鼻中的严重炎症反应的原因。重要的是，LL-37在泌尿系统中天然产生，在尿路感染发作期间显著上调，并且似乎引发严重的膀胱炎症。两种抗炎硫酸多糖目前用于治疗，但都不是特别有效。首先，肝素是膀胱内给药，但抗凝血性能和费用限制其定期使用。第二，Elmiron（戊聚糖多硫酸酯）是口服给药的，起效时间长，仅对<50%的女性有效，生物利用度低。非硫酸化糖胺聚糖（GAG），透明质酸（HA），在美国以外作为Cystistat可获得，但疗效较低。需要更好的治疗。在这个I期项目中，GlycoMira将测试使用新型抗炎GAG衍生物减轻LL-37介导的膀胱炎症的可行性。GlycoMira正在开发一种新的非抗凝、抗炎硫酸多糖，作为安全有效的炎症调节剂，半合成糖胺聚糖醚（SAGE）。SAGE还抑制许多加剧炎症的途径，包括P-和L-选择素结合、阳离子蛋白酶活性和晚期糖基化终产物受体（AGEs）的激活。具体而言，在该I期SBIR项目中，GlycoMira将探索使用SAGE GM-1111涂覆膀胱尿路上皮和减少LL-37介导的膀胱炎症的可行性。首先，将通过膀胱内滴注荧光生物缀合物AlexaFluor-GM-1111来检查SAGE对膀胱组织的定位、结合和渗透，并与AlexaFluor标记的肝素和HA进行比较。第二，我们将通过在膀胱内滴注LL-37的膀胱炎症模型中用GM-1111、肝素或HA进行预处理或后处理来测试GM-1111的治疗潜力。将对组织进行髓过氧化物酶活性的组织学分析，以定量中性粒细胞浸润。初步数据表明，GM-1111覆盖泌尿上皮细胞并减少膀胱炎症。GlycoMira在犹他州大学的合作泌尿科医生认识到GM-1111在临床治疗膀胱炎症方面的潜力。 公共卫生相关性：对美国的许多人来说，影响膀胱的炎症是一个重要的泌尿系统健康问题。特别是在患有称为疼痛性膀胱综合征/间质性膀胱炎（PBS/IC）的衰弱性病症的女性中，这些炎症过程可导致以尿频、膀胱疼痛、排尿困难、尿急和骨盆疼痛为特征的严重症状。拟议的研究是创新的，旨在了解膀胱炎症的原因并开发新的治疗方法。将开发一种生理学相关的方法来创建膀胱炎症，以解开使疾病过程永久化的新途径。此外，将检查新型治疗性硫酸多糖在该模型中成功治疗炎症的功效。该提案的最终目标是更好地了解膀胱炎性发病机制，并为许多患有PBS/IC的患者提供安全有效的新治疗方法。