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（由申请人提供）：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。困扰膀胱的炎症可导致骨盆疼痛、泌尿系统衰弱症状、膀胱纤维化、复发性泌尿道感染和肾功能衰竭。我们根据红斑痤疮皮肤病变的病理生理学推断出膀胱炎症的小鼠模型，该模型表达高水平的抗菌抗菌素肽 LL-37。这种高度阳离子的防御素与红斑痤疮的严重炎症反应相关，并且是其原因。重要的是，LL-37 在泌尿系统中自然产生，在尿路感染期间显着上调，并且似乎会引发严重的膀胱炎症。目前有两种抗炎硫酸多糖用于治疗，但都不是特别有效。首先，肝素通过膀胱内给药，但抗凝血特性和费用限制了其常规使用。其次，Elmiron（多硫酸戊聚糖）是口服给药，起效时间较长，仅对 <50% 的女性有效，且生物利用度较差。非硫酸化糖胺聚糖 (GAG) 透明质酸 (HA) 在美国以外地区以 Cystistat 的形式出售，但功效较低。需要更好的治疗。在此一期项目中，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 正在开发一种新型非抗凝、抗炎硫酸多糖，作为安全有效的炎症调节剂，即半合成糖胺聚糖醚 (SAGE)。 SAGE 还抑制多种加剧炎症的途径，包括 P-和 L-选择素结合、阳离子蛋白酶活性以及晚期糖基化终产物 (RAGE) 受体的激活。具体来说，在这一 I 期 SBIR 项目中，GlycoMira 将探索使用 SAGE GM-1111 覆盖膀胱尿路上皮并在两个具体目标中减少 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共轭物 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。其次，我们将通过膀胱内滴注 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。对组织进行组织学分析，了解髓过氧化物酶活性，以量化中性粒细胞浸润。初步数据表明，GM-1111 覆盖尿路上皮并减少膀胱炎症。 GlycoMira 在犹他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。 公众健康相关性：对美国许多人来说，影响膀胱的炎症是一个重大的泌尿系统健康问题。特别是在患有膀胱疼痛综合征/间质性膀胱炎 (PBS/IC) 的女性中，这些炎症过程会导致严重的症状，包括尿频、膀胱疼痛、夜尿、尿急和盆腔疼痛。拟议的研究具有创新性，旨在了解膀胱炎症的原因并开发新的治疗方法。将开发一种产生膀胱炎症的生理相关方法，以揭示使疾病过程持续下去的新途径。此外，还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症发病机制，并为众多患有 PBS/IC 的患者提供安全有效的新治疗方法。