Developing a Novel Peptide Therapeutic for Interstitial Cystitis/Painful Bladder

描述(由申请人提供)：拟议的第一阶段SBIR项目的总体目标是研究一种治疗间质性膀胱炎/疼痛膀胱综合征(IC/PBS)的新型一流候选药物的体内疗效和作用机制。IC/PBS是一种慢性衰弱的膀胱疾病，以剧烈疼痛、尿急和尿频为特征。在美国，大约有100万人患有这种疾病，其中大部分是女性。目前的治疗选择有限，而且往往无效。然而，由于对这种疾病的发病机制缺乏了解，以及缺乏可靠的诊断测试，新疗法的开发变得复杂起来。马里兰大学医学院的苏珊·基伊博士在IC/PBS患者的尿液中发现了一种内源性糖肽，称为抗增殖因子(APF)。APF在体外能有效地抑制上皮细胞的增殖，并被认为通过阻止IC/PBS患者膀胱上皮的再生愈合而在IC的发病机制中发挥重要作用。基于这一发现，已经设计出一种APF的类似物，它是APF活性的拮抗剂。可使IC患者膀胱上皮细胞在体外正常增殖，并能克服APF对紧密连接蛋白表达和细胞旁通透性的影响。拟议的第一阶段SBIR项目将有助于确定进一步开发这种APF类似物作为IC/PBS治疗方法的潜力，并将协助设计筛选试验，以确定治疗这种疾病的潜在新药。候选化合物在IC/PBS小鼠模型中使膀胱上皮特性正常化的能力将被研究。此外，还将利用流式细胞术对该化合物的作用机制进行评价。在第二阶段SBIR项目中，这些研究将通过分析这种化合物在更广泛的剂量条件下的体内疗效来扩展。临床前安全性研究也将在第二阶段进行。第二阶段的另一个重点将是设计和验证一种高通量筛选试验，以识别APF拮抗剂，使用表达APF受体的适当细胞系。在第二阶段之后，将提交IND以支持第一阶段临床研究。这种APF拮抗剂的未来临床开发将包括招募尿液中可检测到APF的患者，从而将治疗重点放在最有可能做出反应的患者身上，从而有可能克服诊断IC的历史难题，IC是一种可能有多种病因的疾病。 公共卫生相关性：这一第一阶段SBIR项目的总体目标是评估一种治疗间质性膀胱炎/疼痛膀胱综合征(IC/PBS)的新疗法的体内活性和作用机制。IC/PBS是一种慢性衰弱的膀胱疾病，以剧烈疼痛、尿急和尿频为特征。对于这种疾病，需要更有效的治疗方法。

DESCRIPTION (provided by applicant): The overall goals of the proposed phase 1 SBIR project are to investigate the in vivo efficacy and mechanism of action of a novel, first-in-class drug candidate for treating interstitial cystitis/painful bladder syndrome (IC/PBS). IC/PBS is a chronic and debilitating bladder disorder characterized by severe pain and urinary urgency and frequency. It afflicts about one million individuals in the US, most of who are women. Current treatment options are limited and often ineffective. However, the development of new therapies has been complicated by a poor understanding of the pathogenesis of the disease and by the lack of reliable diagnostic tests. Dr. Susan Keay at the University Of Maryland School Of Medicine has identified an endogenous glycopeptide known as Antiproliferative Factor (APF) in the urine of patients with IC/PBS. APF potently inhibits epithelial cell proliferation in vitro and is believed to play a major role in the pathogenesis of IC by preventing the regenerative healing of the bladder epithelium in IC/PBS patients. Based on this discovery, an analog of APF has been engineered that is an antagonist of APF activity. It normalizes the proliferation of bladder epithelial cells from IC patients in vitro and also overcomes the effect of APF on tight junction protein expression and paracellular permeability. The proposed Phase 1 SBIR project will help to determine the potential for further development of this APF analog as a treatment for IC/PBS and will assist in the design of a screening assay to identify potential new drugs to treat the disease. The ability of the candidate compound to normalize bladder epithelial properties in a mouse model of IC/PBS will be investigated. In addition, the mechanism of action of the compound will be evaluated using flow cytometry. In the Phase 2 SBIR project, these studies will be extended by analyzing the in vivo efficacy of this compound under a wider range of dosing conditions. Preclinical safety studies will also be carried out in Phase 2. An additional Phase 2 focus would be the design and validation of a high-throughput screening assay for identifying APF antagonists, using an appropriate cell line that expresses the receptor for APF. Following Phase 2, an IND will be filed to support a Phase I clinical study. Future clinical development of this APF antagonist would involve enrolling patients with detectable APF in their urine, thus focusing the treatment on individuals most likely to respond, potentially overcoming the historic problem of diagnosis of IC, a disease that may have more than one etiology. PUBLIC HEALTH RELEVANCE: The overall goals of this Phase I SBIR project are to evaluate the in vivo activity and mechanism of action of a novel therapeutic for interstitial cystitis/painful bladder syndrome (IC/PBS). IC/PBS is a chronic and debilitating bladder disorder characterized by severe pain and urinary urgency and frequency. There is a significant need for more effective therapies for this disease.