Developing a Novel Peptide Therapeutic for Interstitial Cystitis/Painful Bladder

开发一种治疗间质性膀胱炎/膀胱疼痛的新型肽

• 批准号: 8003429
• 负责人: Graham P Allaway
• 金额: $ 18.06万
• 依托单位: CELEK PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003429
• 关键词: Affinity; Binding; Biological Assay; Bladder; Bladder Diseases; Cell Line; Cells; Chronic; Clinical; Clinical Research; Collaborations; Cytoskeleton; Data; Development; Diagnosis; Diagnostic tests; Differentiation Antigens; Disease; Dose; E-Cadherin; Engineering; Enrollment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Etiology; Evaluation; Exposure to; Flow Cytometry; Frequencies; Future; Gene Expression; Glycopeptides; Goals; Government; Healed; Histology; In Vitro; Individual; Interstitial Cystitis; Label; Maryland; Measures; Monoclonal Antibodies; Morphology; Pain; Pathogenesis; Patients; Peptides; Permeability; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Proline; Property; Proteins; Recovery; Relative (related person); Rhodamine; Rhodamines; Rodent; Role; Screening procedure; Signal Transduction; Small Business Innovation Research Grant; Testing; Therapeutic; Thick; Tight Junctions; Time; Toxicology; UPK3 gene; Universities; Urine; Validation; Woman; analog; base; cell growth; design; drug candidate; effective therapy; healing; high throughput screening; in vivo; intravesical; laser capture microdissection; medical schools; micturition urgency; mouse model; novel; novel therapeutics; painful bladder syndrome; pre-clinical; preclinical safety; prevent; programs; protein expression; public health relevance; receptor; regenerative; research study; safety study

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.

描述（由申请方提供）：拟定的I期SBIR项目的总体目标是研究一种治疗间质性膀胱炎/膀胱疼痛综合征（IC/PBS）的新型一流候选药物的体内疗效和作用机制。IC/PBS是一种慢性和使人衰弱的膀胱疾病，其特征是剧烈疼痛和尿急和尿频。在美国，大约有100万人患有这种疾病，其中大多数是女性。目前的治疗选择有限，而且往往无效。然而，新疗法的开发由于对疾病的发病机制的理解不足以及缺乏可靠的诊断测试而变得复杂。马里兰州大学医学院的Susan Keay博士在IC/PBS患者的尿液中发现了一种称为抗增殖因子（APF）的内源性糖肽。APF在体外有效抑制上皮细胞增殖，并被认为通过阻止IC/PBS患者膀胱上皮的再生愈合在IC的发病机制中起主要作用。基于这一发现，APF的类似物已经被工程化，其是APF活性的拮抗剂。它使IC患者膀胱上皮细胞的体外增殖正常化，并且还克服了APF对紧密连接蛋白表达和细胞旁通透性的影响。拟议的1期SBIR项目将有助于确定进一步开发这种APF类似物作为IC/PBS治疗的潜力，并将有助于设计筛选试验，以确定治疗该疾病的潜在新药。将研究候选化合物在IC/PBS小鼠模型中使膀胱上皮特性正常化的能力。此外，将使用流式细胞术评价化合物的作用机制。在II期SBIR项目中，将通过分析该化合物在更广泛给药条件下的体内疗效来扩展这些研究。临床前安全性研究也将在II期进行。另一个2期重点是设计和验证用于鉴定APF拮抗剂的高通量筛选试验，使用表达APF受体的适当细胞系。在II期之后，将提交IND以支持I期临床研究。这种APF拮抗剂的未来临床开发将涉及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应答的个体上，从而可能克服IC诊断的历史问题，IC是一种可能有多种病因的疾病。 公共卫生关系：该I期SBIR项目的总体目标是评估一种新型间质性膀胱炎/膀胱疼痛综合征（IC/PBS）治疗药物的体内活性和作用机制。IC/PBS是一种慢性和使人衰弱的膀胱疾病，其特征是剧烈疼痛和尿急和尿频。对于这种疾病存在对更有效的疗法的显著需求。