Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder

膀胱内反义疗法治疗膀胱过度活动症的药理学

• 批准号: 8432297
• 负责人: MICHAEL B CHANCELLOR
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432297
• 关键词: Pharmacology; Intravesical; Antisense; Based; Therapy

Because of current, limited options for treating overactive bladder (OAB) or lower urinary tract symptoms (LUTS), there is a great demand for the development of new treatment strategy. In this application, the following key aims utilize unique and innovative expertise, available at William Beaumont Hospital and University of Pittsburgh to develop new therapeutic options for OAB and detrusor overactivity (DO) by especially targeting bladder afferent hyperexcitability, which has been proposed as one of the important mechanisms underlying OAB, using rats with spinal cord injury (SCI). Sequence-specific gene- silencing mechanism is a promising approach for developing therapeutics agent based on rational gene-based drug design. In the current proposal, we propose to use this approach for silencing nerve growth factor (NGF) gene locally in the bladder. Local inhibition of NGF gene in bladder akin to antisense eye drops for corneal angiogenesis can avoid the safety concerns noted with systemic anti-NGF therapy from monoclonal human NGF antibodies (tanezumab) such as paresthesia, hypoesthesia and arthralgia. By comparing the pharmacology of NGF antisense administered via different routes, we propose to investigate the contribution of NGF derived from urothelium on afferent hyperexcitability leading to DO in SCI animals. Secondly, we will also test the hypothesis of OAB pathology triggered by changes in voltage- gated sodium and potassium channels, increased cytokines expression/release as well as muscarinic receptors, and such changes are mediated by excessive NGF expression in bladder. The proposed experiments will use antisense to elucidate whether NGF inhibition could normalize changes in muscarinic and ion channel mechanisms contributing to afferent hyperexcitability resulting in DO/OAB. We will study the changes in the local muscarinic cholinergic mechanism underlying DO, including altered sensitivity to various antimuscarinic agents. This mechanism is important to investigate because there is increasing evidence that non-neural acetylcholine (ACh) released from the urothelium during stretch can activate muscarinic receptors, leading to modulation of afferent pathways during the micturition reflex, and that increased ACh levels in the bladder can induce OAB mediated by the local effects on muscarinic receptors in the urothelium/suburothelium. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of OAB.

由于目前的治疗过度活跃膀胱（OAB）或较低尿路的选择有限 症状（LUTS），对新治疗策略的制定有很大的需求。在 此应用程序，以下关键目的利用了独特和创新的专业知识，可在 威廉·博蒙特医院和匹兹堡大学开发新的治疗选择 尤其是OAB和越野越过的过度活动（DO） 靶向膀胱传入过度兴奋性，已被提出为重要的 使用脊髓损伤（SCI）的大鼠OAB的机制。序列特异性基因 沉默机制是开发基于治疗剂的有前途的方法 基于理性基因的药物设计。在当前的建议中，我们建议将这种方法用于 沉默的神经生长因子（NGF）基因在膀胱中局部。局部抑制NGF基因在 类似于反义眼滴的角膜血管生成的膀胱可以避免安全问题 用单克隆人NGF抗体（Tanezumab）的全身性抗NGF治疗记录 例如异常，低觉和关节痛​​。通过比较NGF的药理学 通过不同的途径施用的反义，我们建议研究NGF的贡献 源自尿路上皮的传入过度兴奋性，导致SCI动物的尿皮性。 其次，我们还将检验由电压变化引发的OAB病理学的假设。 封闭式钠和钾通道，细胞因子表达/释放增加以及 毒蕈碱受体和这种变化是通过膀胱中的NGF表达过多的。 提出的实验将使用反义来阐明NGF抑制是否可以 标准化有助于传入的毒蕈碱和离子通道机制的变化 过度兴奋性导致DO/OAB。我们将研究当地毒蕈碱的变化 DO的胆碱能机制，包括对各种抗毒酸的敏感性的改变 代理商。这种机制对于调查很重要，因为有越来越多的证据表明 在拉伸期间从尿皮上释放的非神经乙酰胆碱（ACH）可以激活 毒蕈碱受体，导致在排尿反射期间调节传入途径， 膀胱中的ACH水平提高可以诱导局部对OAB的介导 尿路上皮/尿皮细胞中的毒蕈碱受体。研究的长期目标 计划将建立新的有效的治疗目标和/或干预策略 OAB的处理。