Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder

由于目前治疗膀胱过度活动症(OAB)或下尿路的选择有限 症状(LUTS)，对发展新的治疗策略有很大的需求。在……里面 该应用程序的以下主要目标是利用独特的创新专业知识，可在 威廉·博蒙特医院和匹兹堡大学将开发新的治疗方案 OAB和逼尿肌过度活动(DO) 针对膀胱传入的高兴奋性，已被提出为重要的 OAB的潜在机制，使用脊髓损伤(SCI)的大鼠。序列特异性基因- 沉默机制是一种很有前途的开发基于 合理的基因药物设计。在目前的提案中，我们建议将此方法用于 在膀胱局部沉默神经生长因子(NGF)基因。神经生长因子基因的局部抑制作用 膀胱类似反义眼药水的角膜血管生成可以避免安全问题 用人NGF单抗(Tanezumab)进行系统抗NGF治疗 如感觉异常、感觉减退、关节痛等。比较神经生长因子的药理作用 通过不同途径给予反义核酸，我们建议研究NGF的作用 来源于尿路上皮对脊髓损伤动物的传入高兴奋性的影响。 其次，我们还将检验电压变化引发的OAB病理假说- 门控钠钾通道，增加细胞因子的表达/释放以及 这种变化是由膀胱中过量表达的NGF介导的。 拟议中的实验将使用反义来阐明NGF抑制是否可以 使参与传入的毒鼠碱和离子通道机制的变化正常化 过度兴奋导致DO/OAB。我们将研究当地毒枭的变化 DO的胆碱能机制，包括对各种抗肌肉碱药物敏感性的改变 探员们。这种机制值得研究，因为有越来越多的证据表明 伸展过程中尿路上皮释放的非神经性乙酰胆碱(ACh)可激活 M受体，在排尿反射中导致传入通路的调制， 而膀胱中ACh水平的升高可以通过局部效应诱导OAB。 尿路上皮/下尿路上皮中的M受体这项研究的长期目标 计划是建立新的和有效的治疗目标和/或干预战略 OAB的治疗。

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.