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），对新的治疗策略的发展有很大的需求。在 此应用程序，以下主要目的是利用独特的和创新的专业知识，可在 威廉博蒙医院和匹兹堡大学开发新的治疗选择， OAB和逼尿肌过度活动（DO），特别是 靶向膀胱传入过度兴奋，这已被提出作为重要的 OAB的潜在机制，使用脊髓损伤（SCI）大鼠。序列特异性基因- 沉默机制是一种很有前途的方法，用于开发基于 基于基因的合理药物设计在目前的建议中，我们建议使用这种方法， 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 膀胱类似于角膜血管生成的反义滴眼液可以避免安全性问题 注意到使用单克隆人NGF抗体（tanezumab）进行全身性抗NGF治疗 例如感觉异常、感觉减退和关节痛。通过比较神经生长因子的药理作用， 通过不同的途径给予反义，我们建议调查的贡献， 来源于尿道刺激对SCI动物中导致DO的传入过度兴奋的影响。 其次，我们还将测试由电压变化触发的OAB病理的假设- 门控钠和钾通道，增加细胞因子表达/释放以及 毒蕈碱受体，并且这种变化由膀胱中过量的NGF表达介导。 拟议的实验将使用反义来阐明NGF抑制是否可以 正常化毒蕈碱和离子通道机制的变化，有助于传入 过度兴奋导致DO/OAB。我们将研究当地毒蕈碱的变化 DO的胆碱能机制，包括对各种抗毒蕈碱药物的敏感性改变 剂.这一机制的研究很重要，因为越来越多的证据表明， 在牵拉过程中，从尿道释放的非神经乙酰胆碱（ACh）可以激活 毒蕈碱受体，导致排尿反射期间传入通路的调节， 膀胱中ACh水平的增加可诱导OAB，这是由局部效应介导的， 在尿道/尿道下裂中的毒蕈碱受体。研究的长期目标 计划是建立新的和有效的治疗目标和/或干预策略， 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.