Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder

描述：由于目前治疗膀胱过度活动症(OAB)或下尿路症状(LUTS)的选择有限，因此对开发新的治疗策略有很大的需求。在这项应用中，以下关键目标利用威廉·博蒙特医院和匹兹堡大学提供的独特和创新的专业知识，通过特别针对膀胱传入高兴奋性，开发OAB和逼尿肌过度活动(DO)的新治疗方案，使用脊髓损伤(SCI)的大鼠，这已被认为是OAB的重要机制之一。序列特异性基因沉默机制是开发基于合理基因药物设计的治疗药物的一条很有前途的途径。在目前的方案中，我们建议使用这种方法来局部沉默膀胱中的神经生长因子(NGF)基因。在膀胱中局部抑制NGF基因，类似于反义眼药水，用于角膜血管生成，可以避免系统抗NGF治疗中出现的人NGF单抗(Tanezumab)的安全性问题，如感觉异常、感觉减退和关节痛。通过比较不同途径给药的NGF反义神经生长因子的药理作用，探讨尿路上皮来源的NGF在脊髓损伤动物DO传入超兴奋性中的作用。其次，我们还将验证OAB病理假说，该假说是由电压门控性钠、钾通道、细胞因子表达/释放增加以及M受体的改变引发的，而这些改变是由膀胱中过度表达的NGF介导的。建议的实验将使用反义来阐明NGF抑制是否可以使导致DO/OAB的传入高兴奋性的M胆碱和离子通道机制的变化正常化。我们将研究DO下局部M胆碱能机制的变化，包括对各种抗M受体药物敏感性的改变。这一机制值得研究，因为越来越多的证据表明，在拉伸过程中从尿路上皮释放的非神经性乙酰胆碱(ACh)可以激活M受体，导致排尿反射期间传入通路的调节，而且膀胱中ACh水平的增加可以通过对尿路上皮/下尿路上皮M受体的局部作用来诱导OAB。该研究计划的长期目标是为OAB的治疗建立新的有效的治疗目标和/或干预策略。

DESCRIPTION: 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.