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

基本信息

批准号：
8528570
负责人：
MICHAEL B CHANCELLOR
金额：
$ 30.49万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/8528570
关键词：
Acetylcholine Adverse effects Afferent Neurons Afferent Pathways Animal Model Animals Anti-Cholinergics Antibodies Applications Grants Arthralgia Attenuated Biotechnology Bladder Bladder Urothelium C Fiber Cells Chronic Constipation Corneal Neovascularization Development Double-Blind Method Drug Design Drug Targeting Eyedrops Foundations Future Gene Silencing Genes Growth Factor Growth Factor Gene Growth Factor Inhibition Human Hypesthesia Increased frequency of micturition Inflammatory Inflammatory Response Injection of therapeutic agent Intervention Intravesical Instillation Ion Channel Label Lead Liposomes Mediating Methods Micturition Reflex Modality Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinic Antagonists Muscarinics Nerve Growth Factor 1 Nerve Growth Factors Neuropeptides Overactive Bladder Paresthesia Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Potassium Channel Production Prostaglandins Pump Quality of life Rattus Receptor Gene Refractory Reporting Research Risk Route Safety Signal Pathway Site Sodium Channel Spinal cord injury Stretching Symptoms TRPV1 gene Techniques Technology Testing Therapeutic Agents Therapeutic Effect University Hospitals Up-Regulation Urine Urothelium Western Blotting Xerostomia base cholinergic comparative efficacy cytokine innovation interest intravesical irritation laser capture microdissection lower urinary tract symptoms mRNA Expression novel novel therapeutic intervention novel therapeutics patch clamp programs prospective protein expression research study therapeutic target therapy design treatment strategy voltage

项目摘要

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.

描述：由于目前的治疗过度活跃膀胱（OAB）或较低尿路症状（LUTS）的选择有限，因此对开发新治疗策略的需求很大。 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).序列特异性基因分解机制是基于基于理性基因的药物设计开发治疗剂的有前途的方法。在当前的建议中，我们建议使用这种方法将膀胱局部局部的神经生长因子（NGF）基因沉默。膀胱中NGF基因的局部抑制作用类似于反义眼滴来进行角膜血管生成，可以避免通过单克隆人类NGF抗体（Tanezumab）（例如异常，心脏hissepthisia和Arthralgia）的全身性抗NGF治疗所引起的安全问题。通过比较通过不同途径施用的NGF反义的药理学，我们建议研究尿皮细胞对传入过度兴奋性的NGF的贡献，从而导致SCI动物的作用。其次，我们还将检验由电压钠和钾通道的变化触发的OAB病理学的假设，细胞因子表达/释放增加以及毒蕈碱受体的增加，并且这种变化是由Bladder中过度NGF表达介导的。提出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，导致导致过度过度兴奋的性能导致DO/OAB。我们将研究DO的局部毒蕈碱胆碱能机制的变化，包括对各种抗毒毒剂的敏感性改变。这种机制对于调查很重要，因为有越来越多的证据表明，在拉伸过程中从泌尿皮上释放的非神经乙酰胆碱（ACH）可以激活毒蕈碱受体，从而导致尿液反射过程中传入途径的调节，并且在膀胱中诱导OAB的ACh在肌肉素的受体中介导的OAB介导的OAB介导的OAB介导的肌肉受体介导的OAB介导。研究计划的长期目标是建立新的有效的治疗靶标和/或干预策略来治疗OAB。