GENE THERAPY FOR BLADDER PAIN

我们计划项目提案的项目2题为“膀胱疼痛的基因治疗”（P.I.：吉村直树， 泌尿科）。这是一项临床前研究，将研究基因治疗方法， 下尿路（LUT）内脏痛的治疗。 间质性膀胱炎（1C）是一种病因不明的疼痛性膀胱综合征，其特征在于慢性盆腔炎。 疼痛、尿频和尿急。它影响了美国估计45万人。尽管 这种高发病率的1C患者的疼痛相关症状往往很难治疗;因此， 对于许多难治性1C患者来说，迫切需要新的疗法。在这个研究项目中，我们 提出了一种新的基因治疗策略，使用单纯疱疹病毒（HSV）为基础的载体来治疗疼痛， LUT内脏疼痛的几种啮齿动物模型。通过利用HSV的天然生物学， 载体可以将基因产物直接递送到靶器官特异性感觉通路， 支配膀胱尿道和骨盆底我们将使用两种方法作为我们的治疗策略。 第一种方法将使用含有前enkaphlin或谷氨酸脱羧酶（GAD）基因的HSV载体， 为了增加内源性阿片肽enkepahlin或抑制剂的量， 神经递质γ-氨基丁酸（GABA）在脊髓的背角（DH）内。第二 一种方法将使用含有抗炎性白细胞介素-4（IL-4）或截短的肿瘤的HSV载体 坏死因子α受体（TNFalphaSR）基因，以减少炎症反应， DH或靶器官。 本文提出的实验结果将确定几个重要问题：（1）基于HSV的 病毒载体可以在局部注射到不同的细胞后将治疗基因转移到传入途径。 （2）膀胱传入通路中HSV载体介导的转基因表达可 预防和/或逆转急性C-纤维的不同动物模型中LUT的疼痛和刺激 （3）HSV载体介导的转基因表达也可以对 慢性动物模型中C纤维过度兴奋诱导的伤害性反应和/或尿频 LUT中的组织炎症或神经损伤。 该研究计划的长期目标是建立一种安全有效的基因治疗方法， 使用携带治疗基因的HSV载体治疗慢性膀胱和/或骨盆疼痛 与疼痛性膀胱综合征相关，包括1C。

Project 2 of our program project proposal is entitled "Gene therapy for bladder pain" (P.I.: Naoki Yoshimura, Department of Urology). This is a preclinical study that will investigate a gene therapy approach in the treatment of visceral pain in the lower urinary tract (LUT). Interstitial cystitis (1C) is a painful bladder syndrome of unknown etiology, characterized by chronic pelvic pain, urinary frequency and urgency. It affects an estimated 450,000 people in the United States. Despite this high incidence the pain-related symptoms in patients with 1C are often very difficult to treat; therefore new therapies are desperately needed for the many sufferers with refractory 1C. In this research project, we propose a novel gene therapy strategy using herpes simplex virus (HSV)-based vectors to treat pain in several rodent models of visceral pain of the LUT. By utilizing the natural biology of HSV, HSV-based vectors can deliver gene products directly to target organ-specific sensory pathways such as those innervating the bladder, urethra, and pelvic floor. We will use two approaches for our treatment strategy. The first will employ HSV vectors containing the proenkaphlin or glutamic acid decarboxylase (GAD) gene in order to increasing the amount of the endogenous opioid peptide enkepahlin or the inhibitory neurotransmitter gamma-amino butyric acid (GABA) within the dorsal horn (DH) of the spinal cord. The second approach will employ HSV vectos containing the anti-inflammatory interleukin-4 (IL-4) or truncated tumor necrosis factor alpha receptor (TNFalphaSR) genes in order to reduce the inflammatory response either in the DH or the target organ. The outcomes of the experiments proposed here we will determine several important issues: (1) HSV-based viral vectors can transfer therapeutic genes to afferent pathways after local injections into the different portions of the LUT, (2) HSV vector-mediated transgene expression in bladder afferent pathways can prevent and/or reverse pain and irritation of the LUT in the different animal models of acute C-fiber sensitization, (3) HSV vector-mediated transgene expression can also have therapeutic effects on nociceptive responses and/or urinary frequency induced by C-fiber hyperexcitability in chronic animal models of tissue inflammation or nerve injury in the LUT. The long-term objectives of the research program are to establish a safe and effective method of gene therapy using HSV vectors carrying therapeutic genes for the treatment of chronic bladder and/or pelvic pain associated with painful bladder syndromes including 1C.