Gene Therapy for Pain

描述(申请人提供)：疼痛是一种带有情感和认知成分的主观体验，是一种“与实际或潜在的组织损伤相关的令人不快的感觉和情绪体验，在提醒个人注意环境中潜在的有害刺激方面起着至关重要的作用”。但慢性疼痛往往使人失去能力，难以治疗，是一个具有巨大社会影响的棘手的医疗问题。单纯疱疹病毒(HSV)外周接种对背根神经节(DRG)神经元具有高效的天然靶向作用。我们已经证明基于HSV的载体可以用来转导DRG的神经元，以达到在炎症性疼痛、神经病理性疼痛和骨肿瘤引起的疼痛模型中的抗伤害效应。这种作用是局部的，与吗啡有协同作用，尽管对吗啡有耐受性，但仍持续存在。这种治疗疼痛的新方法的临床前数据令人信服。作为对RFA的回应，我们提出了一系列研究，以调查HSV介导的基因转移到DRG可能用于治疗慢性疼痛的假设。这些研究旨在克服临床前原则验证实验和人类疾病治疗方法开发之间的障碍，并创建新的载体来加强特定类型疼痛的基因治疗。 概述了五个具体目标。 具体目的1.明确载体介导的镇痛作用的持续时间和量效特征。 具体目的2.构建具有可调控开关的载体，以控制载体介导的脑啡肽在体内的表达。 具体目的3.检测预先免疫对载体转导的影响，以及重组载体激活潜伏病毒的能力，并研究重复接种载体后的抗伤害反应水平和动力学。 具体目的4.系统评价重组脑啡肽表达载体在啮齿动物体内的生物分布和生物安全性。 具体目的5.在神经病理性、炎症性和癌性疼痛模型中创建和测试基于HSV的新型载体。

DESCRIPTION (provided by applicant): Pain is a subjective experience with affective and cognitive components, an "unpleasant sensory and emotional experience associated with actual or potential tissue damage that serves an essential role in alerting an individual to potentially harmful stimuli in the environment". But chronic pain, often disabling and refractory to treatment, represents a difficult medical problem with enormous societal impact. Herpes simplex virus (HSV) naturally targets with high efficiency to neurons of the dorsal root ganglion (DRG) from peripheral inoculation. We have demonstrated that HSV based vectors can be used to transduce neurons of the DRG to achieve an antinociceptive effect in models of inflammatory pain, neuropathic pain, and pain resulting from tumor in bone. The effect is local, synergistic with morphine, and persists despite tolerance to morphine. The preclinical data for this novel approach to the treatment of pain is compelling. In response to the RFA, we propose a series of studies to investigate the hypothesis that HSV-mediated gene transfer to the DRG may be used to treat chronic pain. These studies are designed to overcome the barriers that stand between preclinical proof-of-principle experiments and the development of a treatment for the human disease, and to create novel vectors to enhance gene therapy for specific types of pain. Five specific aims are outlined. Specific Aim 1. To define the duration and dose-response characteristics of the vector-mediated analgesic effect. Specific Aim 2. To construct a vector with a regulatable "switch" to control vector-mediated enkephalin expression in vivo. Specific Aim 3. To test the effect of prior immunity on vector transduction, the potential of the recombinant vector to reactivate latent virus, and to study the level and kinetics of the anti-nociceptive response following repeated vector re-inoculation. Specific Aim 4. To systematically evaluate biodistribution and biosafety of the recombinant enkephalin expressing vector in rodents. Specific Aim 5. To create and test novel HSV-based vectors in models of neuropathic, inflammatory, and cancer pain.