Gene Therapy for Pain

疼痛基因疗法

• 批准号: 6665163
• 负责人: DAVID J. FINK
• 金额: $ 43.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665163
• 关键词: Alphaherpesvirinae; Rodentias; analgesia; cancer pain; chronic pain; disease /disorder model; enkephalins; gene therapy; inflammation; neurotropic virus; nonhuman therapy evaluation; pain; polyneuritis; spinal ganglion; transfection /expression vector

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.

描述（由申请人提供）：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不愉快的感觉和情感体验，在提醒个体注意环境中潜在的有害刺激方面起着重要作用”。但慢性疼痛，往往致残和难以治疗，是一个具有巨大社会影响的难题。单纯疱疹病毒（HSV）通过外周接种自然而高效地靶向背根神经节（DRG）神经元。我们已经证明，基于HSV的载体可以用于转导DRG的神经元，以在炎症性疼痛、神经性疼痛和骨肿瘤引起的疼痛模型中实现抗伤害性作用。这种作用是局部的，与吗啡协同作用，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是令人信服的。针对RFA，我们提出了一系列研究来探讨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理验证实验和开发人类疾病治疗方法之间的障碍，并创造新的载体，以加强对特定类型疼痛的基因治疗。