Gene Therapy for Pain

疼痛基因疗法

• 批准号: 7509496
• 负责人: Carolyn A Fairbanks
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509496
• 关键词: Acute Pain; Adrenergic Receptor; Agmatine; Analgesics; Animal Model; Arginine; Attenuated; Brain Stem; CALCA gene; Calcitonin Gene-Related Peptide; Cerebellum; Characteristics; Chronic; Communities; Conscious; Dependovirus; Development; Dose; Drug Formulations; Enzymes; Excipients; Future; Gene Targeting; Gene Transfer; Genes; Glutamates; Green Fluorescent Proteins; Inflammation; Injection of therapeutic agent; Intravenous; Invasive; Maintenance; Mannitol; Mediating; Methods; Mus; Neurons; Neuropathy; Neurotransmitters; Opioid; Pain; Pain management; Pathway interactions; Penetration; Pharmacologic Substance; Population; Process; Protein Overexpression; Proteins; Protocols documentation; Rattus; Research; Role; Route; S100A12 gene; Safety; Serotyping; Signal Transduction; Spinal Cord; Spinal Ganglia; Spinal Puncture; Spinal Tap; Spinal cord posterior horn; Substance P; System; Testing; Therapeutic; Viral; Viral Vector; adeno-associated viral vector; base; chronic neuropathic pain; chronic pain; design; dorsal horn; gene therapy; genetic manipulation; human S100A12 protein; intravenous administration; neurotransmitter release; novel; painful neuropathy; protein function; therapeutic target; tool; trafficking; vector

DESCRIPTION (provided by applicant): Over the past five decades, the neuroscientific community has made significant progress in our understanding of the organization and function of the spinal cord dorsal horn and dorsal root ganglia (DRG). Many new proteins have been identified as important in the pain signal conduction pathway. Novel gene therapy approaches may offer new opportunities for long-term pain management strategies. The adeno-associated virus (AAV) serotype has been shown to be useful for transduction of neurons in cortex, brainstem, and cerebellum. Its utility for transduction of neurons in the spinal cord and dorsal root ganglia has also been explored; attempts to deliver the AAV vectors to the spinal cord or DRG have only been successful with direct intraparenchymal or intraneural injections. Less invasive and more clinically therapeutic direct lumbar puncture approaches have not successfully transduced the spinal cord. In contrast, we have now succeeded in achieving widespread spinal cord and DRG transduction of the marker green fluorescent protein (GFP) by direct lumbar puncture injection of an AAV serotype 5 (AAV5) in conscious mouse and rat. These preliminary studies support our proposal to optimize delivery and characterize potential function of AAV5 based vectors targeting specific genes known to modulate chronic pain signaling within spinal cord or DRG. Efficient AAV5-mediated genetic manipulation offers substantial opportunities to 1) further study mechanisms underlying chronic pain and 2) develop novel gene-based therapies for the treatment and management of chronic pain using a non-invasive delivery route with established safety margins. The proposed research will assess the utility of delivery of AAV-vector by lumbar puncture as a useful tool for basic scientific study of chronic pain as well as a potential therapeutic delivery option. The primary objectives of the project are: 1) To optimize delivery to the spinal cord and DRG and characterize the distribution of the AAV5-GFP construct. 2) To validate this approach, in a system well established in the pain signal conduction pathway. 3) To apply the approach to a novel non-opioid system that may exert control on the development of chronic opioid tolerance and maintenance of chronic pain. Future applications of intrathecal delivery of AAV5 constructs will enhance study of other novel targets participating in chronic pain at the level of the spinal cord and DRG and may enable translational developments of chronic pain therapies.

描述（由申请人提供）：在过去的五十年中，神经科学社区在我们对脊髓背角和背根神经节（DRG）的组织和功能方面取得了重大进步。在疼痛信号传导途径中，许多新蛋白质被认为很重要。新颖的基因疗法方法可能为长期疼痛管理策略提供新的机会。腺相关病毒（AAV）血清型已被证明可用于在皮质，脑干和小脑中的神经元转导。还探索了它在脊髓和背根神经节中神经元转导的效用。尝试将AAV矢量传递到脊髓或DRG的尝试仅通过直接的核内或内部注射成功。侵入性较小，临床治疗性直接腰椎穿刺方法尚未成功转导脊髓。相比之下，我们现在通过直接腰穿刺注射AAV血清型5（AAV5）在意识的小鼠和大鼠中，成功地实现了标记绿色荧光蛋白（GFP）的广泛脊髓和DRG转导。这些初步研究支持我们优化递送和表征基于AAV5的载体的潜在功能的建议，该载体针对已知的特定基因，该基因已知，该基因已知，该基因已知，以调节脊髓或DRG内的慢性疼痛信号传导。有效的AAV5介导的遗传操作为慢性疼痛的进一步研究机制提供了实质性的机会，2）使用具有既定安全缘的非侵入性递送途径开发基于基因的疗法，用于治疗和治疗慢性疼痛。拟议的研究将评估通过腰椎穿刺传递AAV-VECTOR的实用性，作为对慢性疼痛的基础科学研究以及潜在的治疗递送选择的有用工具。该项目的主要目标是：1）优化向脊髓和DRG的交付，并表征AAV5-GFP构建体的分布。 2）在疼痛信号传导途径中良好确定的系统中验证这种方法。 3）将方法应用于新型的非阿片类系统，该系统可能会对慢性阿片类药物耐受性的发展和慢性疼痛的维持。鞘内输送AAV5构建体的未来应用将增强对参与脊髓和DRG水平上慢性疼痛的其他新型靶标的研究，并可能使慢性疼痛疗法的转化发展。