Treatment of Chemotherapy-Induced Peripheral Neuropathy via Genetic Repression of Sodium Channels

通过钠通道的基因抑制治疗化疗引起的周围神经病变

• 批准号: 10487589
• 负责人: Fernando Aleman Guillen
• 金额: $ 128.32万
• 依托单位: NAVEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487589
• 关键词: Address; Adverse effects; Affect; Analgesics; CRISPR/Cas technology; Cancer Patient; Chemotherapy-induced peripheral neuropathy; Clinical Trials; Congenital Pain Insensitivity; Dependovirus; Dose; Down-Regulation; Drug abuse; Epigenetic Process; Evaluation; Exhibits; Family; Future; Genes; Genetic; Genome; Goals; Guide RNA; Human; Human Cell Line; Human Genome; Hypersensitivity; Intervention; Ion Channel; Lead; Motor; Mus; Mutation; Nociception; Nociceptors; Numbness; Opioid; Organ; Pain; Pain intensity; Pain management; Patients; Persistent pain; Persons; Pharmaceutical Preparations; Phase; Polyneuropathy; Population; Proteins; Quality of life; Reagent; Regulation; Repression; Risk; Safety; Sensory; Severities; Small Business Innovation Research Grant; Sodium Channel; Specificity; Spinal Ganglia; System; Testing; Therapeutic; Toxic effect; Variant; Zinc Fingers; addiction; alternative treatment; animal safety; base; cancer pain; chemotherapy; chronic pain; chronic pain management; chronic pain patient; clinical development; design; dosage; efficacious treatment; epigenome; epigenomics; experience; gene therapy; improved; induced pluripotent stem cell; inhibitor; innovation; mouse genome; mouse model; nonhuman primate; novel; novel strategies; novel therapeutics; pain reduction; pain relief; precision medicine; premature; response; safety study; side effect; small molecule; tool; transcriptome sequencing; transmission process; treatment duration; voltage

Project Summary/Abstract The goal of this project is to develop a gene therapy product that relieves chemotherapy-induced peripheral neuropathy (CIPN) in a non-permanent, non-addictive and long-lasting manner to improve the quality of life of cancer patients. Current management of CIPN and cancer pain is very poor, with 1 in 3 patients not receiving pain medication considered appropriate for the intensity of pain experienced. With the limited efficacious treatment options available, opioids are often prescribed, however these can lead to addiction. We are in urgent need of novel pain therapies that would alleviate the side effects of opioids. Voltage- gated sodium channels (NaV family) have been used in nociceptive transmission and contribution to the hyperexcitability in primary afferent nociceptive neurons. Additionally, many chemotherapy agents induce ion channel expression including NaV1.7 and NaV1.8, leading to CIPN. Hence, these sodium channels have been attractive targets for developing chronic pain therapies. However, the high homology of human NaV proteins has frustrated most efforts to develop selective protein inhibitors. Instead of targeting the protein, Navega proposes to develop a non-permanent epigenome regulation tool to target pain. This novel approach is non-addictive, highly specific, and long-lasting. During Phase I, we determined that the simultaneous inhibition of NaV1.7 and NaV1.8, was more efficacious at reversing CIPN than repressing each channel alone. We also demonstrated the safety of our approach at doses tested in mice. During Phase II we will: 1) perform dose-range studies in mice to determine the therapeutic window; 2) optimize our reagents to target the human genome; and 3) perform GLP definitive safety studies in NHPs. We will prepare an IND application to the FDA, and will submit it at the end of the Phase II project. Our final goal is to develop novel therapeutics that can mitigate CIPN through the use of a specific gene therapy approach that can simultaneously target two voltage gated sodium channels (something not possible with small molecules) and provide an alternative treatment to opioids for patients with chronic pain.

项目摘要/摘要 该项目的目的是开发一种基因治疗产品，以减轻化学疗法诱导的周围 神经病（CIPN）以非永久性，不依赖和持久的方式提高质量 癌症患者的生活。 CIPN和癌症疼痛的当前治疗非常差，其中1例中有1例 接受被认为适合经历的疼痛强度的疼痛药物。有限 可用的有效治疗选择，通常会开处方，但这可能导致成瘾。 我们迫切需要新的疼痛疗法，以减轻阿片类药物的副作用。电压- 封闭式钠通道（NAV家族）已用于伤害性传播和对 原发性伤害性神经元的过度兴奋性。此外，许多化学疗法诱导 离子通道表达式包括NAV1.7和NAV1.8，导致CIPN。因此，这些钠通道 一直是开发慢性疼痛疗法的有吸引力的靶标。但是，人类的高同源性 NAV蛋白使大多数开发选择性蛋白抑制剂的努力感到沮丧。而不是针对 Navega蛋白质建议开发一种非永久性表观基因组调节工具来靶向疼痛。这 新颖的方法是非添加的，高度具体且持久的。在第一阶段，我们确定 同时抑制NAV1.7和NAV1.8，比压抑更有效地逆转CIPN 每个频道。我们还证明了在小鼠中测试的剂量下的方法的安全性。期间 第二阶段我们将：1）在小鼠中进行剂量范围研究以确定治疗窗口； 2）优化 我们的试剂靶向人类基因组； 3）在NHP中进行GLP确定的安全研究。我们将 准备IND申请到FDA，并将在第二阶段项目结束时提交。我们的最终目标 是开发新型疗法，可以通过使用特定基因治疗方法来减轻CIPN 可以同时瞄准两个电压门控钠通道（小而小 分子），为阿片类药物提供替代治疗方法，以缓解慢性疼痛患者。