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

项目摘要/摘要 该项目的目标是开发一种基因治疗产品，以减轻化疗引起的外周症状。 以一种非永久性、非成瘾和持久的方式改善神经病变(CIPN)的质量 癌症患者的生活。目前对CIPN和癌痛的管理非常糟糕，三分之一的患者没有 接受被认为与所经历的疼痛强度相适应的止痛药。与有限的 虽然有有效的治疗选择，但通常会开阿片类药物，但这些药物可能会导致成瘾。 我们迫切需要新的止痛疗法来减轻阿片类药物的副作用。电压- 门控钠通道(NAV家族)已被用于伤害性信息的传递和参与 初级传入伤害性神经元的超兴奋性。此外，许多化疗药物会导致 离子通道表达包括NAV1.7和NAV1.8，导致CIPN。因此，这些钠离子通道 一直是开发慢性疼痛疗法的有吸引力的目标。然而，人类的高度同源性 NAV蛋白质挫败了大多数开发选择性蛋白质抑制剂的努力。与其把目标对准 蛋白质，Navega建议开发一种非永久性的表观基因组调节工具来靶向疼痛。这 新的方法是不会上瘾的，高度具体和持久的。在第一阶段，我们确定 同时抑制NAV1.7和NaV1.8对CIPN的逆转比抑制更有效 每个频道都是单独的。我们还在小鼠身上进行了剂量测试，证明了我们方法的安全性。在.期间 第二阶段我们将：1)在小鼠身上进行剂量范围研究，以确定治疗窗口；2)优化 我们的试剂以人类基因组为靶点；以及3)在NHP中进行GLP决定性的安全性研究。我们会 准备一份IND申请给FDA，并将在第二阶段项目结束时提交。我们的最终目标 是开发新的治疗方法，通过使用特定的基因治疗方法来缓解CIPN 可以同时瞄准两个电压门控钠通道(这是Small不可能实现的 分子)，并为慢性疼痛患者提供阿片类药物的替代治疗。

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.