Supplement to Promote Diversity, Inclusion, and Career Development of a Female Scientist

促进女科学家的多样性、包容性和职业发展的补充

• 批准号: 10534074
• 负责人: Fernando Aleman Guillen
• 金额: $ 13.41万
• 依托单位: NAVEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-31 至 2023-08-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534074
• 关键词: Analgesics; Cancer Patient; Chemotherapy-induced peripheral neuropathy; Dose; Drug abuse; Exhibits; Family; Female; Goals; Human; Human Genome; Ion Channel; Lead; Mus; Nociception; Nociceptors; Opioid; Pain; Pain intensity; Pain management; Patients; Pharmaceutical Preparations; Phase; Proteins; Quality of life; Reagent; Regulation; Safety; Scientist; Sodium Channel; Testing; Therapeutic; addiction; alternative treatment; cancer pain; career development; chemotherapy; chronic pain management; chronic pain patient; diversity and inclusion; efficacious treatment; epigenome; experience; gene therapy; improved; inhibitor; novel; novel strategies; novel therapeutics; precision medicine; safety study; side effect; small molecule; tool; transmission process; 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缓解化学疗法引起的基因治疗产品 以非永久性，不添加和持久的方式以外周神经病（CIPN） 改善癌症患者的生活质量。 CIPN和癌症疼痛的当前管理是 非常差，有三分之一的患者未接受止痛药，认为适合 经历了疼痛的强度。有限的有效治疗选择，阿片类药物是 通常是规定的，但是这些可能导致成瘾。我们迫切需要新颖的痛苦 可以减轻阿片类药物的副作用的疗法。电压通道（NAV） 家庭）已用于伤害性传播和对过度兴奋性的贡献 初级传入伤害神经元。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，高同源性 人类NAV蛋白的大多数努力为开发选择性蛋白质抑制剂而感到沮丧。反而 靶向蛋白质，Navega提议开发非永久性表观基因组调节 目标疼痛的工具。这种新颖的方法是非添加性，高度具体且持久的。期间 第一阶段，我们确定同时抑制nav1.7和nav1.8是更多 有效地逆转CIPN比单独抑制每个通道。我们还证明了 我们在小鼠中测试的剂量的方法的安全。在第二阶段我们将：1）执行剂量范围 在小鼠中进行研究以确定治疗窗口； 2）优化我们的试剂以瞄准人 基因组； 3）在NHP中进行GLP确定的安全研究。我们将准备一个IND申请 向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小说 可以通过使用特定基因治疗方法来减轻CIPN的治疗剂 同时靶向两个电压门控钠通道（小时不可能 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。