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.

项目总结/摘要 该项目的目标是开发一种基因治疗产品， 以非永久性、非成瘾性和持久的方式治疗周围神经病变（CIPN）， 提高癌症患者的生活质量。CIPN和癌痛的当前管理是 非常差，1/3的患者未接受认为适合 疼痛的强度。由于有效的治疗选择有限，阿片类药物 经常开处方，但这些可能会导致成瘾。我们急需新奇的痛 减轻阿片类药物副作用的疗法电压门控钠通道（NaV 家族）已被用于伤害性传递，并在 初级传入伤害感受神经元。此外，许多化疗剂诱导离子 通道表达包括NaV1.7和NaV1.8，导致CIPN。因此，这些钠离子通道 已经成为开发慢性疼痛疗法的有吸引力的目标。然而，高同源性 人类NaV蛋白的研究已经使开发选择性蛋白抑制剂的大多数努力受挫。相反 针对蛋白质，Navega建议开发一种非永久性的表观基因组调控， 针对疼痛的工具。这种新方法是非成瘾性的，高度特异性的，持久的。期间 第一阶段，我们确定NaV1.7和NaV1.8的同时抑制， 在逆转CIPN方面比单独抑制每个通道更有效。我们还展示了 我们的方法在小鼠中测试的剂量的安全性。在第II阶段，我们将：1）进行剂量范围 在小鼠中进行研究以确定治疗窗口; 2）优化我们的试剂以靶向人类 基因组;和3）在NHP中进行GLP确定性安全性研究。我们将准备IND申请 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 可以通过使用特定的基因治疗方法减轻CIPN的治疗剂， 同时靶向两个电压门控钠通道（这是小的 分子），并为慢性疼痛患者提供阿片类药物的替代治疗。