Development of KLS-13019 for Neuropathic Pain

开发用于治疗神经性疼痛的 KLS-13019

基本信息

批准号：
10704175
负责人：
Douglas Eric Brenneman
金额：
$ 100.18万
依托单位：
KANNALIFE SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704175
关键词：
Acute Affect Afferent Neurons Anti-Inflammatory Agents Antiinflammatory Effect Attenuated Biological Assay Biological Availability Biological Markers Calcium Canis familiaris Cannabidiol Cannabis sativa plant Cardiac Chemicals Chemotherapy-induced peripheral neuropathy Chronic Clinical Trials Collaborations Data Dependence Development Dose Drug Kinetics Etiology Evaluation Exposure to Formulation GPR55 receptor Grant High Pressure Liquid Chromatography Histopathology Homeostasis Human Impairment In Vitro Inflammation Inflammatory Laboratories Legal patent Mechanics Mediating Medical Methods Mitochondria Modality Modeling Morphine Nociception Opiate Addiction Opioid Oral Oral Administration Oxidative Stress Oxidative Stress Induction Paclitaxel Pain Pain management Patients Pharmaceutical Preparations Pharmacology Phase Preparation Prevention Process Production Property Quality of life Rattus Reference Standards Regulation Reporting Residual state Risk Role Safety Self Administration Series Small Business Technology Transfer Research Solvents Spinal Ganglia Tactile Toxic effect Toxicokinetics Toxicology Validation Vendor Work abuse liability analog analytical method antagonist beta-arrestin cancer therapy cannabinoid receptor chronic pain management cytokine effective therapy genotoxicity improved in vivo in vivo evaluation inflammatory marker mitochondrial dysfunction mouse model nervous system disorder neural neuroinflammation neuroprotection neurotoxicity pain sensitivity painful neuropathy pharmacologic pre-Investigational New Drug meeting prescription opioid preservation prevent process optimization respiratory success

项目摘要

Neuropathic pain remains a challenging neurologic disorder that adversely affects quality of life and presents a large unmet medical need. Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic, severely debilitating consequence of cancer therapy for which there are no effective management strategies. Upwards of 80-97% of CIPN patients reported using prescription opioids for this pain management. Mitochondrial dysfunction, oxidative stress, and inflammation have all been implicated in CIPN etiology. In a mouse model of paclitaxel-induced pain sensitivity, we have previously reported that cannabidiol (CBD) is effective in preventing the onset of this treatment consequence. Now a new CBD analogue (KLS-13019) has been discovered in our laboratory that has improved drug-like properties in comparison to CBD, while retaining neuroprotective properties. In our Phase 1 STTR, the previous neuroprotective effects of CBD to prevent the development of mechanical sensitivity in the presence of paclitaxel were confirmed and extended to the structural analogue KLS- 13019. Both compounds were equi-effective and equi-potent following oral administration. In the reversal studies, CBD did not attenuate mechanical sensitivity when administered after CIPN was induced by paclitaxel treatment. However, KLS-13019 significantly and dose-dependently attenuated tactile sensitivity in the reversal paradigm and was more potent and effective than treatment with morphine. Importantly, KLS-13019 also attenuated the reinforcing properties of morphine in a mouse model of morphine self-administration. In vitro, we have shown that KLS-13019 and CBD protect against paclitaxel-induced oxidative stress in dorsal root ganglia cultures, and that a mechanism underlying this neuroprotection is regulation of intracellular calcium via the mitochondrial Na+/Ca++ exchanger-1 (mNCX-1). Our central hypothesis is that administration of CBD or KLS-13019 preserves Ca2+ homeostasis by promoting activity of the mNCX-1. Furthermore, our new data demonstrates that the putative cannabinoid receptor GPR55 is induced following paclitaxel treatment and contributes to sensory neuron toxicity and inflammation that can be reversed by KLS-13019, but not CBD. These studies support a pro- nociceptive, pro-inflammatory role for GPR55 that mediates pain associated with CIPN. We predict bi-modal pharmacological effects of KLS-13019 that can both increase viability of sensory neurons exposed to paclitaxel acutely and decrease inducible GPR55 that contributes to long-term neuroinflammation. Evidence has been obtained that KLS-13019 is an antagonist to GPR55 as shown in a β-arrestin assay. In Phase 2, we will optimize the process to prepare KLS-13019, develop analytical methods, optimize formulation, and evaluate in pharmacokinetic studies. A fully battery of genotoxicity, safety pharmacology, toxicokinetic, and toxicology reports will be completed. KLS-13019 will be evaluated in a rat models of CIPN, tolerance, impairment, and abuse liability. At the conclusion of this grant, the data will be submitted to the FDA and a pre-IND meeting will be completed.

神经性疼痛仍然是一种具有挑战性的神经系统疾病，对生活质量产生不利影响并呈现出化疗引起的周围神经病（CIPN）是一种慢性、严重的未满足的医疗需求。癌症治疗带来的令人衰弱的后果，目前尚无有效的管理策略。 80-97% 的 CIPN 患者报告使用处方阿片类药物来治疗线粒体疼痛。在 CIPN 小鼠模型中，功能障碍、氧化应激和炎症都与 CIPN 病因有关。紫杉醇引起的疼痛敏感性，我们之前报道过大麻二酚（CBD）可以有效预防现在我们发现了一种新的 CBD 类似物 (KLS-13019)。与 CBD 相比，该实验室改善了类药特性，同时保留了神经保护作用在我们的第一阶段 STTR 中，CBD 先前的神经保护作用可以防止发展。紫杉醇存在下的机械敏感性得到证实，并扩展到结构类似物 KLS- 13019. 口服给药后，两种化合物的效果和效力相同。紫杉醇治疗诱导 CIPN 后施用 CBD 并不会减弱机械敏感性。然而，KLS-13019 在逆转范式中显着且剂量依赖性地减弱触觉敏感性重要的是，KLS-13019 还可以减弱吗啡治疗的效果。我们在体外证明了吗啡在小鼠自我给药模型中的增强作用。 KLS-13019 和 CBD 可防止背根神经节培养物中紫杉醇诱导的氧化应激，以及这种神经保护的潜在机制是通过线粒体调节细胞内钙 Na+/Ca++ 交换器-1 (mNCX-1) 我们的中心假设是 CBD 或 KLS-13019 的使用可以保留。通过促进 mNCX-1 的活性来实现 Ca2+ 稳态此外，我们的新数据表明紫杉醇治疗后诱导假定的大麻素受体 GPR55，并有助于感觉神经元 KLS-13019 可以逆转毒性和炎症，但 CBD 不能逆转。 GPR55 介导与 CIPN 相关的疼痛的伤害感受和促炎作用，我们预测是双模式的。 KLS-13019 的药理作用可以增加暴露于紫杉醇的感觉神经元的活力已经有证据表明，GPR55 会导致长期神经炎症。正如 β-arrestin 测定所示，我们发现 KLS-13019 是 GPR55 的拮抗剂。在第 2 阶段，我们将进行优化。 KLS-13019的制备过程、开发分析方法、优化配方和评估全面的遗传毒性、安全药理学、毒代动力学和毒理学研究。报告将在 CIPN、耐受性、损伤和损伤的大鼠模型中进行评估。滥用责任在本次拨款结束时，数据将提交给 FDA 并召开 IND 前会议。完成。