Selective actin remodeling of sensory neurons for acute pain management

感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理

• 批准号: 10603436
• 负责人: Paul Blum
• 金额: $ 277.61万
• 依托单位: NEUROCARRUS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603436
• 关键词: ADP ribosylation; Absence of pain sensation; Absenteeism; Actins; Acute; Acute Pain; Acute pain management; Adult; Adverse effects; Affect; Afferent Neurons; American; Anesthetics; Animal Model; Animals; Antibody Formation; Axon; Biological; Biological Assay; Bupivacaine; C57BL/6 Mouse; Canis familiaris; Central Nervous System; Chemistry; Clinical; Clinical Trials; Collaborations; Cytoskeleton; Data; Development; Diabetes Mellitus; Distal; Dose; Drug Formulations; Drug Kinetics; Effectiveness; Engineering; Esthesia; Excretory function; FDA approved; Financial Hardship; Formulation; Functional disorder; Future; G Actin; Gait; Goals; Health; Healthcare; Heart Diseases; Helping to End Addiction Long-term; Hour; Human; Immunology; Individual; Inflammation; Injury; Investigational Drugs; Investigational New Drug Application; Joints; Laboratories; Lead; Lumbar spinal cord structure; Malignant Neoplasms; Marketing; Measurement; Measures; Metabolism; Microbiology; Microscopy; Modeling; Modification; Monitor; Motor; Motor Neurons; Mus; Narcotics; Nerve; Nerve Block; Nervous System; Neurons; No-Observed-Adverse-Effect Level; Nociception; Nociceptors; Operative Surgical Procedures; Opioid; Organ; Pain; Pain management; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Physiology; Polymers; Postoperative Pain; Postoperative Period; Preclinical Drug Development; Preparation; Procedures; Production; Protein Biochemistry; Protein Engineering; Proteins; Public Health; Purinoceptor; Quality of life; Recovery; Research; Research Personnel; Risk; Rivers; Rodent; Safety; Small Business Innovation Research Grant; Specificity; Spinal Cord; Substance Use Disorder; Surgical incisions; Technology; Testing; Therapeutic; Therapeutic Uses; Tibial Fractures; Tissues; Toxicology; addiction; addiction liability; afferent nerve; base; chronic pain; clinical pain; clinically relevant; cost; depolymerization; drug standard; efficacy study; experience; fighting; global health; good laboratory practice; immunogenicity; improved; in vivo; inhibitor; innovation; insight; limb fracture; manufacture; mechanical allodynia; mouse model; multidisciplinary; neuroinflammation; novel strategies; novel therapeutic intervention; opioid epidemic; pain behavior; pain model; pain relief; pain signal; payment; pharmacologic; polymerization; pre-clinical; preclinical study; prevent; safety study; small molecule; small molecule inhibitor; small molecule therapeutics; standard of care; therapy development; tissue injury; tool; welfare

PROJECT SUMMARY There is an urgent need for new approaches to treat acute human pain without the risk of Substance Use Disorders (SUDs). The most effective approved pain pharmaceuticals, including narcotics and anesthetics, are not neuron-specific and consequently suffer from off-target effects like addiction, inhibition of motor neurons, and destruction of the surrounding tissues. When inflammation occurs, actin polymerization occurs in sensory neurons, leading to the sensitization of purinergic receptors and abnormal pain behaviors. Targeted actin remodeling could be an effective approach to reduce acute nociceptive pain, but there are no small-molecule inhibitors with adequate specificity for sensory neurons that correctly modulate the cytoskeleton. Neurocarrus proposes a new therapeutic approach for nociceptive pain based on an innovative engineered protein called N- 001 that selectively targets sensory neurons and acts only at the intra-cellular level inducing limited and reversible depolymerization of the axon-associated actin cytoskeleton. This innovative biologic drug will provide specificity towards sensory neurons while leveraging the features of the peripheral nervous system to eliminate pain locally without interacting with the central nervous system. Neurocarrus has completed an SBIR Phase I that has proven the feasibility of N-001 as a pain management therapy. Results show that N-001 managed nociceptive post operative pain by efficiently reducing mechanical allodynia and gait dysfunction in a mouse paw incision model relative to bupivacaine but with a significantly longer duration of activity. N-001 retained efficacy for 3 days relative to only 6 hours for bupivacaine. N-001 was also assessed as an anesthetic agent in a nerve block model where it also showed a significantly increased duration of post operative pain management relative to bupivacaine. N-001’s mechanism of action was validated in vivo, showing that it co-localizes with CGRP positive sensory neurons not motor neurons, and can be quantitatively monitored using ADP-ribosylated actin as a measure of F to G actin neuronal content. Preliminary ADME, toxicology and immunogenicity assays showed no adverse effects on organ function, provided pharmacokinetic information, and non-neutralizing antidrug antibody formation only after multiple doses. These data establish specific metrics for the use of N-001 as a post operative pain therapeutic thereby strengthening the potential for use of N-001 in clinical pain management. In this SBIR Phase II project, Neurocarrus will optimize the production and formulation of N-001 as well as the development of manufacturing standards and controls for obtaining GLP-grade (Good Laboratory Practice) N- 001. GLP-grade N-001 will be used to perform pivotal pre-clinical studies to demonstrate its in vivo safety using two preclinical animal models (C57BL/6 mice and Beagle dogs). GLP drug will also be used for efficacy studies as a treatment for pain after peripheral joint surgery using a mouse distal tibial limb fracture model. The completion of this project will support an investigational new drug filling (IND) enabling future clinical trials.

项目摘要 迫切需要采用新方法来治疗急性人类疼痛而无需使用药物的风险 疾病（SUDS）。最有效批准的疼痛药物，包括麻醉品和麻醉药，是 不是神经特异性的，因此遭受脱靶效应，例如成瘾，抑制运动神经元和 破坏周围组织。当炎症发生时，肌动蛋白聚合发生在感觉中 神经元，导致嘌呤能受体和异常疼痛行为的敏感性。靶向肌动蛋白 重塑可能是减轻急性伤害性疼痛的有效方法，但没有小分子 对正确调节细胞骨架的感觉神经元具有足够特异性的抑制剂。 Neurocarrus 提议基于一种创新的工程蛋白质，一种新的伤害性疼痛的治疗方法，称为N- 001选择性地靶向感觉神经元并仅作用于细胞内诱导的有限和 轴突相关肌动蛋白细胞骨架的可逆沉积。这种创新的生物药将提供 在利用周围神经系统的特征时，对感觉神经元的特异性 局部疼痛，而不会与中枢神经系统相互作用。 Neurocarrus已经完成了SBIR I期，该阶段证明了N-001作为疼痛管理的可行性 治疗。结果表明，N-001通过有效减少机械性来管理的伤害感受后的操作后疼痛 相对于布比卡因，小鼠爪切口模型中的异常性和步态功能障碍，但显着 活动持续时间更长。 N-001保留了3天的效率，相对于布比卡因仅6小时。 N-001是 在神经阻滞模型中也被评估为麻醉剂，它也显示出明显增加 相对于布比卡因，后操作疼痛管理的持续时间。 N-001的作用机制已得到验证 体内，表明它与CGRP阳性感觉神经元而不是运动神经元共定位，并且可以是 使用ADP-核糖基化肌动蛋白作为对G肌动蛋白神经元含量的F进行定量监测。初步的 ADME，毒理学和免疫原性测定显示对器官功能没有不利影响 只有多剂量后，药代动力学信息和非中和抗抗体抗体形成。这些 数据建立了使用N-001作为后操作疼痛疗法的特定指标，从而加强 在临床疼痛管理中使用N-001的潜力。 在这个SBIR II期项目中，Neurocarrus将优化N-001的生产和公式以及 制定制造标准和控制措施，以获得GLP级（良好的实验室实践）n- 001。GLP级N-001将用于进行关键的临床前研究，以证明其在体内安全性使用 两种临床前动物模型（C57BL/6只小鼠和小猎犬）。 GLP药物也将用于效率研究 用小鼠胫骨远端肢体骨折模型治疗周围关节手术后的疼痛治疗。这 该项目的完成将支持研究新药填充（IND），以实现未来的临床试验。