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.

项目总结