Reversal of preexisting neuropathic pain by spinal delivery of AIBP

通过脊髓输送 AIBP 逆转先前存在的神经性疼痛

基本信息

批准号：
10197482
负责人：
Yury Miller
金额：
$ 37.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197482
关键词：
Affect Agonist American Animal Model Animals Anticonvulsants Antiinflammatory Effect Apolipoprotein A-I Astrocytes Behavioral Assay Binding Proteins Biological Biological Assay Biological Response Modifier Therapy Biological Sciences Blood - brain barrier anatomy Blood specimen Bortezomib Burning Pain California Cell membrane Cellular Membrane Chemicals Chemotherapy-induced peripheral neuropathy Cholesterol Chronic Cisplatin Clinical Collaborations Dependence Development Diabetes Mellitus Dimerization Dose Drug Kinetics Esthesia Excision Formulation Future Goals Harvest Hyperalgesia Inflammation Inflammatory Injections Injury Laboratories Lead Ligation Measurement Mediating Medical Membrane Microdomains Microglia Mononeuropathies Mus National Institute of Neurological Disorders and Stroke Nerve Neuroglia Neuropathy Non-Steroidal Anti-Inflammatory Agents Oncology Opioid Pain Peripheral Nerves Peripheral nerve injury Persistent pain Pharmacodynamics Phase Phenotype Polyneuropathy Prevention Production Protein Chemistry Proteins Protocols documentation Quality of life Regulation Research Research Design Resolution Route Sensory Spinal Spinal Cord Spine pain Stimulus Symptoms TLR4 gene Tactile Testing Therapeutic Therapeutic Equivalency Tissues Translating Trauma Universities Virus Diseases Work addiction allodynia base brain tissue chemotherapeutic agent chemotherapy chronic pain clinical development conditioned place preference cytokine design epigen glial activation human model immune activation in vitro Assay manufacturing process manufacturing scale-up mouse model nerve injury neuroinflammation novel novel strategies pain relief painful neuropathy pharmacokinetics and pharmacodynamics preclinical development programs receptor function research clinical testing response side effect

Affect Agonist American Animal Model Animals Anticonvulsants Antiinflammatory Effect Apolipoprotein A-I Astrocytes Behavioral Assay Binding Proteins Biological Biological Assay Biological Response Modifier Therapy Biological Sciences Blood - brain barrier anatomy Blood specimen Bortezomib Burning Pain California Cell membrane Cellular Membrane Chemicals Chemotherapy-induced peripheral neuropathy Cholesterol Chronic Cisplatin Clinical Collaborations Dependence Development Diabetes Mellitus Dimerization Dose Drug Kinetics Esthesia Excision Formulation Future Goals Harvest Hyperalgesia Inflammation Inflammatory Injections Injury Laboratories Lead Ligation Measurement Mediating Medical Membrane Microdomains Microglia Mononeuropathies Mus National Institute of Neurological Disorders and Stroke Nerve Neuroglia Neuropathy Non-Steroidal Anti-Inflammatory Agents Oncology Opioid Pain Peripheral Nerves Peripheral nerve injury Persistent pain Pharmacodynamics Phase Phenotype Polyneuropathy Prevention Production Protein Chemistry Proteins Protocols documentation Quality of life Regulation Research Research Design Resolution Route Sensory Spinal Spinal Cord Spine pain Stimulus Symptoms TLR4 gene Tactile Testing Therapeutic Therapeutic Equivalency Tissues Translating Trauma Universities Virus Diseases Work addiction allodynia base brain tissue chemotherapeutic agent chemotherapy chronic pain clinical development conditioned place preference cytokine design epigen glial activation human model immune activation in vitro Assay manufacturing process manufacturing scale-up mouse model nerve injury neuroinflammation novel novel strategies pain relief painful neuropathy pharmacokinetics and pharmacodynamics preclinical development programs receptor function research clinical testing response side effect

展开

项目摘要

Project Summary Peripheral nerve injury can lead to anomalous sensations referred to as neuropathic pain. Nerve injury may result from a variety of insults ranging from frank injury to the nerve though sectioning or compression, and is particularly prevalent following chemotherapies used in oncology. Symptoms often include continuous burning pain and abnormal sensory sensations such as allodynia (pain as a result of non-noxious stimuli) and hyperalgesia (an increased response to a normally painful stimulus) Persistent pain after resolution of clinically appreciable signs of injury poses a therapeutic challenge and current therapies do not meet this medical need. Accordingly, novel treatment options that afford additional benefit in prevention or relief of pain are needed. In this proposal, a collaboration initiated between the University of California San Diego (UCSD) and Epigen Biosciences Inc. seeks to fully evaluate the apoA-I binding protein (AIBP), an agent that interferes with inflamed lipid rafts in spinal glia and has been found to reverse facilitated pain states in several mouse models. The goals of this proposal during the R21 phase include the AIBP protein manufacture and characterization, pharmacokinetics studies, design and refinement of experimental animal protocols to assess efficacy and pharmacodynamics of AIBP in mouse models of polyneuropathy (induced by chemotherapeutic agents) and mononeuropathy (L5 nerve ligation), and optimization of pharmacodynamics assays to evaluate AIBP engagement of spinal glia and its anti-inflammatory effects. Contingent upon the successful completion of a set of proposed milestones, the R33 phase will commence to establish dose-dependent efficacy profile for AIBP treatment of neuropathic pain and to correlate it with AIBP pharmacokinetics and pharmacodynamics. The proposal is designed to advance the AIBP project to the point where it can meet the entry criteria for NINDS Cooperative Research to Enable and Advance Translational Enterprises (CREATE) program, with the ultimate goal to develop a novel biologic therapeutics for management of persistent pain states.

项目摘要周围神经损伤会导致异常的感觉称为神经性疼痛。神经损伤可能各种侮辱造成的，从坦率的损伤到神经，通过切片或压缩，是在肿瘤学用于化学疗法后尤其普遍。症状通常包括连续燃烧疼痛和异常感觉的感觉，例如异常性痛（由于刺激性刺激）和临床上解决后，痛苦（对正常疼痛刺激的反应增加）持续疼痛受伤的明显迹象构成了治疗性挑战，当前的疗法无法满足这种医疗需求。因此，需要在预防或缓解疼痛方面获得额外好处的新型治疗选择。在该提案是加利福尼亚大学圣地亚哥大学（UCSD）和Epigen之间的合作 Biosciences Inc.试图完全评估ApoA-I结合蛋白（AIBP），这种药物会干扰发炎脊髓胶质细胞中的脂质筏已被发现在几种小鼠模型中逆转了促进疼痛状态。目标 R21阶段的该提案包括AIBP蛋白质的制造和表征，实验动物方案的药代动力学研究，设计和完善，以评估功效和 AIBP在多神经病的小鼠模型中的AIBP（由化学治疗剂诱导）和单肌病（L5神经结扎），并优化了评估AIBP的药效学测定法脊髓神经胶质的参与及其抗炎作用。取决于成功完成在拟议的里程碑中，R33阶段将开始建立AIBP剂量依赖的效力。治疗神经性疼痛，并将其与AIBP药代动力学和药效学相关。这提案旨在将AIBP项目推进到可以符合NINDS的进入标准的地步合作研究以实现和推进转化企业（创建）计划，并具有最终开发一种新型的生物学治疗剂来管理持续性疼痛状态。