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

• 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
• 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

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 周围神经损伤可导致称为神经性疼痛的异常感觉。神经损伤可能 由各种损伤引起，包括通过切片或压迫对神经的直接损伤， 在肿瘤学中使用的化疗之后尤其普遍。症状通常包括持续燃烧 疼痛和异常感觉，如异常性疼痛（非伤害性刺激引起的疼痛）， 痛觉过敏（对正常疼痛刺激的反应增加）临床症状缓解后持续疼痛 明显的损伤迹象对治疗提出了挑战，而目前的治疗不能满足这种医学需要。 因此，需要在预防或缓解疼痛方面提供额外益处的新型治疗选择。在 这项提议是由加州圣地亚哥大学（UCSD）和Epigen大学合作提出的 Biosciences Inc.旨在全面评估apoA-I结合蛋白（AIBP），一种干扰炎症的药物， 在脊髓胶质细胞中的脂筏，并已发现在几种小鼠模型中逆转易化疼痛状态。的目标 在R21阶段，该提案的主要内容包括AIBP蛋白的生产和表征， 药代动力学研究，设计和完善实验动物方案，以评估疗效， AIBP在多发性神经病（由化疗药物诱导）小鼠模型中的药效学， 单神经病（L5神经结扎），并优化药效学试验，以评估AIBP 脊髓胶质细胞的参与及其抗炎作用。取决于成功完成一套 在拟定的里程碑中，R33阶段将开始建立AIBP的剂量依赖性疗效特征 治疗神经性疼痛并将其与AIBP药代动力学和药效学相关。的 该提案旨在推进AIBP项目，使其达到NINDS的进入标准 合作研究，使和推进翻译企业（创建）计划，与最终 目的是开发一种新的生物疗法来治疗持续性疼痛状态。