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: 9750836
• 负责人: Yury Miller
• 金额: $ 36.99万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750836
• 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; 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; 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; oncology; pain relief; painful neuropathy; pharmacokinetics and pharmacodynamics; preclinical development; preference; 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 周围神经损伤会导致异常感觉，称为神经病理性疼痛。神经损伤可能 由于各种侮辱造成的，从直率的伤害到神经的切断或压迫，并且是 在肿瘤学中使用化疗后尤其流行。症状通常包括持续灼伤。 疼痛和异常感觉，如超常痛觉(非伤害性刺激引起的疼痛)和 痛觉过敏(对正常疼痛刺激的反应增强)临床症状缓解后的持续性疼痛 明显的损伤迹象对治疗构成了挑战，目前的治疗方法不能满足这一医学需求。 因此，需要在预防或缓解疼痛方面提供额外益处的新的治疗方案。在……里面 这项提案是由加州大学圣地亚哥分校(UCSD)和埃皮根共同发起的 生物科学公司寻求全面评估apoA-I结合蛋白(AIBP)，这是一种干扰炎症的试剂 脊髓神经胶质细胞中的脂筏，并已被发现在几个小鼠模型中逆转易化的疼痛状态。目标 该提案在R21阶段的内容包括AIBP蛋白的制造和特性， 药代动力学研究，实验动物方案的设计和改进，以评估疗效和 AIBP在多发性神经病(化疗药物诱导)小鼠模型中的药效学 单神经病变(L5神经结扎)和评价AIBP的药效学方法的优化 脊髓神经胶质细胞的结合及其抗炎作用。视成功完成一套而定 在建议的里程碑中，R33阶段将开始建立AIBP的剂量依赖疗效概况 治疗神经病理性疼痛及其与AIBP药代动力学和药效学的相关性。这个 该提案旨在将AIBP项目推进到能够满足NINDS进入标准的程度 合作研究，以支持和推进翻译企业(CREATE)计划，最终 目的开发一种新的治疗持续性疼痛状态的生物疗法。