Targeting TLR4-lipid rafts to prevent postoperative pain

靶向 TLR4 脂筏预防术后疼痛

• 批准号: 10701528
• 负责人: Patrick M Dougherty
• 金额: $ 41.48万
• 依托单位: RAFT PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701528
• 关键词: Accounting; Acute Pain; Analgesics; Animals; Apolipoprotein A-I; Area; Behavior; Behavioral; Binding; Binding Proteins; Biological Assay; Biological Markers; Blood; Cancer Center; Cancer Patient; Cell membrane; Cells; Chemotherapy-induced peripheral neuropathy; Cholesterol; Clinic; Clinical Trials; Contralateral; Cyclic GMP; Data; Data Set; Day Surgery; Dependence; Development; Development Plans; Dose; Drug Kinetics; Excision; Female; Formulation; Fright; Funding; Future; Generations; Goals; Harvest; Hospitals; Human; Human Activities; Hyperactivity; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Intravenous; Ipsilateral; Laboratories; Link; Macrophage; Mediating; Medical; Membrane; Membrane Lipids; Membrane Microdomains; Methods; Microglia; Modeling; Neurons; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Organ; Pain; Pain management; Patients; Perioperative; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Postoperative Pain; Prevalence; Procedures; Process; Protocols documentation; Publishing; Quality of life; Rattus; Regulation; Reporting; Safety; Secondary to; Sensory; Sex Differences; Side; Site; Small Business Technology Transfer Research; Source; Spinal; Spinal Cord; Spinal Ganglia; Surgical Injuries; Surgical incisions; System; TLR4 gene; Tactile; Testing; Therapeutic; Time; Toxicology; Translating; Variant; Vertebral column; Withdrawal; Work; addiction; adverse outcome; allodynia; cancer survival; chronic pain; clinical development; cost; dermatome; drug candidate; efficacy study; first-in-human; immunogenicity; in vivo; intravenous injection; male; manufacture; nerve injury; neuroinflammation; non-opioid analgesic; novel; novel strategies; pain model; pain relief; pre-Investigational New Drug meeting; prevent; response; safety assessment; safety study; safety testing; sex; side effect; spontaneous pain; tissue injury; wound

PROJECT SUMMARY Postoperative pain is a prevalent source of pain requiring appropriate management to reduce its impact upon quality of life. Even with the availability of several analgesics, postoperative pain is often undermedicated because of concern related to the adverse consequence of the available therapeutics (e.g., NSAIDs and opiates), including addiction and decreased survival of cancer patients. To this end we have undertaken development of RFT1124, a modified apolipoprotein A-I binding protein (AIBP), which exerts its action through specific targeting of membrane lipid rafts by altering local membrane cholesterol dynamics in dorsal root ganglion (DRG) neurons and macrophages and in spinal microglia that express TLR4 (TLR4-rafts) and are known to be engaged in processing acute and chronic pain secondary to nerve and tissue injury. We have discovered that TLR4-rafts are heavily expressed on macrophages and exclusively on nociceptive DRG neurons. We have shown that it is possible to specifically target these TLR4-rafts through the actions of RFT1124 (AIBP), which binds to TLR4 and specifically disrupts the associated lipid rafts. In vitro, AIBP blocks the ectopic activity of human DRG nociceptors isolated from painful dermatomes. In vivo, intravenous injection of AIBP prior to paw incision prevented the development of tactile allodynia in rats. These exciting new data, together with our published studies showing AIBP efficacy and mechanism of action in chemotherapy-induced peripheral neuropathy, suggest the potential of AIBP (RFT1124) in treatment of postoperative pain. In Phase I of this Fast-Track STTR proposal, we will define the efficacy of intravenous RFT1124 delivery on postoperative pain in rats, including: (i) dose response; (ii) dependence on the time of pre or post incision administration; (iii) sex differences. In Phase II, we plan to manufacture and release RFT1124 drug product for expanded efficacy and toxicology studies using cGMP- compatible processes and analytical assays. Further, a pharmacokinetics of RFT1124 in blood and DRG and a non-GLP safety assessment of intravenous delivery of RFT1124 will be conducted to establish an estimate of safety margin and target organs. As an independent biomarker of activity, we will characterize the effects of RFT1124 on hyperactivity in rat DRG neurons otherwise produced by surgical incision in male and female rats. The efficacy studies will be extended to human DRG nociceptive neurons in culture, with the DRG obtained from donors of both sexes. Target engagement will be tested with an AIBP variant, which like RFT1124 alters lipid rafts but does not bind TLR4. We anticipate significant suppression of allodynic behavior and ectopic activity induced by surgical injury after incision by RFT1124 but not the AIBP variant lacking the TLR4-binding domain. These studies will provide the enabling data set to initiate a pre-IND meeting with the FDA in anticipation of moving RFT1124 into first-in-human clinical trials. CONFIDENTIAL

项目概要 术后疼痛是一种普遍的疼痛来源，需要适当的管理以减少其对患者的影响 生活质量。即使有多种镇痛药，术后疼痛也常常用药不足 由于担心现有疗法（例如非甾体抗炎药和阿片类药物）的不良后果， 包括成瘾和癌症患者生存率下降。为此，我们着手开发 RFT1124，一种修饰的载脂蛋白 A-I 结合蛋白 (AIBP)，通过特异性靶向发挥作用 通过改变背根神经节（DRG）神经元局部膜胆固醇动力学来形成膜脂筏 巨噬细胞和表达 TLR4（TLR4 筏）的脊髓小胶质细胞，已知参与 处理继发于神经和组织损伤的急性和慢性疼痛。我们发现 TLR4 筏 在巨噬细胞上大量表达，并且仅在伤害性 DRG 神经元上表达。我们已经证明它是 可以通过 RFT1124 (AIBP) 的作用特异性靶向这些 TLR4 筏，RFT1124 与 TLR4 结合并 特别破坏相关的脂筏。在体外，AIBP 阻断人类 DRG 伤害感受器的异位活性 与疼痛的皮区隔离。在体内，在爪子切开之前静脉注射 AIBP 可防止 大鼠触觉异常性疼痛的发展。这些令人兴奋的新数据以及我们发表的研究表明 AIBP 在化疗引起的周围神经病变中的功效和作用机制表明其潜力 AIBP (RFT1124) 治疗术后疼痛。在此快速通道 STTR 提案的第一阶段，我们将 确定静脉注射 RFT1124 对大鼠术后疼痛的功效，包括：(i) 剂量反应； (ii) 取决于切开前或切开后给药的时间； (三)性别差异。在第二阶段，我们计划 使用 cGMP 制造和发布 RFT1124 药品，用于扩展功效和毒理学研究 兼容的过程和分析测定。此外，RFT1124在血液和DRG中的药代动力学以及 将进行 RFT1124 静脉注射的非 GLP 安全性评估，以确定 安全裕度和目标器官。作为活性的独立生物标志物，我们将表征 RFT1124 对雄性和雌性大鼠手术切口产生的大鼠 DRG 神经元过度活跃的影响。 功效研究将扩展到培养中的人类 DRG 伤害性神经元，DRG 是从 男女捐赠者。将使用 AIBP 变体测试目标参与度，该变体与 RFT1124 一样会改变脂质 筏但不结合 TLR4。我们预计异常疼痛行为和异位活动会受到显着抑制 由 RFT1124 切口后的手术损伤引起，但不是缺乏 TLR4 结合域的 AIBP 变体。 这些研究将提供有利的数据集，以启动与 FDA 的 IND 前会议，以期 将 RFT1124 纳入首次人体临床试验。 机密的