Neupron™: A Neuroprotective Agent for Treating Acute Spinal Cord Injury

Neupron™：一种治疗急性脊髓损伤的神经保护剂

• 批准号: 10255000
• 负责人: VINOD D LABHASETWAR
• 金额: $ 40万
• 依托单位: AXONEURAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255000
• 关键词: Acute; Address; Antioxidants; Apoptotic; Attenuated; Biological; Biomedical Engineering; Cattle; Characteristics; Clinic; Clinical Trials; Consumption; Contracts; Contusions; Cyclic GMP; Data; Development; Dose; Early Intervention; Encapsulated; Endotoxins; Ensure; Enzymes; Event; Flavonoids; Formulation; Free Radical Scavenging; Freeze Drying; Functional disorder; Goals; Grant; Guidelines; Health Care Costs; Human; Incidence; Injectable; Injury; Intervention; Laboratories; Legal patent; Lesion; Locomotion; Longitudinal Studies; Mediating; Mitochondria; Modeling; Molecular; Natural regeneration; Nebraska; Neurodegenerative Disorders; Neuroprotective Agents; Orphan Drugs; Outcome; Oxidative Stress; Phase; Plants; Polymers; Procedures; Process; Production; Proliferating; Property; Protocols documentation; Rattus; Reactive Oxygen Species; Recombinants; Recording of previous events; Recovery; Recovery of Function; Reproducibility; Research; Route; Saline; Schedule; Secondary to; Severities; Site; Small Business Technology Transfer Research; Source; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Superoxide Dismutase; TYRP1 gene; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Variant; Vitamin E; antioxidant enzyme; biomaterial compatibility; catalase; clinical development; commercialization; cost; design; disability; improved; innovation; intravenous injection; meetings; mitochondrial dysfunction; nanomedicine; nanoparticle; neurological recovery; reconstitution; scale up; severe injury; socioeconomics; success; therapeutically effective; trauma centers; young adult

Project Description: The pathophysiology of traumatic spinal cord injury (SCI) involves the initial physical impact, which leads to secondary injury cascades of degenerative cellular and molecular events. The secondary injury spreads along the spinal cord over time, which adds new levels of disability and has devastating effects. Excess reactive oxygen species (ROS) formation at the impact site is an important component of these secondary injury cascades. Neupron™ is patented polymeric nanoparticle composition encapsulating antioxidant enzymes, superoxide dismutase and catalase, with high catalytic activity to neutralize ROS. The preliminary data demonstrated efficacy of Neupron following intravenous injection at 3 hrs after the injury in a rat contusion model of SCI. The treatment neutralized the excess ROS formed after the injury, significantly inhibited the progression of secondary injury, and regained locomotive functions. AxoNeural Therapeutics, Inc., is a new spin off company of Cleveland Clinic Innovation. The goal is to develop Neupron as an early therapeutic intervention to protect the spinal cord from secondary injury and promote regeneration. Such an effective early intervention can minimize severity of the post-injury disability and enhances the prospects of achieving better neurological and functional recovery. Through the R41 STTR Phase I grant, the main objective is to undertake critical formulation development of Neupron. The successful outcome of Phase-I would set the stage for Phase-II application to advance Neupron to the IND stage and ultimately to clinical development. Since there are ~17,000 cases of SCI per year in the US, Neupron will be considered as an orphan drug. Our aims for this proposal are: Aim 1: Establish parameters for pilot-scale production of Neupron: a) Establish a scale-up process that is reproducible for production of Neupron under GLP conditions and b) Evaluate Neupron for initial assessment of its biocompatibility in rat SCI model. Milestones: At least three consecutive production batches showing less than 5% variation in physical and biological (catalytic) characteristics of Neupron and without any toxicity concern. Aim 2: Characterize Neupron produced under cGMP conditions: Nebraska Nanomedicine Production Plant is a contract laboratory with cGMP nanoparticle production capacity. Neupron prepared under cGMP condition will be tested for physical and biological properties to ensure successful transfer of the protocol developed under GLP conditions. Neupron will be evaluated for bioburden and endotoxin levels. Milestones: Neupron meets the FDA guidelines for parenteral products (2l CFR parts 210 and 211). Arrange Pre-IND meeting with the FDA.

项目描述：创伤性脊髓损伤 (SCI) 的病理生理学涉及最初的身体损伤 影响，导致退行性细胞和分子事件的继发性损伤级联。 随着时间的推移，继发性损伤沿着脊髓蔓延，这增加了新的残疾程度，并导致 撞击地点过量的活性氧（ROS）形成是一个重要的影响。 Neupron™ 是这些继发性损伤级联的组成部分，是获得专利的聚合物纳米颗粒组合物。 封装抗氧化酶、超氧化物歧化酶和过氧化氢酶，具有高催化活性 初步数据证明 Neupron 在静脉注射 3 小时后有效。 在大鼠 SCI 挫伤模型中，治疗中和了损伤后形成的过量 ROS。 损伤，显着抑制继发性损伤的进展，恢复运动功能。 AxoNeural Therapeutics, Inc. 是克利夫兰诊所创新公司的一家新分拆公司，目标是发展。 Neupron 作为一种早期治疗干预措施，可保护脊髓免受继发性损伤并促进 这种有效的早期干预可以最大限度地减少受伤后残疾的严重程度和程度。 通过 R41 STTR 增强实现更好的神经和功能恢复的前景。 第一期资助，主要目标是进行 Neupron 的关键制剂开发。 第一阶段的结果将为第二阶段的申请奠定基础，以将 Neupron 推进到 IND 阶段 由于美国每年约有 17,000 例 SCI 病例，Neupron 将最终进入临床开发。 我们将此提案视为孤儿药的目标是： 目标 1：建立 Neupron 中试规模生产的参数：a) 建立放大工艺 在 GLP 条件下可重复生产 Neupron，并且 b) 评估 Neupron 的初始值 评估其在大鼠 SCI 模型中的生物相容性 里程碑：至少连续三个生产批次。 Neupron 的物理和生物（催化）特性显示出小于 5% 的变化，并且没有任何 毒性问题。 目标 2：表征 cGMP 条件下生产的 Neupron：内布拉斯加州纳米药物生产 工厂是具有cGMP纳米颗粒生产能力的合同实验室。 将测试条件的物理和生物特性，以确保协议的成功转移 将评估在 GLP 条件下开发的 Neupron 的生物负载和内毒素水平。 Neupron 符合 FDA 注射用产品指南（2l CFR 第 210 和 211 部分）。 与 FDA 会面。