NINDS CREATE DISCOVERY: Development of dendrimer-N-acetylcysteine for the treatment of neonatal brain injury

NINDS 创造发现：开发用于治疗新生儿脑损伤的树枝状聚合物-N-乙酰半胱氨酸

• 批准号: 9906957
• 负责人: Sujatha Kannan
• 金额: $ 75.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906957
• 关键词: Acetylcysteine; Address; Adrenoleukodystrophy; Adult; Adverse drug effect; Affect; Age; Animal Model; Anti-Inflammatory Agents; Anxiety; Asphyxia Neonatorum; Astrocytes; Attenuated; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cells; Cerebral Palsy; Cerebrum; Child; Childhood; Childhood Neurological Disorder; Chronic; Clinical Data; Clinical Trials; Cyclic GMP; Cysteine; Data; Dendrimers; Development; Developmental Disabilities; Diffuse; Dose; Drug Kinetics; Effectiveness; Etiology; Female; Goals; Health Care Costs; Hippocampus (Brain); Hydroxyl Radical; Immune; Infant; Inflammation; Injury; Intervention; Lead; Learning; Life; Ligands; Magnetic Resonance Imaging; Manufacturer Name; Mediating; Memory; Microglia; Mission; Modeling; Motor; Mus; Nanotechnology; National Institute of Neurological Disorders and Stroke; Neonatal Brain Injury; Neurocognitive Deficit; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neuronal Injury; Normal Range; Orphan; Oryctolagus cuniculus; Oxidative Stress; Patients; Perinatal; Perinatal anoxic ischemic brain injury; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Premature Birth; Process; Production; Public Health; Regimen; Reproducibility; Research; Rewarming; Scheme; Sepsis; Serum; Structure; Testing; Therapeutic; Time; TimeLine; United States National Institutes of Health; Work; base; clinically relevant; comorbidity; delivery complications; disability; fetal; improved; improved outcome; indexing; intravenous administration; male; myelination; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; neuroinflammation; neuronal growth; neuroprotection; novel; novel therapeutics; pre-clinical; scale up; standard of care; therapy development; uptake

Project Summary Cerebral palsy is one of the common chronic childhood neurological disorders and has no effective cure. Half a million children under the age of 18 in the US have CP, and 1 in 6 children have some form of developmental disability. Perinatal hypoxic-ischemic encephalopathy (HIE) and maternal-fetal inflammation/immune dysregulation are major causes of cerebral palsy and related disabilities. Although the collective evidence from at least 6-large clinical trials confirms that therapeutic hypothermia improves outcome, 40%-50% of infants treated with hypothermia still die or suffer significant neurologic disability. There remains a critical need for development of therapies for patients who do not qualify for hypothermia, and for adjunct therapies with hypothermia that improve neuroprotection and address the negative effects of hypothermia and rewarming. This is the goal of this 3½ year NINDS CREATE DISCOVERY project. Recent studies suggest that attenuating neuroinflammation, mediated by activated glia, in the early stages can not only delay the onset, but may also provide a longer therapeutic window for treatment. However, delivering drugs across the blood-brain-barrier to target and treat diffuse neuroinflammation is a major challenge. Our team discovered that systemically-administered hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers (~4 nm) target activated glia in the injured brain, without the need for targeting ligands. Interestingly, intravenous administration of the anti-inflammatory drug N-acetyl cysteine (NAC) conjugated to the dendrimer (D-NAC), in clinically-relevant preclinical models of CP, resulted in striking neuroprotective effects. Building on our strong proof-of concept data using our lead compound D-NAC, we propose to optimize this compound further for use in perinatal/neonatal brain injury, during the discovery phase of the CREATE application, for progressing towards an eventual developmental phase and clinical trials. Three aims are identified, along with appropriate milestones: (1) Optimize the synthesis of D-NAC for scale up production, and demonstrate reproducibility, purity and storage stability. (2) Determine pharmacokinetics, PK-PD relationship, minimal effective dose, optimal dose and elimination of D-NAC in rabbit model of cerebral palsy. (3) Determine long term efficacy of D-NAC at the optimal dose identified in Aim 2, in rabbit model of maternal inflammation induced CP and in term mouse hypoxic-ischemia model with hypothermia.

项目摘要 脑瘫是常见的慢性儿童神经系统疾病之一，没有有效的治愈方法。一半 美国18岁以下的百万儿童患有CP，有1个儿童有某种形式的发育 残疾。围产期缺氧缺血性脑病（HIE）和母体狂热/免疫 失调是脑瘫和相关疾病的主要原因。虽然来自 至少6大临床试验证实，治疗性低温可以改善预后，40％-50％的婴儿 接受体温过低的治疗仍然死亡或遭受严重的神经系统疾病。仍然有关键的需求 为不符合体温过低的患者以及与辅助疗法的疗法开发 改善神经保护并解决体温过低和转换的负面影响的体温过低。 这是这个3。5年Ninds创建发现项目的目标。 最近的研究表明，在早期由活化神经胶质介导的神经炎症衰减 阶段不仅可以延迟发作，还可以提供更长的热窗口进行治疗。然而， 在血脑屏障上输送药物以靶向和治疗弥漫性神经炎症是主要的 挑战。我们的团队发现，羟基终止的聚（amidoamine） （PAMAM）树突聚合物（〜4 nm）靶标在受伤的大脑中激活的神经胶质，而无需靶向配体。 有趣的是，静脉注射抗炎药N-乙酰基半胱氨酸（NAC）偶联 CP的临床临床前临床前模型中的树枝状聚合物（D-NAC）导致了神经保护作用 效果。在我们使用铅化合物D-NAC的强大概念验证数据的基础上，我们建议优化 该化合物进一步用于围产期/新生儿脑损伤，在创建的发现阶段 应用，朝着最终的发展阶段和临床试验发展。三个目标是 确定，以及适当的里程碑：（1）优化D-NAC的合成以扩大生产，并优化 证明可重复性，纯度和存储稳定性。 （2）确定药代动力学，PK-PD关系， 在脑瘫兔模型中，有效剂量最小的剂量，最佳剂量和消除D-NAC。 （3）确定 在AIM 2中鉴定出的最佳剂量下，D-NAC的长期效率在母体炎症的兔模型中 诱导的CP和术语小鼠低氧 - 缺血模型与体温过低。