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 脑性瘫痪是儿童常见的慢性神经系统疾病之一，目前尚无有效的治疗方法。半个 在美国，18岁以下的儿童有100万人患有CP，每6个儿童中就有1个患有某种形式的发育障碍。 残疾。围产期缺氧缺血性脑病与母儿炎症/免疫 神经失调是脑瘫和相关残疾的主要原因。尽管来自 至少6项大型临床试验证实，治疗性低温可改善预后，40%-50%的婴儿 低温治疗仍然死亡或遭受严重的神经功能障碍。仍然迫切需要 为不符合低温治疗条件的患者开发治疗方法， 降低体温，改善神经保护并解决降低体温和复温的负面影响。 这是为期三年半的NINDS创建发现项目的目标。 最近的研究表明，减轻神经炎症，介导的活化胶质细胞，在早期， 分期不仅可以延迟发作，而且还可以提供更长的治疗窗口。然而，在这方面， 通过血脑屏障递送药物以靶向和治疗弥漫性神经炎症是一个主要的 挑战.我们的团队发现，系统性给药羟基封端的聚（酰胺胺） （PAMAM）树枝状聚合物（~4 nm）靶向损伤脑中的活化神经胶质，而不需要靶向配体。 有趣的是，静脉内给予与人前列腺素B1结合的抗炎药物N-乙酰半胱氨酸（NAC）， 树枝状聚合物（D-NAC），在临床相关的临床前模型的CP，导致显着的神经保护， 方面的影响.基于我们强大的概念验证数据，使用我们的先导化合物D-NAC，我们建议优化 该化合物还用于在CREATE的发现阶段期间的围产期/新生儿脑损伤， 应用，以推进最终的开发阶段和临床试验。三个目标是 沿着适当的里程碑：（1）优化D-NAC的合成以扩大生产，和 证明重现性、纯度和储存稳定性。(2)确定药代动力学、PK-PD关系， D-NAC在兔脑性瘫痪模型中的最小有效剂量、最佳剂量和消除。(3)确定 目的2中确定的最佳剂量的D-NAC在母体炎症兔模型中的长期疗效 诱导CP和低温致小鼠缺氧缺血模型。