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.

项目总结