Nanotherapies for the treatment of neurodevelopmental disorders.

用于治疗神经发育障碍的纳米疗法。

• 批准号: 8826117
• 负责人: Kannan Rangaramanujam
• 金额: $ 35.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826117
• 关键词: Adult; Affect; Age; Age-Months; Astrocytes; Autistic Disorder; Birth; Blood - brain barrier anatomy; Blood Circulation; Blood Circulation Time; Brain; Brain Injuries; Cells; Cerebral Palsy; Chemistry; Child; Childhood; Chronic; Clinical; Cysteine; Dendrimers; Development; Diffuse; Disease; Disulfides; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Economic Burden; Esters; Fluorescence; Generations; Goals; Health; Human; Hydroxyl Radical; Immunohistochemistry; Inflammation; Injury; Life; Ligands; Link; Mannose; Mediating; Microglia; Modeling; Motor; Nanotechnology; Neonatal; Nervous System Physiology; Neurodevelopmental Disorder; Neuronal Injury; Newborn Infant; Organ; Oryctolagus cuniculus; Pathogenesis; Pathology; Perinatal; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Positron-Emission Tomography; Prenatal Injuries; Proteins; Public Health; Research; Role; Safety; Surface; Technology; Testing; Therapeutic; Toxic effect; Translations; attenuation; base; cyanine dye 5; design; disability; improved; in vivo; innovation; interest; intravenous administration; mannose receptor; motor function improvement; myelination; nanoparticle; nanotherapeutic; nanotherapy; nervous system disorder; neuroinflammation; novel; novel therapeutic intervention; overexpression; postnatal; prenatal; receptor; social; uptake

DESCRIPTION (provided by applicant): Neurodevelopmental disorders such as cerebral palsy (CP) and autism are chronic disabilities with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP) and autism. Targeting activated microglia/astrocytes in the brain may offer such an opportunity. This is a challenge at multiple levels. Our preliminary studies suggest that, upon intravenous administration, poly (amidoamine) (PAMAM) dendrimers (~4 nm), cross the blood-brain barrier (BBB), and further accumulate selectively in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not in age-matched healthy controls. Importantly, a single 10 mg/kg drug dose in the form of this dendrimer-N-acetyl cysteine conjugate (D-NAC) administered on the day of birth (3 days after injury) intravenously to rabbit kits with CP, resulted in a significant improvement in motor function, attenuation of activated microglia, and decrease in neuronal injury and improved myelination by 5 days. Building on these promising findings, the long-term goal of this research is to develop dendrimer-based therapeutic approaches for the sustained postnatal treatment of neuroinflammation in CP. This will be achieved using the following specific aims: (1) determine whether increasing blood circulation time of dendrimers and using ligand targeting will improve microglial uptake and retention; (2) evaluate the toxicity of the dendrimer vehicle, and pharmacokinetics of NAC conjugated to dendrimers; (3) assess the sustained efficacy of the D-NAC conjugates, in improving motor function, decreasing microglial activation and brain injury up to 30 days. This study is significant because it: (1) explores the potential of targeted post-natal therapy in CP for improvement in motor phenotype, which has been a big challenge; (2) exploits the pathology-dependent differential uptake of PAMAM dendrimers by cells involved in neuroinflammation in CP; (3) will enable sustained attenuation of neuroinflammation during a crucial phase of brain development by providing tailored drug release; (4) uses NAC, a drug with a good safety profile in the perinatal and neonatal period, which can enable clinical translation. This study is innovative, because: (1) we evaluate therapeutic options in the postnatal period for a prenatal insult, to effect an improvement in motor function, with significan implications; (2) we seek to develop nanotherapeutic applications in the perinatal and neonatal period. Pediatric illnesses are often underserved by novel drug delivery technologies, which focus primarily on adults. This is the first study to bring nanotherapeutic approaches to childhood disorders such as CP.

描述（由申请人提供）：诸如脑瘫（CP）和自闭症之类的神经发育障碍是慢性残疾，没有有效治愈，导致了重大的个人，社会和经济负担。由活化的小胶质细胞和星形胶质细胞介导的神经炎症在脑瘫（CP）和自闭症的发病机理中起关键作用。靶向大脑中活化的小胶质细胞/星形胶质细胞可能会提供这样的机会。这是多个级别的挑战。我们的初步研究表明，在静脉内给药后，聚（amidoamine）（PAMAM）树突聚合物（〜4 nm）越过血脑屏障（BBB），并在激活的小胶质细胞和星形胶质层中选择性地积累了与CP的脑兔的大脑中，但在CP的大脑中，但没有年龄匹配的健康对照组。重要的是，该树突聚合物-N-乙酰半胱氨酸偶联物（D-NAC）的单一10 mg/kg药物剂量在出生的当天（受伤后3天）静脉内对具有CP的兔子套件进行了施用，从而导致运动率显着改善，从而使小胶质细胞的功能显着改善，并改善了Neuronal和Neuronal的衰减，并改善了Myeral Myeral Myeral myeral myeral myeral myeral myeral myeral myeral myeral mysove soctiation。 在这些有希望的发现的基础上，这项研究的长期目标是开发基于树突的治疗方法，用于CP中神经炎症后持续的产后治疗。这将使用以下特定目的来实现：（1）确定树枝状聚合物的血液循环时间和使用配体靶向的增加是否会改善小胶质细胞的摄取和保留； （2）评估树枝状聚合物载体的毒性，以及与树枝状聚合物共轭的NAC的药代动力学； （3）评估D-NAC偶联物在改善运动功能方面的持续功效，降低了30天的小胶质细胞激活和脑损伤。 这项研究很重要，因为它是：（1）探讨靶向产后治疗在CP中的潜力以改善运动表型，这是一个很大的挑战； （2）利用参与CP神经炎症的细胞对PAMAM树突聚合物的病理依赖性差异摄取； （3）将通过提供量身定制的药物释放来使神经炎症的持续衰减在大脑发育的关键阶段； （4）使用NAC，这是一种在围产期和新生儿时期具有良好安全性概况的药物，可以实现临床翻译。这项研究具有创新性，因为：（1）我们评估产后损伤的治疗选择，以实现运动功能的改善，具有显着意义； （2）我们试图在围产期和新生儿时期开发纳米治疗应用。小儿疾病通常通过新型药物输送技术的服务不足，这些技术主要集中于成年人。这是将纳米治疗方法引入儿童疾病（例如CP）的第一个研究。