Postnatal combination therapy for cerebral palsy

脑瘫产后联合治疗

• 批准号: 8694873
• 负责人: Kannan Rangaramanujam
• 金额: $ 33.62万
• 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: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694873
• 关键词: Acetylcysteine; Adult; Adverse effects; Affect; Age; Animal Model; Area; Astrocytes; Attenuated; Autistic Disorder; Biodistribution; Birth; Blood - brain barrier anatomy; Brain; Brain Injuries; Cells; Cerebral Palsy; Child; Childhood; Chronic; Combined Modality Therapy; Complex; Data; Dendrimers; Development; Diffuse; Disease; Disulfides; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Transport; Economic Burden; Esters; Evaluation; Glutathione; Goals; Hydroxyl Radical; Inflammation; Inflammatory; Injury; Intravenous; Kidney; Knowledge; Learning Disorders; Link; Methods; Microglia; Minocycline; Modeling; Motor; Nanotechnology; Natural regeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuronal Injury; Newborn Infant; Organ; Oryctolagus cuniculus; Oxidative Stress; Pathogenesis; Pediatrics; Perinatal Brain Injury; Pharmaceutical Preparations; Plasma; Play; Population; Preparation; Public Health; Research; Research Project Grants; Serum; Staging; Testing; Therapeutic; Time; Tissues; Toxic effect; Walking; attenuation; autism spectrum disorder; base; design; disability; improved; in vivo; intravenous administration; motor function improvement; myelination; nanodevice; nanotherapeutic; neurobehavior; neuroinflammation; novel; postnatal; prenatal; public health relevance; repaired; response; social; targeted delivery

DESCRIPTION (provided by applicant): Maternal inflammation-induced perinatal brain injury has been implicated in neurodevelopmental disorders such as cerebral palsy (CP) and autism spectrum disorders. CP is a chronic childhood disability with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP. Targeting these cells may enable sustained therapies till adulthood. Our preliminary studies suggest that intravenous administration of a hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer (~4 nm) results in its selective accumulation in activated microglia and astrocytes in the brain of newborn rabbits with neuroinflammation and CP, but not in age-matched healthy controls. More importantly, a single 10 mg/kg drug dose in the form of dendrimer-N-acetyl cysteine conjugate (D-NAC) intravenously administered on the day of birth (3 days after injury) to rabbit kits with CP, resultd in a significant improvement in motor function and myelination, attenuation of activated microglia, and decrease in neuronal injury by 5 days. Building on these promising findings, our long-term goal is to develop targeted nanotherapeutic approaches for the sustained, post-natal treatment of CP, where improvements persist till adulthood (~1 month in the rabbit model). We propose using a cocktail of dendrimer-NAC and dendrimer-minocycline (D-NAC+D-Mino) for a multipronged approach to attenuate the injury. Our overall hypothesis is that the combination therapy will provide targeted intracellular release of NAC (fast release) and minocycline (sustained release). The first aim relates to the preparation and characterization of (D-NAC+D-Mino) conjugates, while the second aim focuses on the toxicity, pharmacokinetics and biodistribution of NAC and minocycline delivered through the conjugate, in the brain, plasma, and other major organs. Aim 3 will focus on the longitudinal evaluation of the sustained efficacy achieved through this postnatal, combination therapy up to 30 day (when development of major neurologic functions has occurred in rabbits). This study is significant, because it explores applications of nanotechnology for the first time to a debilitating childhood disease, building on positive preliminary results/ This proposal is responsive to the formulations RFA since it directly relates to areas of nanotechnology in pediatrics, delivery to target tissues/cells, sustained delivery, combination therapy, and reducing side effects.

描述（由申请人提供）：母体炎症诱导的围产期脑损伤涉及神经发育障碍，如脑瘫（CP）和自闭症谱系障碍。 脑瘫是一种儿童期慢性残疾，目前尚无有效的治疗方法，给个人、社会和经济造成巨大负担。 由活化的小胶质细胞和星形胶质细胞引起的神经炎症在CP的发病机制中起关键作用。 靶向这些细胞可以使治疗持续到成年。 我们的初步研究表明，静脉注射羟基封端的聚酰胺-胺（PAMAM）树枝状聚合物（~4 nm）导致其在新生兔脑中活化的小胶质细胞和星形胶质细胞中选择性蓄积 神经炎症和CP，但不是在年龄匹配的健康对照。 更重要的是，在出生当天（损伤后3天）静脉内给予患有CP的兔套件树枝状聚合物-N-乙酰半胱氨酸缀合物（D-NAC）形式的单次10 mg/kg药物剂量，导致运动功能和髓鞘形成的显著改善，活化的小胶质细胞的衰减，以及神经元损伤的减少，持续5天。 在这些有希望的发现的基础上，我们的长期目标是开发有针对性的纳米方法，用于持续的产后CP治疗，其中改善持续到成年（在兔模型中约1个月）。 我们建议使用树枝状聚合物-NAC和树枝状聚合物-米诺环素（D-NAC+D-Mino）的鸡尾酒，以多管齐下的方法来减轻损伤。 我们的总体假设是，联合治疗将提供NAC（快速释放）和米诺环素（缓释）的靶向细胞内释放。 第一个目的涉及（D-NAC+D-Mino）缀合物的制备和表征，而第二个目的集中于通过缀合物递送的NAC和米诺环素在脑、血浆和其他主要器官中的毒性、药代动力学和生物分布。 目的3将重点关注通过该产后联合治疗达到的持续疗效的纵向评价，持续时间长达30天（当兔发生主要神经功能发育时）。 这项研究意义重大，因为它首次探索了纳米技术在儿童衰弱疾病中的应用，建立在积极的初步结果的基础上。 涉及儿科纳米技术领域、靶向组织/细胞递送、持续递送、联合治疗和减少副作用。