Postnatal combination therapy for cerebral palsy

脑瘫产后联合治疗

• 批准号: 9270042
• 负责人: Kannan Rangaramanujam
• 金额: $ 33.38万
• 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/9270042
• 关键词: 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; Clinical; Combined Modality Therapy; Complex; Cysteine; Data; Dendrimers; Development; Developmental Disabilities; Diffuse; Disease; Disulfides; Dose; Drug Controls; Drug Kinetics; Drug Transport; Economic Burden; Esters; Evaluation; Formulation; 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; 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; targeted treatment

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）：孕产妇炎症引起的围产期脑损伤与神经发育疾病有关，例如脑瘫（CP）和自闭症谱系障碍。 CP是一种慢性儿童残疾，无法治愈，导致了巨大的个人，社会和经济负担。 由活化的小胶质细胞和星形胶质细胞引起的神经炎症在CP的发病机理中起关键作用。 靶向这些细胞可能会导致持续的疗法直到成年。 我们的初步研究表明，静脉内给药羟基终止的聚（amidoamine）（PAMAM）（PAMAM）树突聚合物（〜4 nm）导致其在活化的小胶质细胞和星形胶质细胞中的选择性积累 具有神经炎症和CP，但没有年龄匹配的健康对照。 更重要的是，单一的10 mg/kg药物剂量以树突二聚体-N-乙酰半胱氨酸偶联物（D-NAC）的形式，在出生当天（受伤后3天）用CP静脉内给药，从而导致运动和降低的运动和降低的Neuron和Neuron的抗衰果，从而显着改善了运动，并在5天的努力中得到了显着改善。 在这些有前途的发现的基础上，我们的长期目标是开发针对性的纳米治疗方法，用于持续的，在CP的持续产后治疗，在这种情况下，改善了直到成年期（在兔子模型中约为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）的鸡尾酒进行多阵方法来减轻损伤。 我们的总体假设是组合疗法将提供NAC（快速释放）和米诺环素（持续释放）的靶向细胞内释放。 第一个目的涉及（D-NAC+D-MINO）共轭物的制备和表征，而第二个目标则侧重于通过在脑，血浆和其他主要的器官和其他主要器官中传递的NAC和米诺环素的毒性，药代动力学和生物分布。 AIM 3将重点介绍通过这种产后，结合疗法达到30天的持续疗效的纵向评估（当兔子发生了主要神经系统功能的发展时）。 这项研究很重要，因为它首次探索了纳米技术的应用，以使衰老的儿童疾病，基于阳性的初步结果/该提案对配方RFA的反应敏感，因为它直接 涉及儿科中纳米技术的领域，递送到靶组织/细胞，持续分娩，联合治疗和减少副作用。