Postnatal combination therapy for cerebral palsy

脑瘫产后联合治疗

基本信息

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
项目类别：
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

项目摘要

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）：母体炎症引起的围产期脑损伤与神经发育障碍有关，例如脑瘫（CP）和自闭症谱系障碍。脑瘫是一种慢性儿童残疾，无法有效治愈，造成严重的个人、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 的发病机制中起着关键作用。针对这些细胞可能能够实现持续治疗直至成年。我们的初步研究表明，静脉注射羟基末端聚酰胺胺 (PAMAM) 树枝状聚合物 (~4 nm) 会导致其在新生兔大脑中的活化小胶质细胞和星形胶质细胞中选择性积累患有神经炎症和脑瘫，但在年龄匹配的健康对照中却没有。更重要的是，在出生当天（受伤后 3 天）对带有 CP 的兔子试剂盒进行单次 10 mg/kg 树枝状聚合物-N-乙酰半胱氨酸缀合物 (D-NAC) 形式的药物剂量静脉注射，结果显着运动功能和髓鞘形成得到改善，活化的小胶质细胞减弱，神经元损伤减少 5 天。基于这些有希望的发现，我们的长期目标是开发有针对性的纳米治疗方法，用于持续的产后脑瘫治疗，改善持续到成年（兔子模型中约 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) 的混合物，采用多管齐下的方法来减轻损伤。我们的总体假设是，联合疗法将提供 NAC（快速释放）和米诺环素（持续释放）的靶向细胞内释放。第一个目标涉及 (D-NAC+D-Mino) 缀合物的制备和表征，而第二个目标侧重于通过缀合物递送的 NAC 和米诺环素在脑、血浆和其他部位的毒性、药代动力学和生物分布。主要机关。目标 3 将重点关注通过这种产后联合疗法长达 30 天（当兔子主要神经功能发育时）所实现的持续疗效的纵向评估。这项研究意义重大，因为它在积极的初步结果的基础上首次探索了纳米技术在治疗衰弱性儿童疾病方面的应用/该提案响应了 RFA 的配方，因为它直接涉及儿科纳米技术领域、递送至目标组织/细胞、持续递送、联合治疗和减少副作用。