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）：脑瘫（CP）和自闭症等神经发育障碍是慢性残疾，无法有效治愈，导致严重的个人、社会和经济负担。由活化的小胶质细胞和星形胶质细胞介导的神经炎症在脑瘫（CP）和自闭症的发病机制中发挥着关键作用。针对大脑中激活的小胶质细胞/星形胶质细胞可能提供这样的机会。这是多个层面的挑战。我们的初步研究表明，静脉注射后，聚酰胺胺 (PAMAM) 树枝状聚合物 (~4 nm) 会穿过血脑屏障 (BBB)，并进一步选择性地在新生兔大脑中活化的小胶质细胞和星形胶质细胞中积累。 CP，但不在年龄匹配的健康对照中。重要的是，在出生当天（受伤后 3 天）静脉内给予带有 CP 的兔子试剂盒，以这种树枝状聚合物-N-乙酰半胱氨酸缀合物 (D-NAC) 的形式单次 10 mg/kg 药物剂量，产生了显着的效果。运动功能得到改善，小胶质细胞活化减弱，神经元损伤减少，髓鞘形成延长 5 天。 基于这些有希望的发现，这项研究的长期目标是开发基于树枝状大分子的治疗方法，用于产后脑瘫神经炎症的持续治疗。这将通过以下具体目标来实现：（1）确定增加树枝状聚合物的血液循环时间和使用配体靶向是否会改善小胶质细胞的摄取和保留； (2)评价树枝状聚合物载体的毒性以及与树枝状聚合物缀合的NAC的药代动力学； (3) 评估 D-NAC 缀合物在改善运动功能、减少小胶质细胞激活和脑损伤方面的持续功效长达 30 天。 这项研究意义重大，因为它：（1）探讨了产后针对性治疗 CP 改善运动表型的潜力，这一直是一个巨大的挑战； (2) 利用参与 CP 神经炎症的细胞对 PAMAM 树枝状聚合物的病理依赖性差异摄取； (3) 通过提供定制的药物释放，能够持续减弱大脑发育关键阶段的神经炎症； (4)使用NAC，一种在围产期和新生儿期安全性良好的药物，可以进行临床转化。这项研究具有创新性，因为：（1）我们评估了产后针对产前损伤的治疗方案，以改善运动功能，具有重大意义； (2)我们寻求开发围产期和新生儿期的纳米治疗应用。新型药物输送技术通常对儿童疾病的治疗不足，这些技术主要针对成人。这是第一项将纳米治疗方法用于治疗脑瘫等儿童疾病的研究。