Targeted Therapies for Rett Syndrome

雷特综合征的靶向治疗

基本信息

批准号：
10395961
负责人：
Sujatha Kannan
金额：
$ 39.72万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395961
关键词：
Achievement Adrenoleukodystrophy Affect Age Anti-Inflammatory Agents Antioxidants Astrocytes Attenuated Autonomic Dysfunction Behavior Birth Blood - brain barrier anatomy Brain Cells Cerebrum Childhood Clinical Trials Combined Modality Therapy Cysteine Cytokine Signaling Dendrimers Diffuse Disease Progression Drug Delivery Systems Drug Targeting Drug usage Enzymes Female Functional disorder Future Genes Glutamates Glutaminase Glutamine Glutathione Hand Hippocampus (Brain)Home Hydroxyl Radical Immune Immune response Immunology Inflammation Inflammatory Inflammatory Response Injury Institutes Intellectual functioning disability Intestines Knockout Mice Mediating Medicine Methyl-CpG-Binding Protein 2 Microglia Modeling Movement Mus Mutation Natural regeneration Neurodevelopmental Disorder Neuroglia Neurological outcome Neurosciences Norleucine Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Pediatric Neurology Peripheral Phagocytosis Pharmaceutical Preparations Phenotype Production Public Health Research Research Personnel Respiration Rett Syndrome Role Seizures Sleep Symptoms Toxic effect Translations Up-Regulation Weight Wild Type Mouse Work antagonist base behavioral phenotyping brain parenchyma clinical translation cytokine developmental disease drug discovery girls improved in vivo inhibitor innovation migration motor disorder mouse model multidisciplinary nanomedicine nanoparticle nanotherapeutic nanotherapy neurobehavior neurobehavioral neurotransmission oxidative damage repaired response side effect symptom management targeted delivery targeted treatment uptake

项目摘要

PROJECT SUMMARY Immune dysregulation in the brain and disruption of glutamate neurotransmission, both mediated by glia, have been implicated in the pathogenesis and worsening of symptoms in Rett syndrome (RTT), a debilitating, developmental disorder that is associated with seizures, intellectual disability, motor and autonomic dysfunction, and non-purposeful hand movements. Microglia and astrocytes appear to mediate the immune response, oxidative injury and glutamate toxicity in RTT. Therapies targeting these key mechanisms by modulating the glial responses could have an impact in RTT by arresting the injury and promoting repair and regeneration. Building on positive preliminary results in the Mecp2 null and Het mice with dendrimer conjugated antioxidant N-acetyl cysteine (D-NAC), we propose an innovative nanotherapeutic approach to attenuate/arrest the injury in RTT. Our overall hypothesis is that targeted delivery of a combination of an anti- inflammatory/anti-oxidant agent, along with a potent glutaminase inhibitor to microglia and astrocytes in Mecp2-null and Mecp2-heterozygous (HET) mice will lead to decreased oxidative injury and glutamate toxicity resulting in improved long term neurobehavioral outcomes in Mecp2-null and HET mice and symptom free survival in Mecp2-null mice. Our preliminary results in RTT demonstrates that (1) systemically administered dendrimer nanoparticles localize specifically in microglia in the RTT mouse brain but not in the brain of wild type mice; (2) D-NAC monotherapy administered systemically once a week to symptomatic Mecp2-null mice, results in significant improvement in neurobehavioral scores at 6-7 weeks of age, while the free drug is not effective; (3) D-NAC is effective in improving the behavioral phenotype and hippocampal glutathione levels in HET mice; and (4) glutaminase, the enzyme responsible for glutamate synthesis, is upregulated in MeCP2 deficient microglia and is specifically inhibited by systemically administered dendrimer-glutaminase inhibitor conjugate. Supported by an R21, we completed D-NAC monotherapy in Mecp2-null and HET mice, and identified the glutamine antagonist DON (6-Diazo-5-Oxo-L-Norleucine) as a potent glutaminase. DON has failed clinical trials due to severe toxicity profile. We propose to determine if 1) Systemic treatment with D-DON results in specific inhibition of microglial glutaminase resulting in improved neurologic outcomes and decreased glutamate toxicity while eliminating the severe peripheral toxicities of free DON, 2) combination therapy with D- NAC+D-DON is more effective in improving survival and long-term neurologic outcomes in Mecp2-null and HET mice, and 3) systemic treatment with D-NAC+D-DON results in improvement in immune response, oxidative injury and function of Mecp2-null microglia isolated from RTT mouse brains. In vivo effects on survival (Mecp2-null mice), behavior, respiration, sleep (HET) will be evaluated. If successful, these initial proof-of-concept studies will lay the groundwork for future work crucial for clinical translation.

项目概要大脑中的免疫失调和谷氨酸神经传递的破坏，两者都是由神经胶质细胞介导的，与 Rett 综合征 (RTT) 的发病机制和症状恶化有关，RTT 是一种使人衰弱、与癫痫、智力障碍、运动和自主神经相关的发育障碍功能障碍和无目的的手部动作。小胶质细胞和星形胶质细胞似乎介导免疫 RTT 中的反应、氧化损伤和谷氨酸毒性。针对这些关键机制的治疗方法调节神经胶质反应可能通过阻止损伤和促进修复来影响 RTT 再生。基于 Mecp2 null 和 Het 小鼠与树枝状聚合物的积极初步结果结合抗氧化剂 N-乙酰半胱氨酸 (D-NAC)，我们提出了一种创新的纳米治疗方法减轻/阻止 RTT 中的伤害。我们的总体假设是，靶向递送抗- 炎症/抗氧化剂，以及对小胶质细胞和星形胶质细胞有效的谷氨酰胺酶抑制剂 Mecp2-null 和 Mecp2-heterozygous (HET) 小鼠将导致氧化损伤和谷氨酸毒性降低改善 Mecp2 缺失小鼠和 HET 小鼠的长期神经行为结果，且无症状 Mecp2 缺失小鼠的存活率。我们在 RTT 中的初步结果表明 (1) 系统地管理树枝状聚合物纳米粒子特异性定位于 RTT 小鼠大脑的小胶质细胞中，但不在野生小鼠的大脑中型小鼠； (2)每周一次对有症状的Mecp2缺失小鼠全身施用D-NAC单一疗法，导致 6-7 周龄时神经行为评分显着改善，而免费药物则不然有效的; (3) D-NAC可有效改善行为表型和海马谷胱甘肽水平 HET 小鼠； (4) 谷氨酰胺酶（负责谷氨酸合成的酶）在 MeCP2 中上调小胶质细胞缺陷，并被全身施用的树枝状大分子谷氨酰胺酶抑制剂特异性抑制共轭。在 R21 的支持下，我们在 Mecp2-null 和 HET 小鼠中完成了 D-NAC 单一疗法，并且鉴定出谷氨酰胺拮抗剂 DON（6-Diazo-5-Oxo-L-Norleucine）是一种有效的谷氨酰胺酶。唐有由于严重的毒性，临床试验失败。我们建议确定是否 1) 使用 D-DON 进行全身治疗导致小胶质细胞谷氨酰胺酶的特异性抑制，从而改善神经系统结果并减少谷氨酸毒性，同时消除游离 DON 的严重外周毒性，2) 与 D- 联合治疗 NAC+D-DON 在改善 Mecp2 缺失和 Mecp2 缺失患者的生存和长期神经系统结局方面更有效 HET 小鼠，3) D-NAC+D-DON 全身治疗可改善免疫反应，从 RTT 小鼠大脑中分离出 Mecp2 缺失小胶质细胞的氧化损伤和功能。体内作用将评估存活率（Mecp2 缺失小鼠）、行为、呼吸、睡眠 (HET)。如果成功的话，这些初始概念验证研究将为未来对临床转化至关重要的工作奠定基础。