Targeted Therapies for Rett Syndrome

雷特综合征的靶向治疗

基本信息

  • 批准号:
    10611922
  • 负责人:
  • 金额:
    $ 37.87万
  • 依托单位:
  • 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 2025-04-30
  • 项目状态:
    未结题

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.
项目总结 大脑中的免疫失调和谷氨酸神经传递的中断,都是由胶质细胞介导的 与Rett综合征(RTT)的发病机制和症状恶化有关,RTT是一种衰弱的 与癫痫、智力残疾、运动和自主神经相关的发育障碍 功能障碍和非目的性的手部运动。小胶质细胞和星形胶质细胞似乎参与了免疫。 RTT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 调节胶质细胞的反应可能通过阻止损伤和促进修复而对RTT产生影响 再生。在MeCP2缺失和Het小鼠中使用树枝状大分子的阳性初步结果 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中的损伤。我们的总体假设是,靶向递送联合抗- 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缺失和MeCP2杂合子(HET)小鼠将减少氧化损伤和谷氨酸毒性 导致改善MeCP2基因缺失和HET小鼠的长期神经行为结果并无症状 MeCP2基因缺失小鼠的存活率。我们在RTT中的初步结果表明:(1)系统管理 树枝状大分子纳米粒子定位于RTT小鼠脑内的小胶质细胞,而不是野生型小鼠的脑内 (2)对有症状的MeCP2基因缺失小鼠每周系统地给予一次D-NAC单一治疗, 结果在6-7周龄时神经行为评分有显著改善,而免费药物没有 (3)D-NAC能有效改善小鼠的行为表型和海马区谷胱甘肽水平。 (4)负责谷氨酸合成的谷氨酰胺酶在MeCP2中上调 缺乏小胶质细胞,并被系统给予树突状分子-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缺失和HET小鼠中完成了D-NAC的单一治疗,并且 鉴定了谷氨酰胺拮抗剂DON(6-重氮-5-氧代-L-去亮氨酸)为一种有效的谷氨酰胺酶。唐有 由于严重的毒性特征,临床试验失败。我们建议确定1)用D-DON进行全身治疗 结果特异性抑制小胶质细胞谷氨酰胺酶导致改善神经功能和降低 谷氨酸毒性,同时消除游离DON的严重外周毒性,2)与D- NAC+D-DON可更有效地改善MeCP2缺失者的存活率和长期神经预后 3)D-NAC+D-DON全身治疗可改善免疫反应, RTT小鼠脑组织中MeCP2缺失小胶质细胞的氧化损伤及功能在体内的影响 将评估存活率(MeCP2基因缺失的小鼠)、行为、呼吸、睡眠(HET)。如果成功,这些初始的 概念验证研究将为未来对临床翻译至关重要的工作奠定基础。

项目成果

期刊论文数量(1)
专著数量(0)
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会议论文数量(0)
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Sujatha Kannan其他文献

Sujatha Kannan的其他文献

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{{ truncateString('Sujatha Kannan', 18)}}的其他基金

Targeted Therapies for Rett Syndrome
雷特综合征的靶向治疗
  • 批准号:
    10395961
  • 财政年份:
    2019
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeted Therapies for Rett Syndrome
雷特综合征的靶向治疗
  • 批准号:
    10132421
  • 财政年份:
    2019
  • 资助金额:
    $ 37.87万
  • 项目类别:
NINDS CREATE DISCOVERY: Development of dendrimer-N-acetylcysteine for the treatment of neonatal brain injury
NINDS 创造发现:开发用于治疗新生儿脑损伤的树枝状聚合物-N-乙酰半胱氨酸
  • 批准号:
    9906957
  • 财政年份:
    2018
  • 资助金额:
    $ 37.87万
  • 项目类别:
Translational Technologies for Ameliorating Brain Injury
改善脑损伤的转化技术
  • 批准号:
    10224681
  • 财政年份:
    2018
  • 资助金额:
    $ 37.87万
  • 项目类别:
Translational Technologies for Ameliorating Brain Injury
改善脑损伤的转化技术
  • 批准号:
    9765382
  • 财政年份:
    2018
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting glutamate carboxypeptidase in perinatal brain injury
靶向谷氨酸羧肽酶在围产期脑损伤中的作用
  • 批准号:
    9263554
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting glutamate carboxypeptidase in perinatal brain injury
靶向谷氨酸羧肽酶在围产期脑损伤中的作用
  • 批准号:
    10631173
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting glutamate carboxypeptidase in perinatal brain injury
靶向谷氨酸羧肽酶在围产期脑损伤中的作用
  • 批准号:
    10530903
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting glutamate carboxypeptidase in perinatal brain injury
靶向谷氨酸羧肽酶在围产期脑损伤中的作用
  • 批准号:
    9923754
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting glutamate carboxypeptidase in perinatal brain injury
靶向谷氨酸羧肽酶在围产期脑损伤中的作用
  • 批准号:
    9346116
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:

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新发脑性肾上腺脑白质营养不良的神经认知和神经影像学标志物
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Novel Role of Peroxisome Proliferator Activated Receptor Beta/Delta in X-Linked Adrenoleukodystrophy
过氧化物酶体增殖物激活受体β/δ在X连锁肾上腺脑白质营养不良中的新作用
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新发脑性肾上腺脑白质营养不良的神经认知和神经影像学标志物
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神经酸的剂量优化——缓解肾上腺脑白质营养不良疾病进展的潜在疗法
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利用髓磷脂敏感成像预测脑肾上腺脑白质营养不良的早期病变发病机制
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使用 IPSC 来定义星形胶质细胞在确定脑肾上腺脑白质营养不良发作风险中的作用
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