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Targeted Delivery of Therapeutics into Motor Neurons for Post-exposure Treatment of Botulism

Targeted Delivery of Therapeutics into Motor Neurons for Post-exposure Treatment of Botulism
将治疗药物靶向输送至运动神经元,用于肉毒杆菌中毒的暴露后治疗
批准号:
10653914
负责人:
Min Dong
金额:
$72.08万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-01 至 2026-07-31

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中文摘要
翻译
项目摘要 细菌毒素家族,肉毒杆菌神经毒素(BoNTs),由芽胞产生- 形成革兰氏阳性梭菌是已知的最有效的毒素。它们导致了 人和动物的致命性麻痹性疾病肉毒杆菌中毒。这些毒素是六种最常见的毒素之一 危险的潜在生物恐怖分子(A类和第1级)。它们以运动神经元为靶标 具有极端特异性,进入神经元的胞浆,阻断神经元的活动,引起 肌肉麻痹。造成BoNTs威胁的一个主要因素是它们极长的半衰期 在运动神经元的胞浆内--毒素在人体胞浆中停留4-6个月。 并导致持续数月的瘫痪。到目前为止,还没有治疗药物可以抑制体内的毒素 神经元的胞浆。 在这里,我们建议为这一重中之重创造一种有效的暴露后治疗 生物恐怖分子和致命的细菌毒素。这种治疗是基于修改最近的一种 发现了新的细菌毒素BONT/X,并利用该工程蛋白提供了融合 抗BoNTs的中和抗体进入运动神经元的胞浆。我们广泛的 初步研究已经提供了工作原型,它完全将老鼠从 多个暴露后模型中BoNTs的全身毒性。在此,我们提出了三个目标 进一步验证我们的假设:(1)完善嵌合毒素平台;(2)优化 针对BoNTs的纳米体载药;以及(3)建立药物动力学参数和 在啮齿动物和豚鼠模型上验证治疗效果。 这些目标的成功将为当务之急创造有效的暴露后治疗 生物恐怖主义制剂,并开发了一种新型的以蛋白质为基础的马达靶向递送平台 神经元,从而提供了新的工具,以靶向胞浆突起和“不可药物”的蛋白质 神经元。
英文摘要
Project Summary The family of bacterial toxins, botulinum neurotoxins (BoNTs), produced by spore- forming Gram-positive Clostridium bacteria, are the most potent toxins known. They cause the deadly paralytic disease botulism in humans and animals. These toxins are one of the six most dangerous potential bioterrorism agents (Category A and Tier 1). They target motor neurons with extreme specificity, enter the cytosol of neurons, and block neuronal activity, causing muscle paralysis. A major contributor to the threat of BoNTs is their extremely long half-life within the cytosol of motor neurons – the toxin resides in the cytosol for 4-6 months in humans and causes persistent paralysis for months. To date, no therapeutics can inhibit toxins within the cytosol of neurons. Here we propose to create an effective post-exposure treatment for this top-priority bioterrorism agent and deadly bacterial toxins. This treatment is based on modifying a recently discovered new bacterial toxin BoNT/X and utilizing this engineered protein to deliver a fused neutralizing antibody against BoNTs into the cytosol of motor neurons. Our extensive preliminary studies have provided working prototypes, which completely rescue mice from systemic toxicity of BoNTs in multiple post-exposure models. Here we propose three aims to further validate our hypothesis by (1) refining the chimeric toxin platform; (2) optimizing the nanobody cargo against BoNTs; and (3) establishing pharmacokinetic parameters and validating therapeutic efficacy in both rodent and guinea pig models. Success of these aims will create an effective post-exposure treatment for a top-priority bioterrorism agent, and also develop a novel protein-based delivery platform for targeting motor neurons, thus offering new tools for targeting cytosolic processes and “undruggable” proteins in neurons.
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Genome-wide CRISPR-Cas9 screens in insect cells to characterize insecticidal toxins
  • 批准号:
    10873497
  • 项目类别:
  • 资助金额:
    $14.57万
  • 财政年份:
    2022
  • 负责人:
    Min Dong
  • 依托单位:
Developmental Pharmacology of Hydroxyurea Across the Age Span for the Treatment of Sickle Cell Anemia
  • 批准号:
    10382052
  • 项目类别:
  • 资助金额:
    $19.6万
  • 财政年份:
    2022
  • 负责人:
    Min Dong
  • 依托单位:
Genome-wide CRISPR-Cas9 screens in insect cells to characterize insecticidal toxins
  • 批准号:
    10502624
  • 项目类别:
  • 资助金额:
    $78.78万
  • 财政年份:
    2022
  • 负责人:
    Min Dong
  • 依托单位:
Developmental Pharmacology of Hydroxyurea Across the Age Span for the Treatment of Sickle Cell Anemia
  • 批准号:
    10551233
  • 项目类别:
  • 资助金额:
    $17.4万
  • 财政年份:
    2022
  • 负责人:
    Min Dong
  • 依托单位:
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