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Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury.
Neurotherapeutics ( IF 5.7 ) Pub Date : 2020-04-21 , DOI: 10.1007/s13311-020-00858-x
Michael L James 1, 2, 3 , Jordan M Komisarow 4 , Haichen Wang 2 , Daniel T Laskowitz 1, 2, 3, 4
Affiliation  

Over the last few decades, increasing evidence demonstrates that the neuroinflammatory response is a double-edged sword. Although overly robust inflammatory responses may exacerbate secondary tissue injury, inflammatory processes are ultimately necessary for recovery. Traditional drug discovery often relies on reductionist approaches to isolate and modulate specific intracellular pathways believed to be involved in disease pathology. However, endogenous brain proteins are often pleiotropic in order to regulate neuroinflammation and recovery mechanisms. Thus, a process of “backward translation” aims to harness the adaptive properties of endogenous proteins to promote earlier and greater recovery after acute brain injury. One such endogenous protein is apolipoprotein E (apoE), the primary apolipoprotein produced in the brain. Robust preclinical and clinical evidence demonstrates that endogenous apoE produced within the brain modulates the neuroinflammatory response of the acutely injured brain. Thus, one innovative approach to improve outcomes following acute brain injury is administration of exogenous apoE-mimetic drugs optimized to cross the blood–brain barrier. In particular, one promising apoE mimetic peptide, CN-105, has demonstrated efficacy across a wide variety of preclinical models of brain injury and safety and feasibility in early-phase clinical trials. Preclinical and clinical evidence for apoE’s neuroprotective effects and downregulation of neuroinflammatory and the resulting translational therapeutic development strategy for an apoE-based therapeutic are reviewed.

中文翻译:

载脂蛋白E模拟物治疗急性脑损伤的治疗性发展:增强内源性反应以减少继发性损伤。

在过去的几十年中,越来越多的证据表明神经炎症反应是一把双刃剑。尽管过分强烈的炎症反应可能会加剧继发性组织损伤,但炎症过程最终对于恢复至关重要。传统的药物发现通常依靠还原论方法来分离和调节被认为与疾病病理学有关的特定细胞内途径。但是,内源性脑蛋白通常具有多效性,以调节神经炎症和恢复机制。因此,“向后翻译”的过程旨在利用内源性蛋白质的适应性特性来促进急性脑损伤后的早期恢复和更大恢复。一种这样的内源蛋白是载脂蛋白E(apoE),它是大脑中产生的主要载脂蛋白。强有力的临床前和临床证据表明,大脑内产生的内源性apoE可以调节急性受伤的大脑的神经炎症反应。因此,一种改善急性脑损伤后预后的创新方法是优化经过血脑屏障治疗的外源性apoE模拟药物。特别是,一种有前途的apoE模拟肽CN-105在早期临床试验中已在多种脑损伤的临床前模型,安全性和可行性方面证明了其有效性。审查了apoE的神经保护作用和神经炎的下调的临床前和临床证据,以及基于apoE的治疗剂的转化治疗发展策略。
更新日期:2020-04-21
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