Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise.
Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise.
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DOI：
10.1016/j.pneurobio.2013.08.004
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发表时间：
2014-02
影响因子：
6.7
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
--
作者：
Irwin, Ronald W.;Brinton, Roberta Diaz
在此，我们回顾了一项旨在将别孕酮作为神经退行性疾病，特别是阿尔茨海默病的再生疗法推向临床的翻译开发计划。别孕酮是一种内源性神经类固醇，随着年龄的增长和神经退行性疾病的减少，它被外源性应用并评估了其安全性和有效性，以促进神经再生、认知功能和减少阿尔茨海默氏症的病理。在阿尔茨海默病小鼠模型中，别孕酮诱导的神经再生与学习和记忆功能的恢复相关，在老年正常小鼠中同样有效。成功的关键是剂量和治疗方案符合大脑再生系统生物学的时间要求。一种遵循大脑再生要求的治疗方案在减少阿尔茨海默氏症的病理方面也是有效的。通过优化的剂量和治疗方案，慢性别孕酮治疗促进了神经发生、少突胶质形成，减少了神经炎症和β-淀粉样蛋白负担，同时增加了白质生成和胆固醇稳态的标志物。别孕酮符合利平斯基规则所描述的四种类似药物的物理化学性质中的三种，这些规则预测临床试验开发中的药物的成功率。讨论了药代动力学和药效学结果、GMP材料的保护、临床可翻译配方的开发以及获得监管部门的批准。对别孕酮作为再生疗法的研究为神经发生和疾病修改的机制靶点、剂量要求、最佳治疗方案、给药途径和必要的适当配方提供了关键的见解，以推进概念验证临床研究，以确定别孕酮作为阿尔茨海默病的再生和疾病修改疗法的疗效。
Herein, we review a translational development plan to advance allopregnanolone to the clinic as a regenerative therapeutic for neurodegenerative diseases, in particular Alzheimer’s. Allopregnanolone, an endogenous neurosteroid that declines with age and neurodegenerative disease, was exogenously administered and assessed for safety and efficacy to promote neuro-regeneration, cognitive function and reduction of Alzheimer’s pathology. Allopregnanolone-induced neurogenesis correlated with restoration of learning and memory function in a mouse model of Alzheimer’s disease and was comparably efficacious in aged normal mice. Critical to success was a dosing and treatment regimen that was consistent with the temporal requirements of systems biology of regeneration in brain. A treatment regimen that adhered to regenerative requirements of brain was also efficacious in reducing Alzheimer’s pathology. With an optimized dosing and treatment regimen, chronic allopregnanolone administration promoted neurogenesis, oligodendrogenesis, reduced neuroinflammation and beta-amyloid burden while increasing markers of white matter generation and cholesterol homeostasis. Allopregnanolone meets three of the four drug-like physicochemical properties described by Lipinski’s rule that predict the success rate of drugs in development for clinical trials. Pharmacokinetic and pharmacodynamic outcomes, securing GMP material, development of clinically translatable formulations and acquiring regulatory approval are discussed. Investigation of allopregnanolone as a regenerative therapeutic has provided key insights into mechanistic targets for neurogenesis and disease modification, dosing requirements, optimal treatment regimen, route of administration and the appropriate formulation necessary to advance to proof of concept clinical studies to determine efficacy of allopregnanolone as a regenerative and disease modifying therapeutic for Alzheimer’s disease.
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影响因子：
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