用于预防阿尔茨海默病的有效 γ-分泌酶调节剂的临床前验证。
Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.
机构信息
Department of Neurosciences, University of California, San Diego, La Jolla, CA.
Department of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL.
出版信息
J Exp Med. 2021 Apr 5;218(4). doi: 10.1084/jem.20202560.
A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.
一种有效的γ-分泌酶调节剂（GSM）已经被开发出来，以规避与γ-分泌酶抑制剂（GSIs）相关的问题，并有可能用于早发性家族性阿尔茨海默病（EOFAD）的一级预防。与 GSIs 不同，GSM 不会抑制 γ-分泌酶的活性，而是通过变构调节 γ-分泌酶，从而减少 Aβ42 的净产生，在一定程度上减少 Aβ40 的产生，同时增加 Aβ38 和 Aβ37 的产生。这种 GSM 在多种物种的急性、亚慢性和慢性研究中表现出了强大的时间和剂量依赖性疗效，包括在转基因小鼠模型中的一级和二级预防研究。基于在无观察到不良效应水平（NOAEL）下系统暴露（AUC）与 50%有效 AUC 或 AUCeffective 的比较，GSM 在大鼠中显示出超过 40 倍的安全性边际，AUCeffective 是降低大鼠大脑中 Aβ42 水平所需的系统暴露量的 50%。
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