期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 218, 期 4, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20202560
关键词
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资金
- SRI International
- Cure Alzheimer's Fund
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- National Institutes of Health/National Institute of Neurological Disorders and Stroke Blue Print and National Institute on Aging [NS 074501, U01AG048986, R01AG055523, R01AG054223, R01AG056061]
- Chen Foundation [R-86U55A]
The potent gamma-secretase modulator has shown robust time- and dose-dependent efficacy in animal studies, with a >40-fold safety margin in rats.
A potent gamma-secretase modulator (GSM) has been developed to circumvent problems associated with gamma-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 gamma-secretase activity but rather allosterically modulate gamma-secretase, reducing the net production of A beta 42 and to a lesser extent A beta 40, while concomitantly augmenting production of A beta 38 and A beta 37. 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 AUC(effective), the systemic exposure required for reducing levels of A beta 42 in rat brain by 50%.
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