Open AccessPreclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention
Author(s) -
Kevin D. Rynearson,
Moorthi Ponnusamy,
Olga Prikhodko,
Yuhuan Xie,
Can Zhang,
Phuong D. Nguyen,
Brenda Hug,
Mariko Sawa,
Ann Becker,
Brian Spencer,
Jazmin Florio,
Michael Mante,
Bahar Salehi,
Carlos F. Arias,
Douglas Galasko,
Brian P. Head,
Graham Johnson,
Jiunn H. Lin,
Steven K. Duddy,
Robert A. Rissman,
William C. Mobley,
Shuai Wang,
Rudolph E. Tanzi,
Steven L. Wagner
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20202560
Subject(s) - gamma secretase , amyloid precursor protein secretase , transgene , pharmacology , medicine , genetically modified mouse , disease , alzheimer's disease , adverse effect , biology , microbiology and biotechnology , amyloid precursor protein , gene , biochemistry
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%.