| First Author | Rynearson KD | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 4 | PubMed ID | 33651103 |
| Mgi Jnum | J:346659 | Mgi Id | MGI:6724811 |
| Doi | 10.1084/jem.20202560 | Citation | Rynearson KD, et al. (2021) Preclinical validation of a potent gamma-secretase modulator for Alzheimer's disease prevention. J Exp Med 218(4) |
| abstractText | 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 Abeta42 and to a lesser extent Abeta40, while concomitantly augmenting production of Abeta38 and Abeta37. 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 Abeta42 in rat brain by 50%. |
