Conference Proceeding

Discovery and development of gamma-secretase modulators for treatment and prevention of Alzheimer’s diseasea

Dr. Steven L. Wagner

Inhibitors of γ-secretase have been developed for Alzheimer’s disease (AD) with the aim of decreasing brain levels of all Aβ peptide species (Aβ42, Aβ40, Aβ39, Aβ38 and Aβ37). Based on the fact that the vast majority of the more than 200 FAD-linked genetic mutations appear to cause a 2-fold increase in the ratio of the longer more oligomeric-prone Aβ42 peptide relative to the shorter Aβ40 peptide, and a large body of data pointing specifically to Aβ42 in AD pathogenesis, a therapeutic rationale that modulates γ-secretase activity to reduce only the level of Aβ42 without affecting overall γ-secretase activity may prove most efficacious. We view gamma-secretase modulation as superior to the use of vaccines and passive immunization which require invasive procedures and immune regulation. In addition, because gamma-secretase modulators (GSMs) directly attenuate the level of Aβ42, while increasing levels of shorter Aβ peptides (Aβ38 and Aβ37) they may prove to be easier to test, evaluate and monitor clinically than compounds which inhibit the activities of either β-secretase (BACE inhibitors such as verubecestat are currently in phase 3 clinical trials), γ-secretase or both. To date GSMs have yet to be tested in AD patients due primarily to adverse events encountered during phase 1 safety studies. We have identified a very potent GSM, BPN-15606, with an excellent pharmacological and toxicological profile which we feel may be suitable ultimately for testing in AD.

Published: 17 October 2017


Copyright: © 2017 Dr. Steven L. Wagner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.