Model and Strategy
Despite knowing for two decades that ApoE4 is the major genetic risk factor for Alzheimer’s disease (AD), the molecular mechanisms by which ApoE4 confers AD risk remain unclear. 5.2 million Americans are currently diagnosed with Alzheimer’s. An estimated 75 million Americans carry the ApoE4 gene, conferring increased risk of disease. This project aims to discover therapeutic targets for the at-risk population. The Bredesen laboratory at the Buck has recently discovered why ApoE4 confers risk for Alzheimer’s, so that for the first time drug candidates can be developed that will modify a key disease-causing target. Furthermore, the drug development proposed herein targets multiple pathways involved in cognitive decline in the aging brain. In combination with a recently developed, transformative, holistic program that shows reversal of cognitive decline this project has the potential to impact the brain health of all older adults and slow, reverse, or prevent the onset of Alzheimer’s.
Impact
The drug screening strategy proposed here is expected to deliver several successful “hits” for potential Alzheimer’s drugs that will be highly replicated and validated using multiple independent methods. For example, potential hits will be retested on primary neuronal cultures isolated from transgenic mice that express the human ApoE4 isoform. These mice, which recapitulate nearly all of the human AD pathology, will serve as a replicable model to test the successful hits. It is anticipated that in a 3-year period, there will be at least 23 highly successful compounds that have been replicated and validated through rigorous scientific method in various models of AD, from human cells to mice. These candidates would then be evaluated for further clinical development that would likely be undertaken in collaboration with a corporate partner to cover the scaling of this project to $100 million plus cost of drug development over the course of 710 years. This partnering model has been successful at Buck recently. Ultimately this project would impact the 5 million plus Americans with AD and the millions more at risk.
Leadership
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Brian Kennedy
CEO