The AD4 Consortium is testing large libraries of FDA-approved drugs and natural products to identify any that could be beneficial against Alzheimer’s disease in a number of different ways. This approach—repurposing—offers significant time and cost advantages over developing a new drug from scratch, a process that for neurology drugs has been estimated to take several billion dollars and 15 years. Drugs approved by the FDA for other diseases already have undergone significant safety testing and have a body of information available for them; natural products have not necessarily undergone the same amount of analysis, but already are being consumed safely.
The AD4 Consortium’s approach to screening repurposing candidates has been empowered by its use of the CureAlz-funded Alzheimer’s in a Dish™ (ADiD) model. This human-derived 3D system recapitulates the key cell types and blood-brain barrier making up the Alzheimer’s environment in the human brain. It has been optimized to allow high-throughput screening of 96 different compounds at a time. Each candidate is being assessed by AD4 for its ability in ADiD to reduce amyloid beta and tau pathology, as well as to modulate neuroinflammation. Candidates with powerful impact then are studied to discern the likely mechanism of action for this impact and their ability to get into the brain. Artificial intelligence and in silico drug screening are applied to the strongest candidates to determine whether other drugs or chemical compounds might achieve the same mechanism of action with even better profiles on other dimensions, suggesting even stronger candidates in turn.
To date, the consortium has successfully analyzed a 2,640-compound drug library, narrowing it down to eight very strong candidates based on their potency in reducing the pathological hallmarks of Alzheimer’s disease. In addition, 803 natural products have been reviewed for their effect on tau pathology, yielding 14 natural compounds of interest. These candidates are now with a CureAlz task force with appropriate pharmacological and clinical trial expertise for further prioritization as drug candidates for AD clinical trials.
AD4 CONSORTIUM: FUNDED RESEARCHERS
Se Hoon Choi, Ph.D., Massachusetts General Hospital
Ana Griciuc, Ph.D., Massachusetts General Hospital
Roger Kamm, Ph.D., Massachusetts Institute of Technology
Doo Yeon Kim, Ph.D., Massachusetts General Hospital
Joseph Park, Ph.D., Massachusetts General Hospital
Luisa Quinti, Ph.D., Massachusetts General Hospital
*Rudy Tanzi, Ph.D., Massachusetts General Hospital
Stephen T.C. Wong, Ph.D., Houston Methodist
Weiming Xia, Ph.D., Boston University School of Medicine