Thursday, November 21, 2024
11/21/2024
SUMMARY Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder caused by interactions among multiple genetic and environmental factors. The strongest genetic factor of AD is apolipoprotein (APO) E genotype— APOE4 increases AD risk and lowers age-onset of AD and APOE4 carriers account for ~60% of all AD cases; the remaining ~40% are APOE3 carriers. The genetic complexity and multifactorial nature of Alzheimer’s disease pose unique challenges for traditional drug development that usually targets a specific gene, protein, or pathway. For the past several decades, new drug development efforts to target specific AD-related proteins or pathways have shown promise in animal studies, only to fail during human trials. Since the process of developing new drugs for Alzheimer’s disease is complicated, time-consuming, and costly, there is a pressing need to consider unconventional drug development strategies, such as repurposing drugs currently approved for other conditions. The approach of drug repurposing has a number of advantages over the development of new drugs and has been used successfully for various disease conditions. The established safety and tolerability of approved drugs can lower the burdensome financial thresholds associated with screening, dose optimization, toxicology, formulation, and manufacturing development. Repurposing approved drugs can also drastically shorten the time for a drug to reach patients. The recent convergence of two factors presents an unprecedented opportunity to advance rational drug repurposing. First is the availability of public databases from large-scale genomic, transcriptomic, and other molecular profiling studies for major diseases in humans. Second is the development of computational approaches and algorithms as well as the network concept of drug targets, which allows us to investigate the ability of a therapeutic agent to perturb entire molecular networks away from disease states. Many therapeutic areas including cancer have benefited from repurposing existing drugs based on the network concept of drug targets. Drug repurposing for central nervous system (CNS) diseases, including Alzheimer’s disease, started recently, with limited success so far, including our recent repurposing of bumetanide for treating APOE4-related Alzheimer’s disease. A major challenge of drug repurposing for CNS diseases, including Alzheimer’s disease, is the lack of whole genome gene expression perturbation databases of approved drugs in human cell types relevant to CNS diseases, including AD. This proposal aims to address this major bottleneck for CNS disease drug repurposing, focusing on AD drug repurposing, by establishing APOE-genotype-dependent and human CNS cell-type-specific Connectivity Maps (hCNS-CMAPs) covering ~12,000 drugs demonstrated safety in humans, using human iPSC-derived CNS cells (Aim 1). We will then apply these hCNS-CMAPs for AD drug repurposing and validate the identified top drugs in a novel mouse model of AD (Aim 2). The outcomes of this project will provide the research and drug development fields with invaluable resources for repurposing the approved drugs toward AD and other CNS diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
