Friday, May 16, 2025
5/16/2025
Systematically screening and validating drug repurposing candidates for Alzheimer's Disease and Related Dementias - Alzheimer's Disease and Related Dementias (AD/ADRD) are common progressive conditions that damage critical mental functions, causing significant emotional, physical, and financial burdens. Currently, there is no cure for AD/ADRD, nor a drug to delay the onset of the disease. New drugs targeting AD/ADRD have had a 99% failure rate, largely attributable to incomplete biological knowledge, an emphasis on testing single therapies, a lack of predictive validity in animal models, and unacceptable adverse effects. Drug repurposing--identifying new uses for existing drugs-- offers an alternative approach that can reduce the time, costs, and risks of failure associated with new drug development. Indeed, genetic research and large biobanks have accumulated a wealth of relevant data for AD/ADRD drug repurposing efforts. However, given the complexity of AD/ADRD pathogenesis, standard efforts to identify and prioritize drug repurposing candidates for downstream analyses have not yielded success; these repurposing efforts generally arise from basic science or clinical observation and result in a one-at-a-time approach focused on candidate validation in clinical trials. Such efforts ignore the opportunities provided by big data (e.g., genetics and electronic health records) for identifying and validating candidates. The lack of standardized approaches to systematically screen and validate drug repurposing candidates represents a critical barrier to the success of leveraging existing public knowledge and clinical data to advance AD/ADRD treatment. We propose integrating genetics, transcriptomics, literature, and clinical data with advanced informatic technologies and computational capabilities to develop and share tools which systematically screen, prioritize, and validate drug repurposing candidates and their combinations for AD/ADRD. The proposal responds to PAR-22-093, incorporating several emphases highlighted in related notices of interest (e.g., NOT-AG-21-045, NOT-AG-21-033, and NOT-AG-21-050). In Aim 1, we will systematically screen and prioritize drug repurposing candidates for AD/ADRD via both virtual transcriptome and Mendelian randomization, validating the candidates in multiple large clinical datasets. In Aim 2, we will identify, assess, and validate candidates from the literature. In Aim 3, we will evaluate and validate combinations of drug repurposing candidates. For all validations, we will assess the candidate drug/drug pair’s benefits for prevention (i.e., pre-morbidity exposure) and treatment (i.e., post-morbidity exposure), including analyses stratified by dose, gender, and race. In Aim 4, we will make our findings, including deployable tools and codes, broadly available on the AD Knowledge Portal and related websites to facilitate future research.
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).