Translating in vivo drug screens to Alzheimer's patients with a pharmaco-epidemiological approach
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Project Summary/Abstract (30 lines) We hypothesize that drug trials, in Alzheimer's disease (AD) have failed in humans because AD entails both proteotoxicity (involving at least Aß and tau) AND microglial activity (clearly demonstrated by GWAS studies), probably with hypersecretion of inflammatory cytokines. Successful treatments will probably require drugs that ameliorate proteotoxicity AND microglial hypersecretion of cytokines, rather than targeting levels of a single protein or peptide. We propose that a phenotype-based screening approach is more likely to lead to overall successful therapies for AD and aging related diseases in general. Although 5 drugs are approved to treat AD, they only treat symptoms, not causes of AD, and it is widely agreed that the clinical significance of these drugs is modest at best. An increasing number of pharmaceutical companies have abandoned the search for treatments for AD. We therefore developed an innovative high-throughput drug screening platform and conducted two unparalleled high-throughput drug-repurposing screens for their ability to protect against Aß toxicity in Caenorhabditis elegans as a model for the more general process of proteotoxicity in vivo. In subsequent studies, the most protective drugs in C. elegans were then rescreened in microglia for their ability to reduce cytokine release (primarily TNF-alpha and IL-6). These screens led us to prioritize approximately 50 FDA- approved drugs that were protective in these phenotypic assays. The objective of the presently proposed studies is to evaluate if treatment with these FDA-approved drugs (or drugs in similar categories) reduce the risk of AD. We propose to use population-level administrative claims data collected from the Centers for Medicare and Medicaid Services (CMS) to assess if FDA-approved drugs that are protective in a C. elegans model of AD also lower the risk for AD and related dementia in humans. The proposed project is an observational retrospective pharmaco-epidemiological case-control study. The team will use a cox proportional hazard regression to obtain hazard ratios of AD associated with each prioritized FDA-approved drug. Data will be acquired from CMS to cover 5 consecutive years and all models will be fitted and adjusted to the covariates. The end goal of the study is to identify drugs to be repurposed to treat AD and related dementia and to accumulate strong epidemiological evidence in addition to the existing evidence from the model organism C. elegans and cell culture studies. This transdisciplinary research between aging biologists, geriatricians, and epidemiologists will yield data and experience essential to launch the applicant’s subsequent research and independent research career. The results of the proposed study will be further compared with data from other population health records and incorporated into the design of a future clinical trial. The research will take place at the Icahn School of Medicine at Mount Sinai, which has a leading Geriatrics Department and world experts in pharmaco- epidemiology.
