Drug repurposing for Alzheimer’s disease based on transcriptional profiling of human iPSC-derived cortical neurons

Gareth Williams*, Ariana Gatt, Earl Clarke, Jonathan Corcoran, Patrick Doherty, David Chambers, Clive Ballard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)
148 Downloads (Pure)

Abstract

Alzheimer’s disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer’s disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer’s disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer’s disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.

Original languageEnglish
Article number220
JournalTranslational psychiatry
Volume9
Issue number1
Early online date6 Sept 2019
DOIs
Publication statusPublished - 2019

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