Project description
A platform for epigenetic drug profiling
Nearly 90 % of drug candidates do not receive regulatory approval due to unexpected toxicity in humans. Considering that these drugs have undergone extensive animal testing before entering Phase I clinical trials, this clearly highlights the importance of improved human cell-based assays. Epigenetic alterations are increasingly recognised drug side-effects. The scope of the EU-funded hmqChIP project is to develop a highly multiplexed, quantitative, chromatin immunoprecipitation sequencing technology (hmqChIP) for screening the epigenetic on- and off-target effects of drugs. The method will be commercialised to provide a platform for high-throughput screening of drugs against various epigenetic markers. The project will provide important insight into the understudied effects of drugs on the human epigenome.
Objective
Here, we develop a highly multiplexed, quantitative, ChIP-Seq technology (hmqChIP-Seq) for commercial exploitation in high-throughput profiling of epigenetic drug on- and off-target effects. Screening efficacy and toxicology of drug candidates in early stages of development has been recognized to be an essential part of drug screening. 90% of all Phase I drug candidates do not reach FDA approval and it is estimated that a quarter of failures relates to unexpected toxicity in humans. This is stunning given that all Phase I drugs have undergone animal-heavy battery of toxicologic tests and showcases the importance of expanding the screening capabilities for drug efficacy and toxicology in human cell-based assays, be it standard culture, organoids or engineered tissues. We believe that the interaction of drugs with the epigenome is an understudied/undervalued area of pre-clinical testing and epigenetic drug profiling will be key in predicting long term outcome in humans. With hmqChIP-Seq, 96 or more drug conditions can be screened against 24 or more epigenomic markers, such as histone or DNA post-translational modifications using specific antibodies and next-generation sequencing read-out. The method development aims to reduce the necessary input material to 1000 cells per condition, allowing it to be placed downstream of typical high-throughput cell-based drug screening assay in a variety of relevant human cell models, such as induced pluripotent stem cells, engineered tissues, organoids. The technology provides a framework for high-throughput, low cost, elucidation of short and long term action and toxicology of epigenetic drugs, or any drug candidate that could affect epigenetic markers.
Fields of science
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicinetoxicology
- natural sciencesbiological sciencesgeneticsepigenetics
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
17177 Stockholm
Sweden