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Highly multiplexed, quantitative epigenetic profiling

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 (EuroSciVoc)

Programme(s)

Topic(s)

Funding Scheme

ERC-POC - Proof of Concept Grant

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Call for proposal

(opens in new window) ERC-2020-PoC

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Host institution

KAROLINSKA INSTITUTET
Net EU contribution
€ 107 000,00
Address
NOBELS VAG 5
171 77 STOCKHOLM
Sweden
Region
Östra Sverige Stockholm Stockholms län
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Beneficiaries (2)