Descrizione del progetto
Una piattaforma per la profilazione epigenetica dei farmaci
Circa il 90 % dei farmaci candidati non riceve l’approvazione regolatoria a causa di tossicità inaspettata nell’essere umano. Considerando che questi farmaci sono stati sottoposti a numerose sperimentazioni animali prima di passare alle sperimentazioni cliniche di fase I, ciò evidenzia chiaramente l’importanza di migliori saggi umani basati sulle cellule. Le alterazioni epigenetiche sono sempre più spesso riconosciute come effetti collaterali dei farmaci. L’obiettivo del progetto hmqChIP, finanziato dall’UE, è quello di sviluppare una tecnologia di sequenziamento della cromatina immunoprecipitata altamente multiplexata e quantitativa (hmqChIP, highly multiplexed, quantitative, chromatin immunoprecipitation) per lo screening degli effetti epigenetici previsti e indesiderati dei farmaci. Il metodo sarà commercializzato allo scopo di fornire una piattaforma per lo screening ad alta produttività di farmaci contro vari marcatori epigenetici. Il progetto fornirà importanti spunti sugli effetti poco studiati dei farmaci sull’epigenoma umano.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
17177 Stockholm
Svezia