Anna Borgström has a versatile scientific background with over 10 years’ experience of working in the field of cell and molecular biology at the crossroad between cell-based assays, cancer biology and diagnostic assay development. She obtained her PhD from the University of Zurich in 2013 and after working on several research projects at different Swiss academic institutions she finally joined InSphero in early 2022. As Senior Scientist and Deputy VP of the Liver Safety team Anna is leading both customer-based service studies and several R&D projects. In her role at InSphero she is determined to drive the development of next-generation testing methods for drug toxicity and to close the gap between in vivo and in vitro testing, by providing solutions for liver safety questions through the application of 3D liver models as an alternative to animal testing.
Leveraging Human Liver Microtissue System Based On High Density Microplates For Hepatoxicity Screening Early In Drug Discovery
Presenting author: Anna Borgström
Lola Fäs1 , Minjun Chen2, Natalia Zapiorkowska-Blumer1, Weida Tong2, Anna Borgström1, Friederike Wenz1, Nicola J. Hewitt3, Hajnalka Varga1, Karolina Kaczmarska1, Monika Tu1, Katarzyna Sanchez1, Maria Vittoria Colombo1, Bruno G.H. Filippi1
1) InSphero AG, CH-8952 Schlieren, Switzerland
2) Division of Bioinformatics and Biostatistics, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR 72079, United States 3) Scientific Writing Services, DE-64390 Erzhausen, Germany
Hepatotoxicity is a major obstacle in drug development, making early detection crucial for focusing resources on viable therapeutic compounds. While cell lines are routinely used for early screening, new in vitro models that better replicate liver morphology and function can improve detection accuracy. Human liver microtissues, comprising spherical co-cultures of primary parenchymal and non-parenchymal liver cells, recapitulate essential liver features and have demonstrated better hepatotoxicity prediction accuracy compared to planar hepatocyte cultures (Proctor et al 2017). To assess their predictivity of hepatotoxicity, the cytotoxicity of 152 FDA (US Food & Drug Administration)- approved small molecule drugs was measured as per changes in ATP content in human liver microtissues incubated in 384-well microplates. The cytotoxicity of the liver microtissues was benchmarked against the in vivo hepatotoxicity and total plasma Cmax concentration reported from the clinics. The results were analysed with respect to drug label information, drug-induced liver injury (DILI) concern class, and drug class. The threshold IC50 ATP-to-Cmax ratio of 176 was used to discriminate between safe and hepatotoxic drugs. The liver microtissues correctly flagged 80% of the withdrawn drugs and 72 % of the “Most-DILI-concern” drugs as hepatotoxic, while it accurately classified 89% of the safe drugs. The correlation between the in vitro cytotoxicity and the in vivo hepatotoxicity of the tested drugs shows the value of human liver microtissues for the detection of hepatotoxic compounds early in the drug development process. The good predictivity, together with the in vivo-like morphology of the liver microtissues and scalability to a 384-well microplate, makes this method a promising and practical in vitro alternative to 2D cell line cultures for the early hepatotoxicity screening of drug candidates.
References:
Fäs L, Chen M, Tong W, Wenz F, Hewitt NJ, Tu M, Sanchez K, Zapiórkowska-Blumer N, Varga H, Kaczmarska K, Colombo MV, Filippi BGH. Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs. Toxicol Sci. 2024 Oct 14:kfae123. doi: 10.1093/toxsci/kfae123. Epub ahead of print. PMID: 39397666.
Proctor WR, Foster AJ, Vogt J, Summers C, Middleton B, Pilling MA, Shienson D, Kijanska M, Ströbel S, Kelm JM, Morgan P, Messner S, Williams D. Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury. Arch Toxicol. 2017 Aug;91(8):2849-2863. doi: 10.1007/s00204-017-2002-1. Epub 2017 Jun 13. PMID: 28612260; PMCID: PMC5515971.
