Therapeutics
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10 Prill, S, Caddeo, A, Baselli, G, Jamialahmadi, O, Dongiovanni, P, Rametta, R, Kanebratt, KP, Pujia, A, Pinitore, P, Mancina, RM, Lindén, D, Whatling, C, Janefeldt, A, Kozyra, M, Ingelman-sundberg, M, Valenti, L, Andersson, TB, Romeo, S (2019). The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci Rep. Aug 12;9(1):11585. doi: 10.1038/s41598-019- 47737-w.
https://www.nature. com/articles/s41598-019- 47737-w. 11 Ströbel, S, Rupp, J, Fiaschetti, K, Guye, P, Rea, A, Thoma, E, Kostadinova, R, (2019). Using 3D human liver microtissues to model NASH progression in vitro for drug discovery and safety testing. 55th Congress of the European Societies of Toxicology (Eurotox), Helsinki, Finland, September 8-11, 2019.
https://insphero.com/science/p ublications/posters/#15039029 77559-47d1dac3-f26d.
drug effect, when more than one cell type is involved. But in contrast to animal models, cell- based systems offer the tremendous advantage that cellular interactions and pathways can be easily deconvoluted by model modification (eg, removing one cell type). For this reason, such modular cell models are particularly valuable tools for mecha- nism of action studies.
A vision for the future of NASH drug discovery The pharmaceutical research community has long been under intense pressure to improve R&D pro- ductivity, reduce animal use and reduce drug attri- tion rates. The most promising drug candidates need to be accurately validated with physiological- ly-relevant preclinical models prior to being advanced to expensive and lengthy clinical trials. This is especially true in the hunt for therapeutics to treat NASH – a complex disease with a growing prevalence and costly impact on society. Multicellular human disease models, such as
those for NASH, are now able to more faithfully recapitulate complex in vivo conditions. They are better suited for mechanistic studies of disease progression and high-throughput drug efficacy screening. These robust, validated models are readily integrated into R&D workflows and can improve discovery and preclinical development efforts. Aware of the current limitations of avail- able models, biotech companies working on the next generation of human in vitro models must maintain an open dialog with pharmaceutical researchers to identify desired enhancements, such as the addition of systemic components (eg, infiltrating blood immune cells or microbiome components). In the near future, scientists will be able to apply emerging ‘organ-on-a-chip’ technol- ogy to create organ networks of liver and pancre- atic tissues with immune cells in a single system that effectively recreate metabolic syndrome at the bench. As the prevalence of NAFLD and NASH contin-
ues to increase, the clinical and economic burden will become even more staggering. Ground-breaking research tools such as these will lead to more effi- cient development of truly-effective NASH therapies and better address this growing pandemic. DDW
Dr Sue Grepper is Senior Application Scientist at InSphero Inc. A toxicologist with nearly 20 years’ experience in industry, Sue applies her extensive knowledge of human liver toxicity and disease to support the efforts of major pharma companies investing in NAFLD and NASH drug discovery and safety testing.
Dr Radina Kostadinova is Lead Product Manager, Liver Platforms, at InSphero AG. An experienced biomedical researcher with extensive knowledge of preclinical mechanistic toxicology, Radina devel- ops and establishes liver tissue models for detection of drug toxicity as well as 3D liver disease models for the study of fibrosis, inflammation, diabetes and obesity.
Dr Eva Thoma is Head of Liver Solutions at InSphero AG. A biomedical scientist with exten- sive experience in cell biology and the development of advanced cell models for drug discovery and development, Eva has held research management positions in pharmaceutical and biotech industries. Her team develops precisely-engineered, inducible liver disease models.
Professor Armin Wolf is Chief Scientific Officer at InSphero AG and Professor of Toxicology at the Technical University of Kaiserslautern, Germany. An accomplished pharmaceutical R&D executive and board-certified toxicologist with more than 30 years’ cumulative experience at Janssen and Novartis, Armin offers a first-hand perspective on the challenges facing the pharmaceutical industry today.
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Drug Discovery World Fall 2019
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