Volker Lauschke

We have developed novel 3D tissue models that accurately reflect the biology and function of human liver. Furthermore, we ANALYZED the pharmacogenomic landscape in 130,000 individuals and found that previously unappreciated rare genetic variants in drug metabolizing enzymes and transporters contribute 30-40% to differ inter-individual differences in drug response.




Scientific Summary

Background. Understanding human physiology, pharmacology and pathogenesis requires model systems that accurately reflect the phenotype of the tissue of interest and recapitulate its function. Currently studies are often performed in animal models; yet, due to important species-specific differences the obtained results are difficult to translate to man. Therefore, human cell models are useful that study human biology. However, conventional in vitro models, such as primary hepatocyte 2D cultures, clearly lack the necessary phenotype and functional stability.

Our results. Supported by the Malin och Lennart Philipson Foundation we have established a highly versatile human 3D cell culture model in which liver cells remain viable and functionally stable for multiple weeks. Using global transcriptomic, proteomic and metabolomic analyses we showed that hepatic phenotypes are maintained at the molecular level and that inter-individual differences in hepatic phenotypes can be accurately mimicked. As a result of the substantially improved phenotypes, the spheroid system exceeds both sensitivity and specificity of all previously published in vitro assays for the detection of hepatotoxicity and provides a powerful platform to accurately distinguish between hepatotoxic and non-toxic structural analogues. Furthermore, we showed in a multicenter trial that liver cells in our model faithfully reproduced in vivo drug toxicity mechanisms in man.

Dissemination. Supported by Karolinska Innovations AB, we have commercialized the platform and brought it to the market and I am one of two co-founders and CEO of HepaPredict AB. We offer in-house evaluations of drug metabolism, pharmacokinetic properties and safety as well as drug target validations based on our novel long-term stable physiological 3D spheroid culture platform.

Research outlook. Building on these succefull developments, we now extend our focus to develop model systems for complex human disease. Specifically we focus on type 2 diabetes mellitus (T2DM), a disease characterized by insulin resistance of muscle, liver and adipocyte tissue in combination with progressive failure of pancreatic βcells that affects more than 400 million patients globally. We work towards the development of a microfluidic multi-organ chip in which we can co-culture tissue models with relevance for T2DM. Specifically, we integrate our liver model with microphysiological long-term stable 3D model systems for pancreas, adipose tissue and muscle and utilize this platform to investigate T2DM biology and to screen for novel anti-diabetic medications.

Summary. I am very grateful to the Malin och Lennart Philipson Foundation and their tremendous contributions to the development of our research. Specifically, the grant was used to finance one PhD student and one postdoc whose exceptional talent, interest and capacity was instrumental for the progress of our projects and provides a solid fundament for our continued research in the years to come.



Additional notes:

We participate in the multinational European trial Ubiquitous Pharmacogenomics (UPGx) that prospectively evaluates the outcomes of preemptive pharmacogenetic genotyping for the guidance of drug treatment.

 

In November 2018 I received my Docentur and am now Associate Professor in Personalized Medicine and Drug Development.



Publications during the grant period:

  1. Lauschke, V.M., Shafagh, R.Z., Hendriks, D.F., Ingelman-Sundberg, M. 3D Hepatic culture systems for analyses of liver diseases, drug metabolism and toxicity: protocols, materials, properties and applications. Biotechnology Journal (In press).
  2. Morgantini, C., Jager, J., Li, X., Levi, L., Azzimato, V., Sulen, A., Barreby, E., Xu, C., Tencerova, M., Näslund, E., Kumar, C., Verdeguer, F., Straniero, S., Hultenby, K., Björkström, N.K., Ellis, E., Rydèn, M., Kutter, C., Hurrell, T., Lauschke, V.M., Boucher, J., Tomcala, A., Krejcova, G., Bajgar, A., Aouadi, M. Liver macrophages regulate metabolism independently of inflammation. Nature Metabolism (In press).
  3. Lauschke, V.M., Ingelman-Sundberg, M. Prediction of drug response and adverse drug reactions: from twin studies to Next Generation Sequencing. European Journal of Pharmaceutical Sciences 2019 130:65-77. PMID 30684656.
  4. Lauschke, V.M., Zhou, Y., Ingelman-Sundberg, M. Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity. Pharmacology & Therapeutics doi: 10.1016/j.pharmthera.2019.01.002. [Epub ahead of print]. PMID 30677473.
  5. Zhou, Y., Fujikura, K., Mkrtchian, S., Lauschke, V.M. Computational methods for the pharmacogenetic interpretation of Next Generation Sequencing data. Frontiers in Pharmacology 2018 9:1437. PMID 30564131.
  6. Tasa, T., Krebs, K., Kals, M., Mägi, R., Lauschke, V.M., Haller, T., Puurand, T., Remm, M., Esko, T., Metspalu, A., Vilo, J., Milani, L. Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records. European Journal of Human Genetics 2019 27(3):442-454. PMID 30420678.
  7. Zhang, B., Lauschke, V.M. Genetic variability and population diversity of the human SLCO (OATP) transporter family. Pharmacological Research 2019 139:550-559. PMID 30359687.
  8. Reisberg, S., Krebs, K., Metsalu, K., Kals, M., Mägi, R., Lauschke, V.M., Vilo, J., Milani, L. Pharmacogenomic recommendations based on different sequencing and genotyping platforms: challenges and solutions for using existing guidelines. Genetics in Medicine doi: 10.1038/s41436-018-0337-5. [Epub ahead of print]. PMID 30327539.
  9. Kozyra, M., Johansson, I., Nordling, Å., Ullah, S., Lauschke, V.M., Ingelman-Sundberg, M. Human hepatic 3D spheroids as a model for steatosis and insulin resistance. Scientific Reports 2018 8(1):14297. PMID 30250238.
  10. Zhou, Y., Mkrtchian, S., Kumondai, M., Hiratsuka, M., Lauschke, V.M. An optimized prediction framework to assess the functional impact of pharmacogenetic variants. The Pharmacogenomics Journal doi: 10.1038/s41397-018-0044-2. [Epub ahead of print]. PMID 30206299.
  11. Zhou, Y., Mägi, R., Milani, L., Lauschke, V.M. Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk. Journal of Lipid Research 2018 59(10):1987-2000. PMID 30076208.
  12. Ingelman-Sundberg, M., Lauschke, V.M. Human liver spheroids in chemically defined conditions for studies of gene-drug, drug-drug and disease-drug interactions. Pharmacogenomics 2018 19(14):1133-1138. PMID 30041575.
  13. Ingelman-Sundberg, M., Lauschke, V.M. Current statistical metrics are pragmatic measures to compare the predictive quality of preclinical assays. Toxicological Sciences 2018 165(1):4-5. PMID 30063796.
  14. Oliva-Vilarnau, N., Hankeova, S., Vorrink, S., Mkrtchian, S., Andersson, E.R., Lauschke, V.M. Calcium signaling in liver injury and regeneration. Frontiers in Medicine 2018 5:192. PMID 30023358.
  15. Jukic, M.M., Lauschke, V.M., Saito, T., Hiratsuka, M., Ingelman-Sundberg, M. Functional characterization of CYP2D7 gene variants. Pharmacogenomics 2018 19(12):931-936. PMID 30040020.
  16. Zhou, Y., Lauschke, V.M. Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews. Journal of Medical Genetics 2018 55(9):617-627. PMID 29970487.
  17. Ingelman-Sundberg, M., Mkrtchian, S., Zhou, Y., Lauschke, V.M. Integrating rare genetic variants into pharmacogenetic drug response predictions. Human Genomics 2018 12(1):26. PMID 29793534.
  18. Vorrink, S.U., Zhou, Y., Ingelman-Sundberg, M., Lauschke, V.M. Prediction of drug-induced hepatotoxicity using long-term stable primary hepatic 3D spheroid cultures in chemically defined conditions. Toxicological Sciences 2018 163(2):655-665. PMID 29590495.
  19. Sonnen, K., Lauschke, V.M., Franke, J., Falk, H.J., Petersen, Y., Funk, M.C., Beaupeux, M., François, P., Merten, C., Aulehla, A. Modulation of phase-shift between Wnt and Notch-signaling oscillations controls mesoderm segmentation. Cell 2018 172(5):1079-1090. PMID 29474908.
  20. Bell, C.C., Dankers, A.C., Lauschke, V.M., Sison-Young, R., Jenkins, R., Rowe, C., Goldring, C., Park, J.K., Regan, S., Walker, T., Baze, A., Schofield, C., Foster, A.J., Williams, D., van der Wen, A.W., Jacobs, F., van Houdt, J., Lähteenmäki, T., Snoeys, J., Juhila, S., Richert, L., Ingelman-Sundberg, M. Comparison of hepatic 2D sandwich cultures and 3D spheroids for long-term toxicity applications: A multi-center study. Toxicological Sciences 2018 162(2):655-666. PMID 29329425.

Highly cited article (in the top 1% of the academic field of Pharmacology & Toxicology).

  1. Lauschke, V.M., Ingelman-Sundberg, M. How to consider rare genetic variants in personalized drug therapy. Clinical Pharmacology and Therapeutics 2018 103(5):745-748. PMID 29313952.
  2. Messner, S., Fredriksson, L., Lauschke, V.M., Roessger, K., Escher, C., Bober, M., Kelm, J.M., Ingelman-Sundberg, M., Moritz, W. Transcriptomic, proteomic and functional long-term characterization of multicellular 3D human liver microtissues. Applied In Vitro Toxicology 2017. doi.org/10.1089/aivt.2017.0022.
  3. Santos, M., Niemi, M., Hiratsuka, M., Kumondai, M., Ingelman-Sundberg, M., Lauschke, V.M., Rodríguez-Antona, C. Novel copy number variations in pharmacogenes contribute to interindividual differences in drug pharmacokinetics. Genetics in Medicine 2018 20(6):622-629. PMID 29261188.
  4. Lauschke, V.M., Milani, L., Ingelman-Sundberg, M. Pharmacogenomic biomarkers for improved drug therapy – recent progress and future developments. AAPS Journal 2017 20(1):4. PMID 29181807.

Highly cited article (in the top 1% of the academic field of Pharmacology & Toxicology).

  1. Ewart, L., Dehne, E.M., Fabre, K., Gibbs, S., Hickman, J., Hornberg, E., Ingelman-Sundberg, M., Jang, K.J., Jones, D.R., Lauschke, V.M., Marx, U., Mettetal, J.T., Pointon, A., Williams, D., Zimmermann, W.H., Newham, P. Application of microphysiological systems to enhance safety assessment in drug discovery. Annual Reviews of Pharmacology and Toxicology 2018 58:65-82. PMID 29029592.

Highly cited article (in the top 1% of the academic field of Pharmacology & Toxicology).

  1. Lauschke, V.M., Barragan, I., Ingelman-Sundberg, M. Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities. Annual Reviews of Pharmacology and Toxicology 2018 58:161-185. PMID 29029591.
  2. Lauschke, V.M. Dysregulation of miR-223 constitutes a promising biomarker that informs about clinical outcomes of acute liver failure. Clinical Science 2017 131(15):2059-2062. PMID 28729435. 
  3. Lauschke, V.M., Ivanov, M., Ingelman-Sundberg, M. Pitfalls and opportunities for epigenomic analyses focused on disease diagnosis, prognosis and therapy. Trends in Pharmacological Sciences 2017 38(9):765-770. PMID 28625497.
  4. Zhou, Y., Ingelman-Sundberg, M., Lauschke, V.M. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clinical Pharmacology and Therapeutics 2017 102(4):688-700. PMID 28378927.

Highly cited article (in the top 0.1% of the academic field of Pharmacology & Toxicology).

  1. Vorrink, S.U., Ullah, S., Schmidt, S., Nandania, J., Velagapudi, V., Beck, O., Ingelman-Sundberg, M., Lauschke, V.M. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. FASEB Journal 2017 31(6):2696-2708. PMID 28264975.
  2. Bell, C.C., Lauschke, V.M., Vorrink, S.U., Palmgren, H., Duffin, R., Andersson, T.B., Ingelman-Sundberg, M. Transcriptional, functional and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metabolism and Disposition 2017 45(4):419-429. PMID 28137721.
  3. Lauschke, V.M., Mkrtchian, S., Ingelman-Sundberg, M. The role of microRNAs in liver injury at the crossroad between hepatic cell death and regeneration. Biochemical and Biophysical Research Communications 2017 482(3):399-407. PMID 27789285.
  4. Sison-Young, R., Lauschke, V.M., Johann, E., Alexandre, E., Antherieu, S., Aerts, H., Gerets, H., Labbe, G., Schofield, C., Stahl, S., Lovatt, C., Holder, J., Richert, L., Kitteringham, N., Jones, R., Elmasry, M., Weaver, R., Hewitt, P., Ingelman-Sundberg, M., Goldring, C., Park, B.K. A multi-center assessment of the application of primary human hepatocytes, HepG2, HepaRG and Upcyte cells as single cell models of acute hepatotoxicity. Archives of Toxicology 2017 91(3):1385-1400. PMID 27344343.

Highly cited article (in the top 1% of the academic field of Pharmacology & Toxicology).

  1. Kozyra, M., Ingelman-Sundberg, M., Lauschke, V.M. Rare genetic variants in cellular transporters, metabolic enzymes and nuclear receptors can be important determinants of inter-individual differences in drug response. Genetics in Medicine 2017 19(1):20-29. PMID 27101133.

Highly cited article (in the top 1% of the academic field of Clinical Medicine).