Screening out irrelevant cell-based models of disease


The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates.

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Figure 1: Novel assay technologies and their integration.
Figure 2: Evolution of more physiologically relevant cell-culture assay systems.
Figure 3: Contributions of new cell-based assay technologies to the early-stage drug discovery pipeline.
Figure 4: Precompetitive consortia facilitating predictive assay development, experimental and personalized medicine strategies.


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The authors thank H. Ebner for assistance in the writing of this manuscript. E.D.N is supported by the program Paris Alliance of Cancer Research Institutes (PACRI), Investissements d'Avenir, launched by the French government with the reference ANR-11-PHUC-002. N.A. and S.L.S. are grateful for support from the 7th Framework Programme of the European Commission (LEISHDRUG project, 223414) and the French Government (L'Agence nationale de la recherche (ANR)) programmes: Investissements d'Avenir programme ('Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases'; grant ANR-10-LABX-62-IBEID); France BioImaging (FBI; grant ANR-10-INSB-04-01) and the Fondation Française pour la Recherche Médicale (FRM; Grands Équipements Program). N.O.C. acknowledges a fellowship award from Research Councils UK (RCUK). P.H. acknowledges support from the Hungarian National Brain Research Program (grant MTA-SE-NAP B-BIOMAG). V.P. and P.H. acknowledge support from the TEKES Finland Distinguished Professor Programme (FiDiPro) Fellow Grant (40294/13). M.C.M is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) foundation, and received funding from the Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505), MINECO (grant BIO2014-62200-EXP) and the Innovative Training Networks (ITN) EU Horizon 2020 (EU-H2020) programme (grant 641639 BIOPOL). V.P. and P.Ö. received funding from the European Union's 7th Framework Programme (FP7/2007–2013; grant 258068); EU-FP7 Systems Microscopy Network of Excellence (NoE) project, the Sigrid Juselius Foundation, the Cancer Society of Finland, the Academy of Finland (Centre of Excellence in Translational Cancer Biology), the Magnus Ehrnrooth foundation and the TEKES FiDiPro Fellow Grant (40294/13), and TEKES New Generation Biobanking Grant (40294/11). Research in the Kallioniemi group at the Science for Life Laboratory received funding from K. Wallenberg and A. Wallenberg (grant 2015.0291), and the Karolinska Institutet. G.T. is supported by École Polytechnique Fédérale de Lausanne (EPFL) and the Swiss National Science Foundation/ National Centres of Competence in Research (SNF/NCCR) in Chemical Biology. D.E. acknowledges research support from Cancer Research UK (CRUK) and the Higher Education Funding Council for England (HEFCE).

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Correspondence to Neil O. Carragher.

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Competing interests

L.P. is a founder and shareholder of OcellO B.V., a contract research organization that offers drug screening services. The content of the article is not influenced in any way by his involvement.

P.H. is the founder and a shareholder of Single-cell technologies Inc., a biodata analysis company. The content of the article is not influenced in any way by his involvement.

A.M.D. is the inventor of the suspension technology referred to in the article as Happy Cell. He is also a board member, director and shareholder of the company that distributes this technology. The content of the article is not influenced in any way by his involvement.

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Horvath, P., Aulner, N., Bickle, M. et al. Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 15, 751–769 (2016).

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