Design of experiments for the automated development of a multicellular cardiac model for high-throughput screening.

Autor:	Raniga K; The Biodiscovery Institute, University of Nottingham, Nottingham, UK, NG7 2RD; GlaxoSmithKline R&D, Stevenage, UK, SG1 2NY., Stebbeds W; LifeArc, Stevenage, UK, SG1 2FX., Shivalingam A; Synthace, The WestWorks, London, UK, W12 7FQ., Pemberton M; GlaxoSmithKline R&D, Stevenage, UK, SG1 2NY., Denning C; The Biodiscovery Institute, University of Nottingham, Nottingham, UK, NG7 2RD. Electronic address: chris.denning@nottingham.ac.uk.
Jazyk:	angličtina
Zdroj:	SLAS discovery : advancing life sciences R & D [SLAS Discov] 2023 Oct 28. Date of Electronic Publication: 2023 Oct 28.
DOI:	10.1016/j.slasd.2023.10.006
Abstrakt:	Cardiovascular toxicity remains a major cause of drug attrition in early drug development, clinical trials, and post-market surveillance. In vitro assessment of cardiovascular liabilities often relies on single cell type-based model systems coupled with functional assays, like calcium flux and multielectrode arrays. Although these models offer high-throughput capabilities and demonstrate good predictivity for functional cardiotoxicities, they fail to consider the vital contribution of non-myocyte cells, thus limiting the potential for integrated risk assessment. Complex 3D hPSC-derived multicellular cardiac model systems have been growing in popularity; however, many of these models are limited to low-throughput with lengthy development timelines and high costs, which hampers their suitability to drug discovery. To optimize the development of an in vitro multicellular model system containing human-induced pluripotent stem-cell derived cardiomyocytes, endothelial cells and cardiac fibroblasts, we employed the Synthace platform, which enables scientists to express complex experimental intent in a simple format (e.g. Design of Experiments) and to translate this to automation protocols using no-code. Utilizing this approach, we systematically screened the impact of multiple cell culture parameters, including the co-culture of three cell types, on cardiac contractility, with minimal hands-on time. Our platform accelerates the assay development process, providing users with an efficient means to explore and optimize the experimental space for the development of multicellular models. This is particularly valuable in scenarios involving variable biological responses and limited understanding of underling mechanisms. Moreover, users can make better use of resources, streamline their workflows, and drive data-driven decision-making throughout the assay development journey. Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michelle Pemberton reports a relationship with GlaxoSmithKline Inc that includes: employment. Will Stebbeds reports a relationship with LifeArc that includes: employment. Arun Shivalingam reports a relationship with Synthace that includes: employment. Will Stebbeds was previously employed by GlaxoSmithKline pre-2023 (Copyright © 2023. Published by Elsevier Inc.)
Databáze:	MEDLINE
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