Phenotypic Screening – Complex and Disease-Relevant Human Primary Cell Assays

The Opportunity

In the past few years, there has been a revival of phenotypic screening for hit discovery and profiling. It is generally accepted that overexpression of targets in heterologous systems has a risk of creating functional artefacts, and in principle, such an assay is single-target focused. As the understanding of the complex interplay of networks and pathways within cellular processes increases, the need for ways to screen compounds in the correct disease context also grows. Now practitioners are starting to appreciate polypharmacology and can also harness the knowledge gained from clinical genetics using human primary cells from patients, drug discovery research and high-throughput screening is going through the next paradigm shift. Charles Rivers Laboratories now offers Customized assay development, along with screening with readouts including high-content screening and multiparameter analyte or biomarker detection.

The Assay Portfolio

Through more than 15 years of research, Charles River Laboratories have developed over 100 medium- and high-throughput customised human primary-cell-based assays for screening against multiple disease indications within 25-plus different human primary cell types. These cells are derived from (patient) tissue, blood and differentiated stem cells, all of which are sourced with ethics approval and informed consent. As a follow-up to phenotypic hit discovery, they also offer mechanism of action studies using our adenoviral SilenceSelect® and FLeXSelect® libraries.

A Case Study

One of Charles River Laboratories’ clients developed a natural product drug discovery platform involving the design of novel chemical entities based on known natural product scaffolds and employing novel chemistry. The project was based on the concept of phenotypic discovery through bioprofiling in a range of human, disease-relevant assays. They developed 13 human primary-cell-based assays, either from healthy control donors or from donors with rheumatoid arthritis (RA), idiopathic pulmonary fibrosis (IPF) or type 2 diabetes (T2D). A screen of 1,600 compounds in each of these phenotypic assays not only provided valuable starting points for further optimisation of the compounds, but also highlighted which assays in inflammation, fibrosis and metabolic syndrome help identify unique mechanisms of action.

Speaker

David F. Fischer, Senior Director of Biology for BioFocus, a Charles River company, and Site Head of Charles River Leiden, the Netherlands

David Fischer joined BioFocus, a Charles River Company in October 2005 and has responsibility for the Charles River target discovery and primary cell-based screening activities in Leiden, the Netherlands. David holds a degree in Chemistry and a PhD in Molecular Genetics, both from Leiden University. During six years of post-doctoral fellowships at the Netherlands Institute for Neuroscience in Amsterdam (an Institute of the Royal Netherlands Academy of Arts and Sciences) and the Free University Amsterdam, he focused on neurodegenerative diseases, in particular Alzheimer’s and Huntington’s Disease. David also mentored two graduate students, at the University of Amsterdam and at Leiden University. He has published over 50 patent applications and peer-reviewed papers in the fields of neurodegenerative disease, oncology, gene regulation and RNAi screening.

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