The Phenomics Discovery Initiative (PDi), a unique collaboration between the pharmaceutical industry and academia, has unveiled its first series of novel phenotypic assays.

The assays are under development within the labs of the National Phenotypic Screening Centre (NPSC) – a collaboration between the Universities of Dundee, Edinburgh and Oxford - and are designed to identify new molecules with pharmacological activity in respiratory, oncology, immunology and cellular stress indications.

The consortium is building a strong portfolio of novel and complex cell-based assays, sourced from the global academic community. The NPSC will screen high-quality compound collections from industry against these validated assays, providing new therapeutic starting points with higher chances of success than those derived from traditional biochemical screening approaches. 

Professor Neil Carragher, of the University of Edinburgh and Chief Scientific Officer for the PDi, said, “We are excited to work with our academic and industry collaborators to translate cutting-edge scientific breakthroughs into assays that can generate new knowledge on disease pathways and deliver starting points for new therapies. We are confident that the assays we have selected for screening will be useful to our industry partners in generating new leads for drug discovery programmes.”

Dr Paul Andrews, Director of Operations for the NPSC at the University of Dundee, said: “We have  teams of highly talented biologists and screening scientists in the three labs busily working on these assays and we are making great progress. The interactions with our industry partner are highly productive and also very rewarding to our own scientists and those from the academic labs we work with. By spending time focussing on recapitulating aspects of human physiology, we hope to accelerate the development of more effective drugs.”

To enable broad scientific participation in the work of the PDi, NPSC created an online assay submission portal, which is easy to use and can be accessed globally. After six months of operation, the NPSC has attracted over 100 proposals, 14 per cent of which came from outside of the UK.

Assay proposals representing major areas of unmet therapeutic need are well represented with 22 per cent of projects being relevant to oncology, 12 per cent to CNS diseases, 9 per cent to gastrointestinal disease, and 9 per cent to immunology. Respiratory, cardiovascular, metabolic and rare diseases are also represented. The portal remains open for assay submissions: https://npsc.awardsplatform.com

The following six assays are currently being prioritised for compound library screening:

A complex human brochoepithelial cell (HBEC) assay, with an air-liquid interface mimicking the real situation in the lung, will be used to screen for novel anti-virals in common respiratory diseases.

Manipulation of immune function is becoming increasingly recognized as an effective method to combat disease, particularly in autoimmunity and cancer treatment. A selected assay submitted by Professor Doreen Cantrell’s laboratory at the University of Dundee will aim to identify novel ways of boosting cancer immunotherapies by reactivating “exhausted” T cells.

Drugs that control Endoplasmic Reticulum (ER) stress will be applied to a range of protein misfolding disorders known as serpinopathies. This was the rationale for PDi selecting King’s College London, Dr. Tamir Rashid’s assay, which targets this cellular mechanism as a therapy for alpha-1 antitrypsin deficiency in liver cells. 

Controlling cancer cell “stemness” could have a significant impact in a range of oncology treatments, which is why PDi selected an assay submitted by Dr. Steven Pollard from the MRC Centre for Regenerative Medicine at University of Edinburgh aimed at manipulating cancer cell self-renewal in the brain cancer glioblastoma, a highly refractory cancer that has an extremely poor survival rate.

Senescent cells and the factors they produce are detrimental to the health and function of aging tissues. PDi selected an assay submitted by Juan Carlos-Acosta from the MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, which aims to identify novel approaches that either bypass cellular senescence or selectively target senescent cells (e.g. senolytics) which may reduce age-related tissue dysfunction (e.g. in atherosclerosis, neurodegeneration, osteoporosis, type II diabetes, cancer) and prolong healthy lifespan.

Targeting signalling in cell proliferation as an approach in cancer treatment is being addressed with an assay that aims to influence the so-called “Hippo” pathway that was submitted by Dr. Carsten Hansen from the MRC Centre for Inflammation Research, University of Edinburgh.

The selected assays encompass the latest advances in primary, patient-derived and human induced Pluripotent Stem Cell (hiPSC) model systems combined with CRISPR/Cas9 gene editing and novel imaging reagent tools. The cutting-edge assay development and screening technologies available at NPSC allow multi-parametric high-content analysis to be performed to industry scale and standards on complex cellular models such as patient tissue, hiPSC, organoids and multicellular co-cultures. Screened against large annotated and diverse chemical libraries, these assays generate pre-competitive data that is high-quality, physiologically relevant, and a potential start-point of new therapies and new drug targets.

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