Phenomics Discovery Initiative expands portfolio to new disease areas, translating the best biology into novel therapeutics

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Dundee, 6th March 2018

The Phenomics Discovery Initiative (PDi) has expanded its assay portfolio to a total of 11 complex phenotypic assays that are relevant to human pathophysiology in areas of unmet clinical need including neuropsychiatric illnesses, dementia, cancer and respiratory infections.

PDi is a public-private consortium joining the pharmaceutical industry and the National Phenotypic Screening Centre (NPSC). This expansion of its assay portfolio confirms its ability to source and deliver a cutting-edge phenotypic screening pipeline that addresses high-profile disease areas to meet pharmaceutical industry needs for developing novel therapeutics.

Since June 2016, the consortium has demonstrated it can build a strong portfolio of novel and complex cell-based assays that are openly crowdsourced from the global scientific community. Key to the success of the operation is the process of broad project recruitment via a simple application process, combined with agile project selection and collaborative Terms and Conditions (T&Cs) designed to benefit all partners.

PDi relies on top-down and bottom-up approaches for efficient and geographically-extensive project recruitment to create the best programme portfolio. Assays are selected by the PDi scientific committee, balancing selection criteria such as scientific excellence, proximity to disease state, translational potential, commercial relevance and collaboration partner quality.

The NPSC will develop and implement the phenotypic screens against high-quality compound collections from industry to provide new therapeutic starting points with higher chances of clinical efficacy than those derived from traditional biochemical screening approaches.

Professor Neil Carragher, University of Edinburgh and Chief Scientific Officer for the PDi, said, "After two very successful rounds of project selections, we are confident we can meet our industry partners' needs in terms of the quality and quantity of disease-relevant phenotypic assays. Since mid-2016 we have fine-tuned our operations, allowing us to build complex cell-based assays from innovative biology that we have crowdsourced from academic labs, clinicians, and subject matter experts. Our assay development teams have successfully developed this novel biology into screenable protocols that can be applied in multiparametric high content assays and carried out in high throughput formats."

The following five assays from PDi's second round of selections have been prioritised for development and compound library screening:

1. A High Content (HC) screen in human white blood cells will attempt to identify compounds that inhibit NLRP3 inflammasome activation. This assay, which focuses on one of the nodes of intracellular stress pathways, was submitted by Ana Andrezza's group at the Department of Pharmacology and Toxicology at the University of Toronto, and has immediate applications in bipolar disorder and other neuropsychiatric diseases."


2. Controlling neuroinflammation is also the focus of an assay put forward by John Davis from the Alzheimer's Research UK (ARUK) Oxford Drug Discovery Institute (ODDI), in this case applied to finding treatments for Alzheimer's disease. The phenotypic assay, based on a mouse bone marrow derived macrophages (BMDMs) cell line will be used as a model to find inhibitors of the NLRP3 inflammasome before further testing in human in vitro assays.

3. Stuart Forbes and Lara Campana at the MRC Centre for Regenerative Medicine, University of Edinburgh, provided PDi with a multiparametric flow cytometry-based assay that measures phagocytic performance in primary murine macrophages. Phagocytosis plays a key role in clearance of bacteria and apoptotic cells in infected or damaged tissues and its impairment has been implicated in chronic inflammatory diseases, autoimmune diseases and solid tumour oncology. NPSC will aim to find small molecules that stimulate mouse macrophage phagocytosis, whilst converting the model to utilise equivalent human cells.

4. Targeting immune suppressive molecules expressed by tumour-associated macrophages is thought to be a good way to improve efficacy of immunotherapy against metastatic breast cancer. NPSC will be working on a co-culture cell model in collaboration with Takanori Kitamura from the MRC Centre for Reproductive Health at the University of Edinburgh to find small molecules that inhibit macrophage-mediated Natural Killer (NK) cell suppression in order to enhance cell-based immunotherapies.

5. NPSC is working with Fiona Tulloch and Martin Ryan from the University of St. Andrews to establish a novel phenotypic screen aiming to discover small molecules to reduce the replication of enteroviruses that are increasing linked to mild and severe respiratory diseases. This novel safety-contained approach allows gene encoding viral capsid proteins to be replaced with a fluorescent reporter, allowing transcript RNA and genome replication to be monitored by live-cell imaging without the production of live pathogenic viruses. The long-term aim is to incorporate this assay methodology to the complex cellular model of the human bronchial epithelia that is in late-stage development within the NPSC in collaboration with Janssen Pharmaceutica NV.

The PDi assay portal remains open for project submissions: https://npsc.awardsplatform.com

About the Phenomics Discovery Initiative
Launched in 2016, the Phenomics Discovery Initiative (PDi) is a public-private consortium that aims to enhance translation of phenotypic biology into novel therapeutics. Founding members are Janssen Pharmaceutica NV, part of the Pharmaceutical Companies of Johnson & Johnson, and the Universities of Dundee, Edinburgh and Oxford. PDi assays encompass the latest advances in primary, patient-derived and human induced Pluripotent Stem Cell (hiPSC) model systems combined with CRISPR/Cas9 gene editing, organoids and multicellular co-cultures. 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 screened against novel annotated and diverse chemical libraries, these assays generate pre-competitive data that is high-quality, physiologically relevant, and a potential start-point for drug development and aid the validation of new drug targets.
Learn more at http://npsc.ac.uk/pdi

About the National Phenotypic Screening Centre
NPSC is a world-class facility for automated, high content, phenotypic screening. The goal of the NPSC is to bring advances in industrial drug screening capabilities to academic investigators. NPSC is a partnership between the Universities of Dundee, Edinburgh and Oxford. The project was established with an £8M infrastructure award from the Scottish Funding Council to the Scottish Universities Life Science Alliance (SULSA). NPSC operates as an open centre and aims to collaborate globally to develop the physiologically-relevant assays from biologists who are keen to achieve impact by seeing their best research ideas translated from the lab into the drug discovery pipeline. Learn more at www.npsc.ac.uk

About the University of Dundee - School of Life Sciences
With more than 900 scientists, research students and support staff from 61 countries and external funding in excess of £50 million per annum, the School of Life Sciences at the University of Dundee is one of the largest and most productive Life Sciences research institutes in Europe. The University of Dundee is the central hub for a multi-million-pound biotechnology sector in the east of Scotland, which now accounts for 16% of the local economy. Learn more at www.lifesci.dundee.ac.uk

About the University of Oxford - Nuffield Department of Medicine
The University of Oxford has been top rated for Medicine (Clinical, Pre-clinical and Health subjects) for the last 5 consecutive years and hosts one of the largest groupings of biomedical scientists in the university sector. The Nuffield Department of Medicine (NDM) is a large multi-disciplinary department that links high quality clinical research with medical application. The underpinning motivation behind all research carried out by NDM is the pursuit of academic excellence and the positive impact of research on the health and wellbeing of the global community. NDM employs around 1000 scientific research staff within the UK, and a further 1,500 staff overseas. Its researchers also contribute to the teaching of 450 medical students within Oxford University's Clinical School, further solidifying its bench to bedside philosophy. Learn more at http://www.ndm.ox.ac.uk

About the University of Edinburgh - Schools of Medicine and Biological Sciences
The University of Edinburgh is rated in the world's top 15 for medicine, biology, and computer science, with over 3000 scientists working in these areas alone. It offers the ideal platform for understanding disease and then designing and developing new drugs to help patients.
Work at the Edinburgh hub will be carried out at the Edinburgh Phenotypic Assay Centre (EPAC) a joint initiative between Edinburgh's renowned Schools of Medicine and Biological Sciences spear-headed by Professors Neil Carragher, Margaret Frame and David Gray. Learn more at http://www.ed.ac.uk/medicine-vet-medicine/edinburgh-medical-school
http://www.ed.ac.uk/biology

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