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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.

5. 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.

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.

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