Open Targets aims to provide evidence on the biological validity of therapeutic targets and provide an initial assessment of the likely effectiveness of pharmacological intervention on these targets, using genome-scale experiments and analysis. This open innovation, public-private partnership aims to provide an R&D framework that applies to all aspects of human disease, and to share its data openly with the scientific community.
Open Targets brings together expertise from four complementary institutions. GSK is a leading, global pharmaceutical company that has developed some of the most successful drugs of the past three decades. Biogen one of the world’s oldest independent biotechnology companies discovers, develops and delivers worldwide innovative therapies for people living with serious neurological, autoimmune and rare diseases. The European Bioinformatics Institute (EMBL-EBI) is a global leader in the management, integration and analysis of public domain life science data. The Wellcome Trust Sanger Institute is a world-leading genomics institution with expertise in human genetics, cancer and infectious disease.
Different disease research areas are at different stages of maturity. For example, prioritisation in oncology might involve examining established lists of high-confidence oncogenes, tumour suppressors and their pathway neighbours. The challenge for oncology is, therefore, primarily in determining which targets, and in which cellular context, can be modulated to have a substantial effect on cancer endpoints. By contrast, prioritisation for most chronic disease is still at the stage where such effective target lists must be generated.
There will be considerable interplay between research areas at different stages. For example, phenotypic screening may provide an effective target prioritisation strategy where a disease-relevant assay is available via a genome-wide screen (e.g. RNAi, CRISPR/Cas9), or where the assay is amenable to application over a panel of in vitro cellular models (i.e. an outbred QTL study). Similarly, understanding the impact of modulating the activity of cancer targets in assays might allow for the development of better prioritisation metrics from cancer genomics data.
Across all themes, the central driver is to understand the disease-relevant pathways and the points at which intervention in those pathways is most likely to be effective.
Two intertwining strands are needed for a practical approach to target validation. The first is biological validity: ranking a list of gene products based on the likelihood that they contribute causally to the development of a specific disease. The second is biological impact assessment, which provides either experimental or in silico estimation of the potential effectiveness of pharmaceutical intervention on this target.
Biological validity involves prioritising all human gene products according to which are most likely to impact a disease process when modulated. Biological validity looks beyond associations between gene products and disease development (i.e. the basis for genome-wide association studies), and beyond identifying gene products that change during disease. It draws on relevant information such as common and rare genetics, pathway information, animal models and large-scale screens (e.g. chemical, RNAi) of cell models.
Biological impact assessment is fundamentally about defining and developing appropriate assays to expand the evidence base for a target, or to identify new targets. Ideally, assays investigated by Open Targets will have applications across multiple diseases and will be suitable for genome-scale experimentation. These may be relevant to downstream development activities, such as the assay systems used in screening for bioactive molecules.
A key component in assay development is the choice of in vitro and in vivo models. Open Targets will integrate prioritisation and assessment in order to clarify which aspect of the disease phenotype is being targeted and, thereby, which assays and endpoints are most informative.
In drug discovery, the validation of a target refers to the creation of a specific entity that modulates that target’s activity to provide therapeutic benefit to individuals with a disease. The ultimate validation of a target – the creation of an effective therapeutic molecule – is a long and costly endeavour with more failures than successes. The goal of Open Targets is to transform this process by predicting whether modulation of a target is likely to provide therapeutic benefit, much earlier in the drug discovery process than is currently possible (and far in advance of having a final, approved medicine).