GSK is strengthening its pipeline through a focus on oncology and immunology underpinned by significant investments in human genetics (e.g. 23andMe), advanced functional genomics technologies and Artificial Intelligence/Machine Learning (AI/ML – see www.gsk.ai) to help identify the most promising new medicines.
To maximise the probability of success of their genetics- and genomics-informed oncology and immunology-centred R&D strategy, GSK have a strategic focus on increasing the depth and breadth of understanding of cancer and immune biology as it relates to normal physiology, disease mechanisms, response to infection and potential therapeutic approaches. The success of this strategy will be enabled in part by collaborations with trusted clinical and academic collaborators, selected based on world-class expertise and access to high-quality relevant patient samples.
Note: Applicants must demonstrate how proposed projects will leverage key UK Life Sciences Infrastructure to maximise potential research impact for patients. See accompanying video for further information.
UK Life Sciences Infrastructure includes for example the UK Biobank, NIHR-Bioresource, HDR-UK Digital Innovation Hubs and Genomics England 100K Genomes Project (see 2020 LSIS update). GSK has provided support and investment to establish this infrastructure and is keen to leverage this investment.
GSK is looking to build on its internal capabilities and existing partnerships by establishing programmes of research associated with four key areas:
- Patient centric research - Linking genomic variants to cell-specific function and disease mechanisms requires comprehensive analysis of genome regulation across a range of cell types and tissues from large numbers of patients. Access to appropriate cellular resources (primary cells, IPS capabilities and organoids) is a core requirement of a successful FxG campaign. Such resources may include primary cells or patient-derived iPSCs, organoids from both “healthy” individuals and patients at key disease stages (e.g. IBD flare). These should be linked to longitudinal medical records.
- Technologies enabling further understanding of molecular phenotype - There is no shortage of common variants associated with a wide number of different diseases. The real obstacle is turning this information into a better understanding of mechanisms that might be targeted to provide therapeutic benefit. GSK are seeking unbiased novel approaches in order to perform deep molecular profiling e.g. single cell multi-‘omics/cellular fingerprinting methodologies to translate information on genetic variants into insights into gene regulation and disease.
- Technologies associated with perturbation – The ability to intervene/perturb cellular systems via an increasing range of gene editing technologies and to measure the consequences via the application of bespoke functional readouts allows GSK to identify targets based on screening for disease relevant phenotypes and to validate mechanistic hypotheses.
- Best in class data analysis capabilities – FxG approaches generate huge and complex data sets creating a need for reliable data science infrastructure to enable data interrogation using advanced analytics such as AI/ML. Seamless wet-dry lab integration is highly desirable to maximise value.
1Functional Genomics comprises a set of technologies and analytical methods used to measure and perturb at scale to determine the function of genes and genomes. At GSK, these technologies are especially applied to the understanding of human disease mechanisms and the identification of novel high quality and genetically validated targets.
Many genetic signals (~80%) from genetic studies such as GWAS, map to non-coding regions of the genome, presenting challenges in linking common and rare variants to the causal disease gene and ultimately to a function (the so-called variant to function (V2F) challenge). This makes it difficult to confirm potential new drug targets, slowing down the development of effective therapies and reducing the number of successful clinical trials.
2Synthetic lethality describes a concept of context restricted gene essentiality that has been used, for example, to identify novel tumour cell specific therapeutic targets in oncology (Behan, F.M. et al., Nature 568, 511–516 (2019)). The historical lack of scalable methods to probe gene function has left this a relatively untapped space. Rapid recent advances in functional genomic technologies and complex disease models have created significant opportunities for target discovery of synthetic lethal targets or more broadly to run gene modifier large scale screens.