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Early identification of patient variability and pharmacogenomics strategies: a new approach to the development of stratified medicines The need for improved target validation: many compounds ineffective in high % of patients Source: Technology Strategy Board, “Accelerating Stratified Medicines in the UK”, 2010. www.innovate10.co.uk/uploads/ Stratified%20Medicine.pdf Decline in 24 hr glucose levels (mg/dL) Urgent need to stratify patients before designing clinical trials Clinically-desired goal: drop by 40 mg/dL Study mean: overall drop of 28 mg/dL = trial fails Individual patients with diabetes Identifying responders and non-responders in fresh, disease-relevant human tissue Poor responder All donors “responders” Good responder Responder Patient variation in drug responses to common bronchodilators, measured in fresh, surgical residual tissues at Biopta’s laboratory. The graphs show bronchodilatation to increasing concentrations of two beta-adrenoceptor agonists, formoterol and salmeterol in human isolated airways from three separate individuals. Objectives of the Collaboration • Create a powerful exemplar project showcasing the combined strengths of Scottish organisations • Improve the selection of patient stratification criteria based on a combination of genomics and associated functional data from studies in human tissue samples Workflow Fresh functional tissues Whole exome sequencing of each patient 25 donors: COPD 25 donors: Inflammatory Bowel Disease VCFs, microRNA expression and cytokine data placed on Aridhia-managed database at SMS-IC Send DNA Fios extracts data from Aridhia database and conducts analysis Freeze the tissues Measure microRNA Measure drug responses in living tissues Bioinformatics review by Prof Palmer and Prof Satsangi Review by Group and Steering Committee Patient stratification strategies Relate drug response to genotype and miRNA (as an assessment of phenotype) Variation exists between donors when intact fresh tissues are exposed to common drugs for COPD in the ex vivo culture system Inter-individual variation not apparent from mean data Each data point is a different donor: reveals extent of patient variation in drug response Experimental logic – Buenestado et al. Roflumilast Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α and Chemokine Production by Human Lung Parenchyma. PLOS ONE 2013; 8: 9. Fios analysis indicates possible bimodal stratification in two treatment groups Identifying high and low responses to drug treatment in vitro Fios report: “The density plots show bimodal properties for some of the treatments, in particular "LPS + Rof (100nM) + Flut(1uM)" and "LPS + Roflumilast (100nM) + Formoterol (10uM)". This could indicate a stratification into two groups for these drug combinations.” Could a lower CYP2E1 expressing haplotype explain the differences in drug responses? • Low CYP2E1 expressing haplotype associated with good anti-inflammatory response to the test drugs in vitro (by measuring TNFa reduction) • Hypothesis: CYP2E1 increases ROS (reactive oxygen species) inhibiting drugmediated reductions in TNFa expression. • • • TT 3/3 = “High responder” TC 5/8 = “High responder” CC 10/14 = “Low responder” Low CYP2E1 A future roadmap for preclinical patient stratification Research Pre clinical Clinical Medication Patient Tissue Informed consent • Fresh and frozen tissue Target market: Pharma Residual Tissue Blood CRF miRNA NGS • Bioinformatics expertise • “In vivo- like” culture methods to test drug efficacy in each fresh tissue Pharma Sponsored projects Proof of efficacy; relate efficacy to genomics and clinical history • Relate fresh tissue response to gene panels Value proposition: design smarter clinical trials through improved preclinical characterisation of reasons for variation in drug response Maximising opportunities from the Exemplar: what comes next? Sep Oct Fios: Finalise reports based on feedback from academic experts Nov Dec Jan Prepare marketing materials showcasing Scotland and all parties involved in the project Meeting between SMS-IC and ReproCELL to discuss routes to commercial exploitation Feb March April Presentations, posters, conferences Scientific publication on the collaboration Execute PR plan: • press • web/social media channels • involve commercial groups of all parties Visits to Pharma: generate commercial leads May June Win first Pharmafunded projects Summary: a novel collaboration to link data from fresh functional tissues to patient stratification • Exemplar project that demonstrates uniqueness of the Innovation Centre • Offers a new approach to application of pharmacogenomics by providing the missing links between genomics and translational medicine (measurements of drug efficacy during preclinical development) • Successful collaboration between the NHS, academia and industry Email: [email protected] Tel: +44 141 330 3831