Personalized Human Genome Sequencing Dr. Stefan Platz DABT, Global Head Drug Safety & Metabolism Biomedical research: strengths & limitations of non-animal alternatives 06 December 2016
The Human Genome Project Genome science will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases Genome science will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases Clinton 2000 President Clinton, 2000 first complete sequences of individual human genomes published 2001 2016, cost to generate a whole-exome sequence below $1,000 2
The Human Genome 23 chromosome pairs ~ 3,000 million bases (or ~3 billion bases) Exons ~ 1.5% of DNA as protein coding regions ~ 21,000 protein-encoding genes ~ 250,000 to one million proteins in human cells Introns, integral to gene expression regulation Still significant gaps in the understanding of DNA regulation 3
What Genomics has achieved >24000 1.5 x 21 SNP associations (p<1.0 x 10-5 ) increase in approvals of new drugs vs 2000 New drugs for orphan diseases 6% -9% 1% Heritability in common diseases e.g. T2 diabetes explained change in new drugs for complex disease vs 2000 10-year survival with some common cancers e.g. pancreatic 4
AstraZeneca s Genomics Strategy - bring better medicines to patients, faster 5
Applied comprehensively from Discovery to Launch Innovative drug targets linked to molecular mechanisms: genome sequencing unlocks hidden causes of disease, transforming our disease understanding and research The right clinical trials: selecting patients for therapies that target the underlying genomic mechanisms of disease through genomic biomarkers Delivering better medicines, faster: the right patients for the right, targeted therapies 6
Insight from Rare Diseases Loss-of-function mutations in PCSK9 described 2005 Low plasma LDL levels and strong protection against early CHD Inhibition of PCSK9 new therapeutic target - First clinical studies 2006 - Two inhibitors approved 2015 Impact on CHD outcomes expected 7 Harper et al 2015, Nature
Patient Stratification: Finding the right patient Olaparib (Lynparza) a poly ADP ribose polymerase (PARP) inhibitor, acts against cancers with hereditary BRCA1 or BRCA2 mutations (includes some ovarian, breast, and prostate cancers) Maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation 8 Ledermann J et al. N Engl J Med 2012
Minimising Safety Risks Bleeding complications due to warfarin - a leading cause of severe adverse drug events genetic polymorphisms in CYP2C9 and VKORC1 affect the pharmacological and safety outcomes of warfarin therapy. 9 Mega et al, the Lancet 2015
The Complexity Biology Regulation of Transcription of DNA Translation and post translational modifications Epigenetic and environmental changes IT Datasharing platforms / Big Data Algorhythm / Machine Learning Chen et al 2016 Cell reports 10
Governance and Bioethics Ethical aspects Protecting data privacy and patient confidentiality Used within the informed consent 11
Human Genomics & Animal Models in Research Translational Medicine Increased understanding of a disease Specific animal models to allow studying of diseases targeted gene-editing using custom endonucleases, specifically TALENs and CRISPR/Cas 9 Examples Cancer models Muscular disease (Duchenne) Neuroscience (Alzheimers) Diabetic research More targeted use of Animal Studies 12
Conclusion Personalized Human Genome Sequencing Significant opportunity to change our treatment of diseases by Increasing our mechanistic understanding of diseases e.g. rare diseases Identification of novel human drug targets Selection of the right patient Minimising safety risks Current knowledge still with significant gaps in understanding regulation of phenotypic changes by the genotype 13
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