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

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“Genome science … will revolutionize the

diagnosis, prevention and treatment of

most, if not all, human diseases”

President Clinton, 2000

• first complete sequences

of individual human

genomes published 2001

• 2016, cost to generate a

whole-exome sequence

below $1,000

“Genome science … will revolutionize the

diagnosis, prevention and treatment of most, if

not all, human diseases” Clinton 2000

The Human Genome

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• 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

What Genomics has achieved

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>24000

1.5 x 21

6% -9% 1%

SNP associations

(p<1.0 x 10-5)

increase in approvals of

new drugs vs 2000 New drugs for orphan

diseases

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

AstraZeneca’s Genomics Strategy

- bring better medicines to patients, faster

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Applied comprehensively from Discovery to Launch

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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

Insight from Rare Diseases

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Harper et al 2015, Nature

doi:10.1038/nrg4017

doi:10.1038/nrg4017

• 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

Patient Stratification: Finding the right patient

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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

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

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Mega et al, the Lancet 2015

genetic polymorphisms in CYP2C9 and

VKORC1 affect the pharmacological and

safety outcomes of warfarin therapy.

The Complexity

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Chen et al 2016 Cell reports

• Biology

• Regulation of

• Transcription of DNA

• Translation and post

translational modifications

• Epigenetic and environmental

changes

• IT

• Datasharing platforms / Big Data

• Algorhythm / Machine Learning

Governance and Bioethics

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• Ethical aspects

• Protecting data privacy and patient confidentiality

• Used within the informed consent

Human Genomics & Animal Models in Research

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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

Conclusion

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• 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

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