pharmacogenomics and personalized medicines jean-marie boeynaems [email protected]
TRANSCRIPT
Pharmacogenomics and personalized medicines
Jean-Marie [email protected]
OUTLINE
• Definitions : SNP, omics• Personalized choice of the medicinal product• Personalized dosage of the medicinal product• Problems and first achievements• Individualized treatment of cancer• Genome-wide association studies• Technological evolution of sequencing : • « The 1,000 $ genome challenge »• Generalization of genome sequencing : • ethical, legal and practical issues
A representative sample of the slides that will be presented and discussed during the course is
displayed hereafter.
Different types of SNP
• Outside genes : no impact
• In the genes coding sequence :
• change of base but not of amino acid (cf redundancy of genetic code : GCA et GCC both code for alanine)
• change of amino acid : more or less impressive
modification of function (loss or gain)
• In the promoter region : or transcription of the gene and protein expression
• In the mRNA 3’-untranslated region : (or ) sensitivity to miRNA (that inhibit translation and destabilize mRNA).
Ome, Omics
• Genomics: all the genes• pharmacogenomics : choice of personalized medicine • nutrigenomics : choice of best diet• toxicogenomics : prediction of toxicity
• Epigenomics: all epigenetic changes in genome• Transcriptomics: all the mRNAs microarrays• Proteomics : all the proteins• Interactomics : all interactions between all proteins• Metabolomics (or metabonomics) : all metabolites • …
« Personalized medicines »based on pharmacogenomics
• Identification of genes conferring to individuals who carry them a better sensitivity to the therapeutic action of a medicine or a better tolerance (drug metabolizing enzymes, disease susceptibility factors)
• Genotyping before inclusion in a clinical trial statistical power and cost
• Simultaneous marketing of a medicinal product and availability of a genetic test to identify patients to treat
• Restriction of the market but higher price since efficacy is optimized (or adverse effects decreased) .
From personalized medicine to precision medicine
• Some are skeptical that medicine will really be personalized, while others say that physicians have always adapted treatment to their individual patients.
• Precision medicine implies that diseases are defined by underlying molecular mechanisms rather than traditional signs and symptoms.
Lancet 378 : 1678, 2011
Toward precision medicine
US National Research Council, nov 2011
Cancer Pharmacogenomics and Tumor and Germline Genomes
Wang L et al. N Engl J Med 2011;364:1144-1153.
Anticancer drugs approved by the Food and Drug Administration with labeling regarding pharmacogenomic biomarkers
Wang L et al. N Engl J Med 2011;364:1144-1153.
Lebrikizumab treatmentin asthma : efficacy related to serum periostin
Corren et al NEJM 2011
Lebrikizumab is a monoclonal
antibody that neutralizes IL-13. IL-13 induces bronchial epithelial cellsto secrete periostin. Patients with high serum periostin respond better.
DNA cleaved in fragmentsFragments fixed on beads (excess)PCR amplification in emulsion (1 bead/droplet)Transfer to multi-well (pL) slide(1 bead/well)Addition of smaller beads covered with enzymes involved in sequencing
Elongation of fragmentsSequential injection of nucleotidesIf the nucleotide is incorporated, generation of light detected by a
camera
Cost of genome sequencing
• Genome of C Venter : 100x106 $• Genome of J Watson : < 1.5x106 $• X Prize Foundation challenge : 10,000 $• Race for $ 1,000 genome : 1,000 $• Complete Genomics in 2009 : 4,400 $• Cost of the detection of a single mutation by
Belgian genetics laboratories : 300
Report freely accessibleon www.deloitte.com
Take home messages
• The business model of biopharma is changing and can now include personalized medicines.
• The major difficulty is to identify SNPs with a strong impact on treatment choice/dosage.
• Personalized medicines are making progress especially in cancer treatment, but also in asthma.
• A key element is the astounding evolution of technology with a dramatic decrease in the cost of sequencing.