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Personalized Medicine - Genomics

Personalized Medicine - Genomics. Maria Judit Molnar. 2014. The Personal Genome Project is a long term, large cohort study

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Personalized Medicine - Genomics

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  1. Personalized Medicine - Genomics Maria Judit Molnar 2014

  2. The Personal Genome Project is a long term, large cohort study Aims to sequence and publicize the complete genomes and medical records of 100,000 volunteers, in order to enable research into personal genomics and personalized medicine. It was initiated by Harvard University in 2005.

  3. Personal Genome Project The individuals agree to make their genome and their health records public. „volunteers… willing to share their genome sequence and many types of personal information with the research community and the general public, Aim: to understand genetic and environmental contributions to human traits.”

  4. The project publish the • genotype (the full DNA sequence), • phenotype: medical records, various measurements, MRI images, etc. • all data are within the public domain • made available over the Internet so that researchers can test various hypotheses about the relationships among genotype, environment and phenotype.

  5. Risks • Curiositymay be justsuspicionco-optedbyendorphins. I had no idea what I wasblunderinginto. But I figuredIcould start learningnowaboutprivacy and publicgood, researchandentrepreneurship, riskandsusceptibility – allthedangers of knowingthefull story – or I couldbumpupagainstthemlater, alongwiththe rest of unwittinghumanity. Richard Powers

  6. Dealing with bad news • Weknowwhathappenstopeoplewhodogettheworstnews. Theydon’t sinkintodespairorthrowthemselvesoffbridges; theyhandleitperfectlywell. Most of uscopeusingsomecombinationofdenialresignation and religion. Steven Pinker

  7. Genotype and phenotype • Whentheconnectionbetweenthe ACTN3 gene and muscletypewasdiscovered, parentsandcoachesstartedswabbingthecheeks of childrensotheycouldsteertheoneswiththefast-twitchvariantinto sprinting and football. Steven Pinker

  8. Some variants predicting severe effects in the PGP-10 Some variants predicting severe effects in the PGP-10

  9. PGP Harward PGP UK PGP Canada

  10. Risk-Benefit Ratio

  11. The roots „ It’s far more important to know what person the disease has than what disease the person has.” Hippocrates (BC. 400)

  12. The paradigm of the classic treatments Trial and error Symptom Diagnosis TreatmentDosage Non specificNon selectivUniformized Phenotype Does not evaluate the different therapeutic response - the blockbuster concept

  13. The medicine in the XX. century „Onefitstoall” The target is thedisease Evidencebasedmedicine statistical approach using the rule of large numbers, resulting in statistically meaningful conclusions

  14. “The dosemakesthepoison.” But differently for genetically different individuals The revolution of themolecularbiology: Right Disease Right Patient Right Drug Right Time Paracelsus (1493-1541)

  15. Ineffective therapies – waste money HypertensionDrugs10-30% ACE Inhibitors$390 million – $1.2 billion HeartFailureDrugs15-25% BetaBlockers$345 million – $575 million Anti Depressants20-50% SSRIs$2.3 billion – $5.8 billion CholesterolDrugs30-70% Statins$3.8 billion – $8.8 billion AsthmaDrugs40-70% Beta-2-agonists $560 million – $1.0 billion

  16. The results in 2013 The most drugs are not or partially effective in the 60% of the treated patients Side effects are responsible for 100,000 death 2 million hospitalisations 100 billion USD cost for healthcare in USA 50%- of the cases is related genetics

  17. Personalized Medicine: The Answer? Definition The use of information and data from a patient’s genotype and phenotype (level of gene expression and/or clinical information) to: • stratify disease • select a medication • provide a therapy • initiate a preventative measure that is particularly suited to that patient at the time of administration

  18. PersonalizedMedicineis an emergingpractice of medicinethatuses an individual's geneticprofiletoguidedecisions made inregardtotheprevention, diagnosis, and treatment of disease Focusontheclinicalneeds! “Bench to Bedside”“Bedside to Bench to Bedside” Howevergenomicdeterminatethepotentialbiological and physiologicalreactions of theindividual, wecannotmisstheanalysisoftheenvironmentaleffects. The bigestweakness of theclinicnowadays is thelack of theexactdiagnosisand theinapropriatedetermination of thestadiumofthedisease.

  19. The classical therapy: Observation Observation Treatment Testing (Biomarker) Treatment Uncertain respond Independentlyfromtheheterogeneity of thepopulationtrytogetinlargecohortspositivresults/risk ratio withthetreatment(clinicalutility) Targetedtherapy: Differenciate, diagnostics and drugco-development Predicted respond Targetedtherapieshelpbyidentificatioon of thepatientswiththebestrespond and less sideeffects Biomarkersaresuchdiagnostictools, wichmaypredictthetherapeuticrespondto a certaindrug Uniformisation

  20. Economicalpressure: Cost / benefit ratio Healthcarepressure: Risk / benefit ratio New Technologies: Expandingpossibilities The keydrivers of theparadigmchange inthehealthcare - 2013 Needs of highlydifferentiatedhealthcare, whicheffectsthehealthoftheperson and society Onlythereallyinnovativemedicine is justified Innovative ~ Personalized, Differentiated

  21. The Power of Information - Moore’s law Computer processingpoweris doubling every 18 months Amount of data is doubling every 18 months Power of technology

  22. Technological improvement • Genomicrevolution of the end of the 20.th century • Completingthe Human Genom Project (2000) • „Only” 25 thousandgenes – vs 100 thousand • Computedgenotyping, DNA microarray • „$1000 Genom” • „Nobodyexpected”: • 25thousand genes – 9 million SNP • The function of 30% of thegenes is uncleared • The role of deletions, duplications, CNVs • Microsatellitepolymorphisms • Epigenetic Forrás: Jose de Leon, Pharm Res 59 (2009) 81-89 alapján

  23. PM impacts diagnostic categories

  24. A new era in genomics medicine? • Human genome project • Direct-to-consumer genomics • Intellectual property disputes • Catalona • Myriad Genetics • Henrietta Lacks • Personal Genome Project

  25. Drug discovery paradigm shift: a problem or an opportunity? • Ever increasing demand for safer medicine • Stark realization that drug discovery is expensive and slow • shrinking budgets, consolidation, outsourcing • Current drug inventory is large, diverse and possibly has a lot more to offer than was initially thought • Increasing availability of genomic data and tools to use/understand it

  26. Genomicdatainthepatientcare

  27. MonogenicvsComplexDisorders

  28. MonogenicDisorders: Success story

  29. Complexdisorders: limited successrate Age related macula degeneration

  30. Apolipoprotein E Genotype and Alzheimer Disease • Metaanalysis of 40 study • 5.930 patient and 8.607 control

  31. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline and Alzheimer Disease • ThorlakurJonssonet al. • Nature 2012; 488, 96–99 (02 August 2012) doi:10.1038/nature11283 • A codingmutation (A673T) intheAPPgeneprotectsagainst Alzheimer’s disease • Thissubstitutionresultsin an approximately 40% reduction • intheformation of amyloidogenicpeptidesin vitro.

  32. The change of diseaseconcept Traditional: reductionist,onesinglefactor Causalfactor Disease New conception: multifactorial Basic risk Irreversible changes Preclinical progression Disease progression Disease onset Environmental factors

  33. Environment Environment Other SNPs Other SNPs New DiseaseConcept Monogenicdisease Mutation Egészségre gyakorolt hatás Effect on the health Intermedier phenotype intermediatephenotype Complex, polygenic, multifactorialdisease Effect on the health Egészségre gyakorolt hatás Intermedier phenotype Köztesfenotípus SNP combinations

  34. The old paradigm: Treatment of the disease Switch drug again Switch drug Select drug Diagnosis Diseaseseverity Time Reactivemedicalcare

  35. To effective health management Right Drug Monitoring Diagnosis/Prognosis Diseaseseverity Predisposition Screening Time Efficientmedicalcare

  36. Social expectations Cheaper, more effective drug development Forrás: Business Insights: Expanding Applications of Personalized Medicine, 2009

  37. Social expectations

  38. Scruples • Healthpolitical questions • Regulatory issues • Financing aspects • Insurance consequence • USA: Genetic Information Nondiscrimination Act (2008) • Ethical questions • How to sell the test laymens?

  39. FDA prohibited to sell the test

  40. What will likely happen?? Personalized medicine will involve pharmacogenomic treatment approaches that transcend the „one-size-fits-all” approach Personalized medicine will focus on keeping people well and treating disease at its earliest stages! Laboratory medicine will lead the way! „Disease signatures” comprised of hundreds or thousands of data point will be the biomarkers of the future Drug companies will develope their markets around interventional treatments for „disease signatures”!!

  41. The POTENTIAL for Personalized MedicineA „Wellness” Vision • A new comprehensive and integrated approach to wellness –prevention of chronic disease, early detection of disease risk and individualized treatment plans • Predictive toxicology for new drug candidates – ability to predict which individuals will benefit and those who might be most at risk for experiencing serious side-effects Healthy Pre-disease Diseased Recovering Earlier disease detection New interventional therapies New diagnostics Disease prediction Preventative therapies Personalized treatment Informed treatment decisions Routine ComprehensiveHealth Status Monitoring New diagnostics Accurate disease diagnosis Real-time Disease Reoccurrence Monitoring • Improvedeconomics of diseasescreening • Reducedoccupationalexposures • More timelytherapy • Reducedunnecessaryreferrals • More efficienttreatmentplans • Improvedoutcomes • Timelymedicalinterventions • Reducedhospitalizations • Peopleadoptinghealthierlifestyles • Timely testing of environmentalexposures

  42. The POTENTIAL for Personalized MedicineIncreased Healthcare Quality and Reduced Costs (?) Predict and prevent chronic diseases Keep people out of the hospital Eliminate adverse drug events Improve drug development Create new markets

  43. Today HC markets on numbers of sick people might be treated with a new drug Metric Morbidity and mortality rates Outcome People suffer and die from chronic and preventable diseases with multiple hospitalizations Tomorrow HC markets based on numbers of people with preventable diseases Metric Number of people positive for valid predictive biomarkers Outcome New era of interventional therapeutics People will live healthier, pain-free lives and die of old age or trauma with minimal hospitalizations The POTENTIAL for Personalized MedicineTransform Healthcare Markets Multiplex biomarkers to predict and guide treatment of early chronic Dz

  44. We Can’t do This Now!!

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