ECOGENE-21 translational research in genetics and omic sciences for application to clinical practice at the community level
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ECOGENE-21 provides concise summaries in 3 sentences or less that provide the high level and essential information from the document. ECOGENE-21 (E-21) is a center focused on translating genetics and omics research into clinical practice at the community level. E-21 has supported various projects including developing low-cost genetic tests, conducting early phase clinical trials, and identifying new disease targets. Moving forward, E-21 aims to establish partnerships and develop expertise in orphan diseases to better support clinical sites and trials through services like training and quality oversight.
ECOGENE-21 translational research in genetics and omic sciences for application to clinical practice at the community level
- 1. ECOGENE-21 translational research in genetics and omic sciences for application to clinical practice at the community level Daniel Gaudet MD PhDDaniel Gaudet MD PhD Dept of Medicine, Université de MontrealDept of Medicine, Université de Montreal
- 2. SummarySummary ECOGENE-21: What’s in a name? ECOGENE-21 Then and now Activities and accomplishments E-21 tomorrow
- 3. ECOGENE-21 What’s in a Name?
- 4. ECOGENE-21: PatientsECOGENE-21: Patients’’ Centered ApproachCentered Approach of P4 Medicine Adapted to the Personality ofof P4 Medicine Adapted to the Personality of CollectivitiesCollectivities What is a collectivity? What is Personalized medicine? What is P4 medicine? What is E-21 then?
- 5. What is a community?What is a community? The word community comes from the Latin communis, meaning “common, public, shared by all or many”; In the broadest sense, the term community may describe any association of interacting living species sharing a common ecosystem; There are different kinds of human communities: communities of geographic location, communities as organizations or communities of shared culture; ECOGENE-21 specifically refers to cohesive social entities of individuals sharing a same environment or biological background within the context of the larger society: founder populations, collectivities of orphan diseases.
- 6. What is Personalized Medicine?What is Personalized Medicine?
- 7. Personalized Medicine: A CIHR SignaturePersonalized Medicine: A CIHR Signature InitiativeInitiative Personalized medicine will not only focus on the identification of biomarkers and genetic signatures for prevention and prediction of therapeutic response, but will also enhance awareness about lifestyle and preventive lifestyle changes. The overall goal of the CIHR Personalized Medicine Signature Initiative is to enhance health outcomes through patient stratification approaches by integrating evidence- based medicine and precision diagnostics into clinical practice.
- 8. The 4 Ps of P4 MedicineThe 4 Ps of P4 Medicine Predictive Preventive Personalized Participatory Systems Biology/ Systems approaches Patient’s/Con sumer/collecti vity driven; Social networks new technologies P4
- 11. « Standard of care » Public health and Health services
- 12. « It takes an estimated average of 17 years for 14% of new scientific discoveries to reach day to day clinical practice » JM Westfall et al JAMA 2007;2007;297:403. Clinical Research to Clinical Practice: Lost in Translation?
- 13. Clinical Research to Clinical Practice: Lost in Translation? « Less than 33% of patients with coronary artery disease are prescribed aspirin... » « ...Let's be realistic: If If we didn't do it with aspirin, how can we expect to do it with DNA? » C. Lenfant NEJM 2003;349:868
- 14. The E-21 Approach Narrows Translational Gaps and Contributes to Identify new Targets
- 16. Ecogene-21 Then and Now
- 17. E-21 ComponentsE-21 Components E-21 clinical trial center HQP Facilities GCP/CCRP Training SOPs CRO-21 Core lab Services Monitoring PoC study management Support to networks and clinical sites AT-omics: R&D, Innovations and applied translational unit Biobank and Biorepository (Genome Quebec Technology Centre)
- 20. Activities and AccomplishmentsActivities and Accomplishments Support to a Quebec pilot project of a population-based carrier screening program for four recessive disorders in the French Canadian Population. Using clinical trials benefits: conception, validation, IP protection, and transfer to the health services of a low-cost community-wise Multiplex test; With CIHR-IHRT grant: 5-years contribution to the evaluation of the pilot project (including global performance , social perceptions and impacts)and to its coordination; With support of the Ministry of health: blinded evaluation of the validity and clinical performance of the multiplex test;
- 21. Multiplex SNP Panel Developed for the Pilot ProjectMultiplex SNP Panel Developed for the Pilot Project •Tyrosinaemia IVS12+5G/A •Leigh syndrome (LSFC) 1119C/T •ARSACS 6594delT, 5254C/T •Polyneuropathy (SLC) 2436delG . Covers gene variants explaining the majority of cases of 4 targeted recessive diseases In the SLSJ French Canadian founder population
- 22. Multiplex SNP Panel Developed for the Pilot ProjectMultiplex SNP Panel Developed for the Pilot Project •Tyrosinaemia IVS12+5G/A •Leigh syndrome (LSFC) 1119C/T •ARSACS 6594delT, 5254C/T •Polyneuropathy (SLC) 2436delG . Covers gene variants explaining the majority of cases of 4 targeted recessive diseases In the SLSJ French canadian Founder population Median cost of each test in 2003: $150.00 Cost in 2006: $35 Cost with the multiplex test in 2010: $2.20
- 23. Activities and AccomplishmentsActivities and Accomplishments Development and transfer to health services of other quantitative assays: eg: JAK2 Development and transfer for use in clinical trials of step- wise community-sensitive multiplex tests: LPLD (french-canadian panel, SA panel, etc.) FH (french-canadian panel) Disorders of glycerol metabolism
- 24. Genetic Drift:Genetic Drift: The Community-wise, Personalized ApproachThe Community-wise, Personalized Approach “Alleles” in original population “Alleles” remaining after bottleneck Personalized Genotyping tools
- 26. FCS-causing Gene Mutations: they TravelFCS-causing Gene Mutations: they Travel From China To North American west coast Gaudet et al. 2014
- 27. Examples of Isolates and Founder PopulationsExamples of Isolates and Founder Populations IcelandersIcelandersIcelandersIcelanders French CanadiansFrench CanadiansFrench CanadiansFrench Canadians HutteritesHutteritesHutteritesHutterites AmishAmishAmishAmish TicunaTicunaTicunaTicuna AfrikanersAfrikanersAfrikanersAfrikaners FinnsFinnsFinnsFinns SardiniansSardiniansSardiniansSardinians AshkenazimAshkenazimAshkenazimAshkenazim BedouinsBedouinsBedouinsBedouins PolynesiansPolynesiansPolynesiansPolynesians AboriginesAboriginesAboriginesAborigines
- 28. Activities and AccomplishmentsActivities and Accomplishments Clinical expertise in gene replacement therapy from the bench to bedside Conception of clinical studies/program clinical coordination and execution; Drug preparation and administration; core lab activities (genotyping, specialized analyses) identification of targets fine phenotyping scientific and clinical evaluation and translational dimensions.
- 29. AAV2-LPLS447X ITR CMV LPLS447X WPRE pA ITR AAV1-capsid Glybera: AAV2-LPLS447X Gene Replacement Therapy
- 31. Mechanism of Action Nineteen Canadians treated yet; Cost of the treatment in Europe: 500K euros (not considering the cost of genotipic confirmation of the diagnosis) Value to Canada: $20,000,000
- 32. Activities and AccomplishmentsActivities and Accomplishments Identification of new variants, new disease causing genes, new diseases, new pathways, new targets; New FCS causing gene variants New FH causing gene variants Genes and biomarkers linking statin intolerance and statin-induced diabetogenicity Markers of glucose intolerance LPL independent pathways of fat metabolism;
- 33. Lessons Learned from Orphan Drug Development:Lessons Learned from Orphan Drug Development: Role of ApoC3 in Plasma Triglyceride MetabolismRole of ApoC3 in Plasma Triglyceride Metabolism 33 Gaudet D et al. N Engl J Med 2014;371:2200-2206
- 34. Activities and AccomplishmentsActivities and Accomplishments Conception and execution of early phase and PoC studies for orphan and/or complex lipid diseases Covering the full spectrum of systems biology Conception and execution of early phase and PoC studies for cardiometabolic diseases; Support for other genetic diseases: ROC POP strategy
- 35. Approche ROC POP et développement de Rx
- 36. System Approaches of Emerging Therapies for Orphan Lipid Disorders Gene replacement therapy Genome Editing (CRISPR, TALen) Pre mRNA AON siRNA miRNA piRNA Aptamers •Cell pathway pharmacology •Peptide mimetics, • linker technology •New Rx, biodrugs • and targets ) EMERGING TREATMENTSEMERGING TREATMENTS •.nutritional support •Nitrigenetic treatments •Life habits • Family-sensitive approaches •Personalized community medicine • Public Health TARGE TDOMAINDOMAIN Proteome/metabolome/interactome Transcriptome Genome Lipoproteins phenome/ human phenomes Sociome •Functional meals •Disease adapted meals •Life habits •Epigenetic therapy (diet, epi-drugs) Epigenome Population/communi ty systems Genes/mutations/epimutations mRNA transcripts Proteins/networks Phenotypes/individuals
- 37. Activities and AccomplishmentsActivities and Accomplishments Conception , preparation, shipment, monitoring and biobanking (for audit purposes) of disease-adapted meals to be used in clinical trials and for genetic diseases prevention; Recipes from well-known chefs; Adapted to different health conditions and different cultures (casher, halal, vegetarian, etc.); Standardized. Epicurian approach of diseases; Control for the effect of the diet when assessing treatments or interventions where the diet can be a confounder; Have been shipped in 8 countries on 3 continents in multicentric trials.
- 38. Prepared FCS adapted Meal :Prepared FCS adapted Meal : Marengo vealMarengo veal - >150 standardized low-fat recipes/meals -Prepared with chefs and nutritionists -Shipped in 8 countries -Support clinical trials (confounding effect of the diet) -Auditable
- 39. Prepared Meals Visual AspectPrepared Meals Visual Aspect
- 40. Activities and AccomplishmentsActivities and Accomplishments Support to population genomics Support to the conception and development of Cartagene (2000-2007) Support to recruitment in CaG (2007-2010) Elaboration of SOPs for recruitment Training of QP of all sites outside Montrea lRecruitment in the SLSJ founder population Development and management of the Cartagene Biobank Management of the Genizon Biosamples
- 41. DNA Storage: Room TemperatureDNA Storage: Room Temperature DNA Plates are dried, sealed and stored in the Dynamic Archive using a combination of procedural manual and complex robotic handling steps.
- 43. E-21 TomorrowE-21 Tomorrow E-21 is actually at a crossroads: Built on the existing expertise to foster development of Patient’s Centered Approach of P4 Medicine Adapted to the Personality of Collectivities; Establish partnership with key players in Canada and internationally; Develop “niche CRO” capacities in omics and orphan diseases; Support clinical sites interested in participating in clinical trials in genetics including gene-based treatments: GCP training, internal audits, provide the toolbox and rubber stamp of quality; Support SMASH development and…?
- 44. SMASH WP5 Biobank registry PARTNERS Patients Advisory Boards Companion tests Clinical innovations WP5E WP5D WP5C WP5B WP5A WP5F Translational AT-OMICS Unit Clinical platforms, SOPs GCP/omics training of HQP and expertise Core labs (ISO) Clinical trials Conception and/or execution OMiCS Contract Research Organization (OCRO-21) SMB Network of Investigational Sites (National, international) Orphan, extreme lipid disorders National: FH Canada, CORD International Provinclal
Editor's Notes
- #17: Criteria: For investigation of trisomy 21, 18 or 13 ONLY. □ Singleton gestation (NIPT in the context of twin pregnancies requires consultation with a geneticist or maternal fetal medicine specialist (see Section B)) with appropriate pre-test counselling including a discussion of the limitations of the test. And any one of the following: □ A maternal multiple marker screening test (eg. FTS/IPS/Quad etc.) positive for aneuploidy. □ Women of advanced maternal age, defined as > 40 years of age at expected time of delivery. □ Fetal nuchal translucency (NT) > 3.5mm □ Pregnancy history of aneuploidy / previous child with aneuploidy. OR Combined risk factors identified by a genetics or maternal fetal medicine (MFM) specialist