Rare Diseases: Genetic Testing and Targeted Therapy

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1 Rare Diseases: Genetic Testing and Targeted Therapy Meral Özgüç Hacettepe University Faculty of Medicine Department of Medical Biology & DNA/Cell Bank

2 RDs Definition! Low prevalence (Less than 5/10000)! ~30 M EU, ~30 M USA, ~250 M worldwide patients! diseases! Many unknown genes, no therapy for most RDs! 80% genetic background- all Mendelian disorders are rare! Rare cancers and infectious diseases

3 Classification! Lack of specific codes in international classification systems! Only 500 RDs in the WHO - ICD-10! Lack of interoperability between individual databases Hum Mutat 2012; 33:

4 Challenges in RDs! Timely and accurate diagnosis! Lack of information and experience in the healthcare system! Fragmented research! Slow drug development and treatments! Limited number of patients for clinical trials

5 Delay in Diagnosis In a group of RDs, 25% of patients waited for 5 to 30 for a diagnosis and initial diagnosis was wrong in 40% of the cases (EURORDIS 2007)

6 Governance Rare diseases is a priority area where global approach and multinational strategies is needed Together for Health: A Strategic Approach for the EU ! National Plans for Rare Diseases! IRDiRC-International Rare Diseases Research Consortium, 2012 (EU-NIH) Cooperation and coordination in RDs research Vision to develop 200 new therapies and diagnose most RDs

7 Road Map for Diagnosis Gene Identification! Candidate gene approach! Linkage analysis - large families with multiple affecteds! Homozygosity mapping -consanguineous families, AR Mendelian diseases! Whole exom sequencing (WES) - only protein coding regions! Whole genome sequencing (WGS)

8 Biobanks are essential infrastructures for family collections for gene identification V:18 V:19 V:25 V:26 VI:15 VI:16 VI:17 VI:18 VI:19 VI:20 VI:21 VI:22 VI:25 VI:27 VI:28 VII:1 VII:3 VII:4 VII:5

9 GENETIC TESTING Genetic testing is testing for variations in germline DNA sequences, or for products/effects arising from changes in heritable sequences, which are predictive of significant health effects. OECD! Diagnostic Testing! Newborn Screening! Carrier detection! Presemptomatic Testing! Predictive Testing! Pharmacogenetics

10 Genetic Testing in Rare Diseases Identification of the genetic variation in the causative gene Assessment of the phenotype Confirmation of diagnosis Counseling and therapy *Today ~2000 genetic tests are available for rare diseases *Genomic Testing. Fact Sheet: Identifying Opportunities to Improve Health and Transform Healthcare. CDC 24/7.

11 Bottlenecks in Designing Genetic Tests! One gene - one universal mutation - sickle cell anemia! Ethnic groups - Tay Sachs (Ashkenazi Jews) Mutation Frequency 1278insTATC ~82% IVS12 +1 ~15% 99% G269S ~2% *Data from the International TSD Data Collection Network, 2007

12 Bottlenecks in Designing Genetic Tests! Phenotypic heterogeneity many gene variants-single phenotype different mutations-same gene-different phenotypes LGMD mutations at more than 50 loci have been reported, making accurate diagnosis and genetic counseling a challenge Gene Reviews 2012! Modifiers MBL (Mannose Binding Lectin) protein is a possible modulator of CF (Cystic Fibrosis) phenotype Glycobiology 2011; 21;3: Dominant modifier DFNM1 suppresses recessive deafness DFNB26 Nature Genetics 2000; 26:

13 Next Generation Technologies Advantages of whole genome sequencing (WGS)! Identification of de novo mutations in dominant monogenic diseases Nature Reviews 2012; 13: ! Identification of de novo mutations in common diseases Nat Genetics 2011; 43: ! Identification of variations in noncoding regions that may affect the expression of the disease phenotype The Encyclopedia of DNA Elements (ENCODE) Consortium

14 Next Generation Biobanks! Human Biobanks and Genetic Research Databases are structured resources. and which include: (a) human biological materials and/or information generated from the analysis of the same; and (b) extensive associated information. (OECD)! Keepers of WGS data for future clinical use

15 Whole Genome Sequencing From data to clinical application Association of the allele with human pathology! model organisms,! biochemical studies,! in silico algorithms,! patient derived ips cells Nature Reviews 2013; 14:

16 WGS Newborn Screening A new NIH Programme Hundreds of US babies will be pioneers in genomic medicine through a US$ 25 million programme to sequence their genomes soon after they are born Nature News Blog 04 Sep 2013

17 Genomics Medicine Personalised Medicine Personal omics profiles Data management and clinical bioinformatics Disease description at cellular and molecular level Understand biological mechanisms Patient stratification Deep phenotyping * Targeted therapy *Hum Mutat 2012; 33:

18 Orphan Drug Policies! Orphan Drug Act 1983, USA! EMA - Committee for Orphan Medicinal Products, 2000! Creating Hope Act 2010 Bill Priority Review Voucher System to Rare Pediatric Diseases

19 Therapy for RDs! Pharmaceutical drugs! Diet restriction - PKU! Vitamins as cofactors! Suppression of toxicity Wilson s Disease (copper accumulation)

20 Therapy for RDs Advance products for therapy! Monogenic protein replacement therapies (MPRT) *(88% approval for clinical trials)! Cell and gene therapy products! Oligonucleotides! Fusion proteins! Monoclonal antibodies *Sci Transl Med 2013; 5: 178fs10.

21 Targeting the Cause of Disease (CF) I II III IV V No synthesis Block in processing Block in regulation Altered conductance Reduced synthesis G542X, R553X, W1282X, R1162X, 621-1G T, G A, 1078DT, 3659DC DF508, DI507, N1303K, S549N VX-809 Corrector G551D, R560T Kalydeco (Ivacaftor) Potentiator R117H, R334W, G85E, R347P KbC T, G A, A455E

22 From Research to Genetic Test in the Healthcare Environment! Decrease in cost/ increase in resolution! Decrease in sample size and non invasive techniques (prenatal diagnosis) cell free DNA in maternal blood! Turn-around time of the test! High quality sample (biobank)! Clinical bioinformatics/literacy in data interpretation

23 Rare Disorders Provide Insight for Common Disorders Type I Gaucher s Disease (GD) patients (Deficient glucocerebrosidase (GBA) gene) share clinical features similar to Parkinson patients (PD-GBA phenotype) Cell Metabolism 2013; 17:

24 RARE DISORDERS COMMON DISORDERS Bridging the gap

25 Education for all in the PPPM Era! Public! Funding agencies! Healthcare providers! Nurses and genetic counsellers! Funding agencies! Ethics review committees Genomics divide between countries: capacity building activities to aid diagnosis and management is required (Consanguinity belt countries - high prevalence of AR monogenic diseases)

26 Acknowledgements Prof. Dr. Meral Özgüç Hacettepe Rare Diseases Study Groups Department of Medical Biology, Center for Biological Resources and Genomics, Departments of Pediatrics and Internal Medicine Department of Medical Genetics, Department of Pathology

27 References! Katsanis SH, Katsanis N. Molecular genetic testing and the future of clinical genomics. Nature Reviews 2013; 14: ! O Roak BJ, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 2011; 43: ! Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nature Reviews 2012; 13: ! Riazuddin S, et al. Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nature Genetics 2000; 26: ! Genomic Testing. Fact Sheet: Identifying Opportunities to Improve Health and Transform Healtcare. CDC 24/7.! Gilissen C, et al. Unlocking Mendelian disease using exome sequencing. Genome Biology 2011; 12: 228! Robinson PN. Deep Phenotyping for Precision Medicine. Hum Mutat 2012; 33: ! Rath A, et al. Representation of Rare Diseases in Health Information Systems: The Orphanet Approach to Serve a Wide Range of End Users. Hum Mutat 2012; 33: ! Salari K. The Dawning Era of Personalized Medicine Exposes a Gap in Medical Education. PLoS Medicine 2009; 6(8): e ! Crunkhorn S. Enhanced chance of success for protein replacement therapies. Sci Transl Med 2013; 5: 178fs10.! Osellame LD, et al. Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease-Links to Parkinson s Disease. Cell Metabolism 2013; 17:

28 ! Forman J, et al. The need for worldwide policy and action plans for rare diseases. Acta Paediatrica 2012; 101; ! 2012 Report on the state of the art of rare disease activities in Europe of the European Union Committee of Experts on rare diseases. Part IV: European Medicines Agency Activities and Other European Activities in the Field of Rare Diseases.! Auffraf C, et al. Genome Medicine: past, present and future. Genome Medicine 2011; 3: 6.! Kong A, et al. Rate of de novo mutations and the importance of father s age to disease risk. Nature 2012; 488: ! Sifferlin A. Single Genetic Glitch May Explain Most Allergies and Asthma. Asthma & Allergies.! Ledford H. Drug bests cystic-fibrosis mutation. Nature 2012; 482: 145.! Van Goor F, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011; 108(46): ! Chalmers JD, et al.impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: A review and meta-analysis. Glycobiology 2011;21(3):271-82! Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview. Gene Reviews 2000 Jun 08 [updated 2012 Aug 30]! Nature News Blog 04 Sep 2013! References