Canada's path forward for rare diseases: Discovery to translation
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1. The document outlines Canada's plan for rare diseases which includes discovering genomic causes, determining disease mechanisms, and developing therapies. 2. The plan involves creating a trans-Canadian rare disease pipeline that includes rare disease gene discovery, phenotyping and mechanism studies, and therapeutic discovery and validation. This pipeline will involve over 4000 rare disease samples, 90 mechanism projects covering over 200 rare diseases. 3. The goals are to solve 56% of over 4000 rare disorders, add new genes to the known gene list, develop disease models and screening methods to identify drug targets and leads, and validate potential therapies. Several rare diseases have already seen benefits from applying this approach.
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Canada's path forward for rare diseases: Discovery to translation
- 1. Kym Boycott PhD, MD, FRCPC, FCCMG Clinician Scientist, University of Ottawa, Canada Canada's path forward for rare diseases: Discovery to translation
- 2. 1. Discover genomic causes of rare diseases 2. Determining how these genes cause disease 3. Use this information to configure therapies Addressing the ‘grand challenge’ World-class transformative research
- 4. 4 Trans-Canadian RD pipeline 44 Rare Pediatric Disease Gene Discovery Disease Phenotyping and Mechanism Therapeutic Discovery and Validation >4000 rare disease samples 90 mechanism projects >200 rare diseases to enter pipeline
- 5. Patient Samples Rare Pediatric Disease Gene Discovery 1. Orchestrated RD pipeline 3500 Genes Known Gene Unknown
- 6. Dr. Gudrun Aubertin Dr. Jan Friedman Dr. Francois Bernier Dr. Ordan Lehman Dr. Bridget Fernandez Dr. Sarah Dyack Dr. Edmond Lemire Dr. Albert Chudley Dr. Victoria Siu Dr. Malgorzata Novaczyk Dr. Linda Kim Dr. Peter Kannu Dr. David Chitayat Dr. Rosanna Weksberg Dr. Marjan Nezarati Dr. Sarah Nikkel Dr. Sandra Farrell Dr. Jacques Michaud Dr. Sebastian Levesque Dr. Régen Drouin Dr. Bruno Maranda Canadian Genetics Network
- 7. Project Teams -validation studies- National Data Coordination Centre -data sharing- Vancouver Toronto Montreal STICs -exome sequencing- Share resources and expertise
- 8. 417 disorders out of pipeline … 56% Solved Am J Hum Genet 2014; 94:809-817 Novel 71 Known 161
- 10. PhenomeCentral Orion Buske, U of Toronto Algorithm development HPO terms Candidate genes Pairwise matching
- 11. CCMG guidelines: phenotype or family history suggests monogenic etiology causal mutation unknown Diagnostic translation Phenotype High degree of genetic heterogeneity Diagnostic odyssey Specific genetic tests have failed to arrive at a diagnosis Cost effectiveness Genome-wide sequencing is a more cost- effective approach than available individual or gene panel testing
- 12. 2. Orchestrated RD pipeline Cell Models Yeast Models Zebra fish Models Mouse Models Disease phenotyping and mechanism ‘Omics Profiling High-content imaging Mutation Gene Protein Pathway Disease expertise Triaging
- 13. RD Models and Mechanisms Network GeneX $25K $2.3 M Catalyst Grant
- 14. RDMM activity to date 17 applications 13 moved forward 8 new candidate disease genes 3 for new diseases with known genes 2 for known disease genes Number of researchers registered: 337 Genes Added: 4044
- 15. 3. Orchestrated RD pipeline Screening FDA-approved pharmacopeia Pharma’s shelved Phase II assets Druggable target identification Yeast RNAi Drug lead validation in model systems Protein-Drug Interactions Discovery Therapeutic Discovery and Validation Validation
- 16. 95 known disease genes revealed by NGS First therapeutic opportunity Therapy initiated • Hunter syndrome • Riboflavin transporter defect • Cerebral Folate Transport deficiency Therapy adjusted • Primary adrenal insufficiency • Infantile myofibromatosis • Intractable epilepsy
- 17. Glucocorticoid deficiency therapy adjusted • Diagnosed with Primary adrenal insufficiency • Presented with hyopglycemia, comma, N electrolytes, low serum morning cortisol, high serum ACTH level, red hair, mild obesity • Combined cortisol and aldosterone replacement therapy (15 years) • WES trio: compound het mutations in POMC • Withdrawal Florinef Mark Samuels, J Clin Endocrinol Metab 98: 736, 2013
- 18. Riboflavin transporter defect • Childhood onset sensory neuropathy, hearing loss, optic atrophy • WES identified homozgyous mutation in SLC52A2 consistent with Brown- Vialetto-VanLaere type 2 • Riboflavin supplementation Bernard Brais, Montreal therapy initiated
- 19. therapeutic opportunity Patient Ion Levels Mn Cd Zn Blood (nmol/L) 20 (ERC) (273-728) 0.9 (ERC) (0.20) 11.4 (S) (8-20) Urine (umol/mol CR) 9.10 (0.17-1.20) 0.11 (0-1.91) 0.28 (0.12-0.81) ZIP8 SLC39A8 Mn deficiency syndrome
- 20. Diverse opportunities DMD CF SMA Glut 1 Farber Dravet SCA15 Fronto- temporal dementia MAPT CMT1B Spondylo epiphyseal dysplasia tarda HSP Type 4 Cerebellar atrophy short stature Familial Hemiplegic Migraine type 2 Optic atrophy type 1 Loeys-Dietz syndrome Creatine transporter deficiency Dysferlinopathies HSP54 D-bifunctional protein deficiency SCA28 Benign chronic pemphigus ARSACs POLR3A Leuko
- 21. Canadian Networks will … Accelerate genomics momentum in Canada Build national capacity for the interrogation of mechanism and therapeutic discovery
Editor's Notes
- Which frames the RaPiD pipeline to be enabled by the requested infrastructure. Discovering the genomic causes of rare diseases, Determining how the mutation of genes cause disease and, where conditions for success are met, use this information to configure therapies.
- This translates into >4000 samples for rare disease gene discovery, 90 mechanism projects, and 200 rare diseases entering the into therapeutic configuration pipeline.
- The RaPiD pipeline begins with rare diseases that affect Canadian families. For 50% of rare diseases we need to understand the genomic underpinnings. We will use targeted, WES, WGS and RNASeq to optimize gene discovery and develop tools for downstream diagnostic translation.
- FORGE 264 disorders
- Next we must understand disease mechanism. Depending on the gene, pathway and system affected, the disorders selected for further study will be triaged to an institution where cellular and at least one other model will be generated. This will be supported, in part, by the recently awarded Rare Diseases Models and Mechanisms grant from CIHR, which will fund 90 such projects. Both systems based profiling and high content imaging will be undertaken; the type of omic profiling will be dictated by the nature of the disease and causal gene.
- A smaller subset of profiled disorders with “winning” criteria will undergo a multi-pronged approach for therapeutic discovery guided by our new understanding of disease mechanism. The first step will be drug target identification. At this stage a diversity of systems based approaches as well as medium throughput genetic and drug screens will result in the identification of a number of drug leads for testing in animal models.
- We harbour no illusion about the scope of our challenge. With therapies just now emerging for subsets of CF, DMD and SMA, it is clear that therapeutic configuration will not be trivial for many disorders. However, we have with the number of known rare disease genes, the current pace of gene discovery and the profound heterogeneity of pathogenesis, a very large number of potential targets. This, in combination with the latest system wide platforms and the application of drug discovery operating principles will ensure therapeutic advances for a number of diseases.
- In conclusion, RaPiD is both anchored in and springs from multicenter rare disease initiatives. It brings together critical and currently unavailable infrastructure that will both maintain our genomic discoveries as well as facilitate their translation to treatment for this vulnerable and under-served demographic. The Canadian rare disease research community has shown in the last few years how it can be mobilized to achieve great impact on rare disease gene discoveries, we are poised to do the same for diagnosis, mechanism and therapy.