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Integrative Genomics Discoveries and Development at the Center for Applied Genomics at CHOP

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Integrative Genomics Discoveries and Development at the Center for Applied Genomics at CHOP The Children’s Hospital of Philadelphia Integrative Genomics Discoveries and Development at The Center for Applied Genomics at CHOP Novel Genome-based Therapeutic Approaches Hakon Hakonarson, MD, PhD, Professor of Pediatrics CHOP’s Endowed Chair in Genetic Research Director, Center for Applied Genomics The Children’s Hospital of Philadelphia University of Pennsylvania, School of Medicine Duke Center for Applied Genomics and Precision Medicine 2019 Genomic and Precision Medicine Forum Nov 07, 2019 Genomics in the 21st Century Disclosures Dr. Hakonarson and CHOP own stock in Aevi Genomic Medicine Inc. developing anti-LIGHT therapy for IBD. Dr. Hakonarson is an inventor of technology involving therapeutic development of ADHD, GLA and HCCAA Novel Therapeutic Stem Cell/Gene Editing Approaches § iPS and stem cell therapy shows early promise § Gene therapy for LCA (RPE65) at CHOP via AAV § Targeted T cell therapy for cancer (UPENN/CHOP) § CRISPR-cas9 gene editing § Single cell sequencing The Center for Applied Genomics (CAG) at CHOP u Founded in June 2006 u Staff of 70 u Over 100 active disease projects with CHOP/Penn collaborators u TARGET: Genotype 100,000 children u ~450k GWAS samples >130k kids u IC - participation in future studies >85% u Database u Electronic Health Records u extensive information on each child u >1.2 million visits per year to Population Genomics Research CHOP Recruitment of CHOP/PENN HealthCare Network Patients u High-level of automation ADHD, Autism, Diabetes, IBD, Autoimmunity, Asthma/Atopy, Cancer, RDs - all high priority Children's Hospital of Philadelphia Center for Center of Mitochondrial Applied and Center for Genomics Epigenomic Developmenta Medicine Center for l Biology and Biomedical Pediatric Informatics Disorders Center for Center for Pediatric Cellular and Clinical Molecular Effectiveness Therapeutics Center for Childhood PolicyLab Cancer Center for Research Center for Injury Autism Research and Research Prevention CAG Repository (Major Disease Areas) Category # of § Major pediatric and samples adult diseases are represented Total CAG/CHOP (internal) 132,752 • Healthy Controls (0-21) 18,423 § EHR have unlimited potential regarding • Psychiatric 19,351 9 Longitudinal f/u • Autism/Developmental Delay 13,972 9 Medication use • Autoimmune/Inflammatory 31,643 9 Development • Cancer 9,585 9 AEs/SAEs/DDIs • Metabolic 13,760 § We have established • Malformations 8,954 over one hundred • Rare/Mendelian Diseases 22,436 collaborations world- wide for discovery Samples through collaboration 334,534 and replication Total number of samples @ CAG 467,286 purposes CAG Biobank – biomarker driven research § 450,000 unique patients in CAG biobank § Over 100,000 children from CHOP (>85% re-contact permission) § Blood samples from >95% § High quality DNA from with over 2/3 of samples GWAS genotyped § PBMCs - opportunity for EBV, iPS and tissue/organ differentiation § RNAseq, single cell sequencing § Cell based assays § Epigenetics § Plasma – for target driven biomarker measures § Thousands of different phenotypes in CAG § Clinical disease traits in the multi-hundred’s § Other: blood, chemistry, radiology, cardiology, sleep, u 2 Million Samples in tubes PFTs, meds etc. § Consortium networking u 10 Million Plated Samples collaborations § Multiple partnerships with biotech and pharma CAG CLIA certificate CAG Discovery and Development Pipeline Objective: To identify biomarkers indicative of the genetic Family- underpinnings of a disease for based novel innovative therapies Analysis u Three databases: 1. Family-based Samples 2. Genomic Database New drug 3. Health Records & Disease Phenotypes disovery and Genomic Database development u We integate these databases of biomarkers together in search for new target and diagnositc biomarkers and diagnostic products products u High level of IT and Technology Structure Health Records u All cloud based and Disease u Highly integrative Phenotypes u Cost effective discovery platform Precision Medicine in the Context of “Big Data“ Creating and turning data assets into insights. • CAG database has >450k patients GWAS genotyped and imputed to >30M variants • 15,000 whole genomes are sequenced and growing • 20,000 whole exomes are sequenced and growing • Thousands of phenotypes to mine for new targets Cells, RNA, Plasma available from these patients for biomarker development Representative CAG Milestones Research is enabled by our unique, scalable biobank with sample collections that are highly enriched for rare disease causing variants Reference, https://scholar.google.com/citations?user=nLerrWsAAAAJ&hl=en Personalized/Precision Medicine Paradigm u There are 6 billion bases (3 million pairs) in the human genome u SNPs occur every 100- 300 base pairs u The greatest number of DNA variations that are associated with diseases or traits are u Missense mutations u Nonsense mutations u Deletions (structural variants) u Today we can run an exome for <$350 and a genome for <$1000 and identify all know PGx and disease causing variants Genetic Influence in Pediatric Diseases Impact of pediatric age on genetic risk u Early Onset Disease: u Distinct, genetically driven u Severe burden of illness u Aggressive progression u Less responsive to standard of care Pediatric studies generally produce much larger genomic signals than studies in adults. Neuroblastoma u Embryonal cancer u Misappropriation of normal sympathetic neurodevelopment pathways u Common pediatric cancer u Median age diagnosis 17 months u 15% of childhood cancer mortality u Approximately 2/3 of patients cured Familial Neuroblastoma Locus Chromosome 2p23-24 TELOMERE--NAG - DDX1 - MYCN - FAM49A - VSNL1 - KCNS3 - RDH14 - NT5C1B - OSR1 - TTC32 - WDR35 - MATN3 - LAPTM4A - SDC1 - PUM2 - RHOB - HS1BP3 - GDF7 - C2orf43 - APOB - ATAD2B - UBXD4 - LOC388931 - C2orf44 - FKBP1B - SF3B14 - TP53I3 - PFN4 - FLJ30851 - ITSN2 - NCOA1 - LOC391356 - CENPO - ADCY3 - RBJ - POMC - DNMT3A - DTNB - ASXL2 - KIF3C - RAB10 - HADHA - HADHB - GPR113 - SELI - C2orf39 - OTOF - LOC339778 - CIB4 - KCNK3 - C2orf18 - CENPA - DPYSL5 - MAPRE3 - FLJ20254 - AGBL5 - EMILIN1 - KHK - CGREF1 - ABHD1 - PREB - C2orf53 - TCF23 - SLC5A6 - C2orf28 - CAD - SLC30A3 - DNAJC5G - TRIM54 - UCN - MPV17 - GTF3C2 - EIF2B4 - SNX17 - ZNF513 - PPM1G - NRBP1 - KRTCAP3 - IFT172 - FNDC4 - GCKR - C2orf16 - ZNF512 - CCDC121 - XAB1 - SUPT7L - SLC4A1AP - MRPL33 - RBKS - BRE - FOSL2 - PLB1 - PPP1CB - SPDYA - FLJ20628 - WDR43 - LOC165186 - FLJ 34931 - CLIP4 - ALK - YPEL5 - LBH - LYCAT - CAPN13 - GALNT14--CENTROMERE Identification of Heritable Mutations in the ALK Tyrosine Kinase Domain Unaffected grandfather * Affected grandmother Unaffected father 1 * Obligate carrier mother Unaffected father 2 * Affected child Affected child * Affected child * Mosse, Nature 2008 ALK is the Major Familial Neuroblastoma Gene Familial NB u A germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas u Resequencing in high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. u Nine of the ten mutations map to critical regions of the kinase domain (oncogenic drivers). u Several companies have ALK inhibitors in development (preclin to Phase I) u CHOP is pursuing clinical development and with first patient to be enrolled in April Neuroblastoma: Crizotinib Personalization and Repositioning Case Study CHOP Target New Genomically Repositioned Identified Patient Enriched Mutations Compound Population Clinical Trials • ALK • Lung cancer • Lymphoma • Phase I n=18 • Neuroblastoma • Phase I n=23 • mGluR • Dementia • ADHD • Phase I n=18 • Phase IIa n=60 u The tumors have responded in a robust way in those who are ALK mutation positive• Schizophrenia and receive• Future Xalkori trial • Autism • Future trial u Both germ-line and somatic mutation cases are responsive to Xalkori Discovery of Mutations (copy number variations/CNVs) in ADHD u CNVs affecting glutamatergic neurotransmission genes observed to be over-represented in multiple ADHD cohorts (~10 fold) u 3,500 ADHD cases and 12,000 controls u Replication accomplished across multiple ADHD cohorts GRM: Glutamate receptors metabotropic CNVs: Copy number variants Elia, Glessner et al. Nature Genetics, 2012 The Drug NFC1 Activates the mGluR Pathway NFC-1 (fasoracetam): üAn mGluR agonist üWell tolerated in previous preclinical and clinical studies üShown to ameliorate cognitive impairment and slow down locomotor activity in animal models üStructure-similar compounds have good safety profiles Genotyping or resequencing methods identify the ADHD children at risk Prior Studies conducted on NFC-1 Preclinical (N=21) Clinical (N=7) Clinical Trial Design ADHD (GREAT STUDY) New IND filed to the FDA and approval obtained to treat 30 mGluR biomarker positive children for 5 weeks age 12-17 year old Week 1 Week 2 Week 3 Week 4 Week 5 Week 9 Day 7 (±2) Day 14 (±2) Day 21(±2) Day 28 (±2) Day 35 (±2) Day 75 (±2) Adverse event monitoring X X X X X phone Laboratory Safety Tests (blood and urine)A X X X X X Physical Examination X X X X X Vital Signs: BP, HR, RR X X X X X Body Weight (all points) & Height (week 1 X X X X X only) 12-lead ECG X X X X X Urine b-hCG test (menstruating females only) X X X X X Contraception verification (selected females) X X X X X Vanderbilt Parent Rating Scale X X X X X BREIF (Parent; Self) X X X X X QuotientâADHD test X X X X X PERMP-Math test X X X X X Actigraphy (continuous monitoring) X X X X X CGI-I & CGI-S X X X X X Dispense study drugB X X X X NFC-1 or placebo
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