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TRANSLATIONAL SCIENCE: PROGRESS TOWARDS PERSONALIZED MEDICINE FOR IPF – BIG DATA MEETS PATIENT CARE SESSION LEADERS: IVAN O. ROSAS, MD CHRISTINE KIM GARCIA, MD, PhD NOVEMBER 13, 2015 AN OVERVIEW OF PERSONALIZED MEDICINE FOR PULMONARY FIBROSIS IVAN O. ROSAS, MD TRANSLATIONAL SCIENCE: PROGRESS TOWARDS PERSONALIZED MEDICINE FOR IPF – BIG DATA MEETS PATIENT CARE FUNCTIONAL STATUS NOVEMBER 13, 2015 Pulmonary Fibrosis Personalized Medicine Nature Bahcall 2015 Precision Medicine is a innovative multidisciplinary clinical strategy that aims to integrate key research teams and clinical practice to guide individualized patient care 3 The “Low-Cost Genome” is here… 4 • 15 years after the Human Genome Project the gradual reduction in cost has led to explosion in genowide sequencing projects • Capability has increased by six magnitudes in eight years HiSeq X Ten system developed by Illumina of San Diego, California, can sequence more than 18,000 human genomes per year • Genome sequencing is generating ~ 40 petabytes (40 million gigabytes) each year … not as big as Google, Facebook or Utube • Population-scale sequencing programmes: Precision Medicine Initiative (US) 1x106, Beijing Genomics Institute (China) 1x106, Genomes Project (United Kingdom) 1x105 Key Stakeholders are Committed to Precision Medicine Fox Nature Biotechnology 2015 5 Patients and Translational Teams are Key Stakeholders in Precision Medicine Aronson Nature 2015 6 Integration of Deep Genomic and Phenotypic Models – A Critical Asset of the PF Research Community “Wringing clinical value from the flood of genomic information, would depend on the more pedestrian practice of phenotyping — clinically characterizing traits that signify health or disease, such as a fever, a rash, a limp or an irregular heartbeat” - Isaac Cohan, Harvard School of Public Health mid 1990’s - Delude Nature 2015 7 Precision Medicine and Phase lll Clinical Trials 8 Industry Investment in Precision Medicine Milne Nature Reviews – Drug Discovery 2015 9 How does “Big Data” become Precision Medicine 10 • The long term goal is to integrate genomics into the electronic medical health care record (EMR) • Integrate molecular data (genome/epigenome, transcriptome, proteome and metabolome) with clinical diagnosis (phenomics) and patient generated data (PRO and wearable devices) Potential Roles of Precision Medicine in Pulmonary Fibrosis • Molecular Classifier: Complement diagnosis of IIPs and identify novel clinically relevant phenotypes 11 Genomic Signatures that Predict Usual Interstitial Pneumonia Kim Lancet Respir Med 2015 12 Potential Roles of Precision Medicine in Pulmonary Fibrosis • Molecular Classifier: Complement diagnosis of IIPs and identify novel clinically relevant phenotypes • Prediction of outcomes: Stratification in clinical trials and prioritization of lung transplant candidates 13 Validated Genetic Variants Associated with Idiopathic Interstitial Pneumonias Chu Semin Respir Crit Care Med In Press 14 Telomere Lengths Predict Survival for IPF Patients Stuart Lancet Respir Med 2014 15 PBMC Gene Expression Profiles Predict Poor Outcomes in IPF Herazo Sci Transl Med 2013 16 Potential Roles of Precision Medicine in Pulmonary Fibrosis • Molecular Classifier: Complement diagnosis of IIPs and identify novel clinically relevant phenotypes • Prediction of outcomes: Stratification in clinical trials and prioritization of lung transplant candidates • Pharmacogenomics: Predict response to therapy and development of adverse events or side effects 17 CO Dosing and Administration •CO gas or placebo delivered through a CPAP mask. •Mask connected to tubing with a one-way expiratory valve to prevent accumulation and rebreathing of the exhaled gas. •Gas mixtures contain the predetermined CO gas concentration. •Size of cylinders and concentration of CO gas are designed in single use units. 18 18 MMP7 Serum Concentration (pg/ml) Matrix Metallo-Proteinase 7 (MMP7) Concentrations are not Modulated by CO Rosas ATS 2015 19 CO Modulates Relevant Biological Pathways in PBMCs of IPF Patients Garcia ATS 2015 20 Multi-disciplinary Teams that Support Precision Medicine Pulmonary Genetics Center <16 years of age Pa ent referral ≥16 years of age MGH BWH Visit 1: Baseline evaluation Clinical assessment Pre-testing counseling Consenting Genetic Evaluation Biomarker testing Sequencing panels Medical genetics consultation Visit 2: Follow-up Disclosure of results Treatment & Management Secondary subspecialist referral Genetic Counseling Carrier testing Preclinical case identification Research Initiatives Long-term surveillance (via GeneInsight) Iterative interpretation of test results based on new knowledge 21 PulmoGene™ Sequencing Panel Short Telomeres, Telomeropathy, and Subclinical Extrapulmonary Organ Damage in Patients With ILD George Chest 2015 22 Lymphocyte Telomere Length in Patients with ILD Disease and Suspected Short Telomeres 23 Telomere Length (kb) Personalized Approaches to Lung Transplantation for Pulmonary Fibrosis Granulocytes • 51 y.o. female with fibrosis – – – – MCV 97.3 Gray patches in mid 20’s Telomeres: 1st-10th percentile x 5 lines PSP: c.XXXXG>A (p.ArgXXXHis) • Age Novel pathogenic variant • Marrow dysfunction confirmed on BM biopsy (20% cellularity) despite normal peripheral smears. • Transplanted in early February with diagnosismotivated less aggressive immunosuppression regimen • No post-op myelosuppression or liver failure • Discharged in late February in clinic last week doing well 24 Potential Roles of Precision Medicine in Pulmonary Fibrosis • Molecular Classifier: Complement diagnosis of IIPs and identify novel clinically relevant phenotypes • Prediction of outcomes: Stratification in clinical trials and prioritization of lung transplant candidates • Pharmacogenomics: Predict response to therapy and development of adverse events or side effects • Preventive Strategies: Primary and Secondary 25 Precision Medicine and the NHLBI Strategic Vision 2015-2025 … what if we could expand the frontiers of scientific knowledge and revolutionize how we diagnose, prevent, and treat disease by leveraging the power of big scientific data systems? Kiley AJRCCM 2015 26 Lung Cancer Screening Guidelines 2014 The Centers for Medicare & Medicaid Services (CMS) has determined evidence is sufficient to support annual screening for lung cancer with low dose computed tomography (LDCT) – – – – Moyer Ann Intern Med 2014 – Age 55 – 77 years; Asymptoma c (no signs or symptoms of lung cancer); Tobacco smoking history of at least 30 pack-years; Current smoker or one who has quit smoking within the last 15 years Wri en order for LDCT lung cancer screening CMS CAG-00439N, Feb 2015 27 Timeline Precision Medicine and Prevention of Pulmonary Fibrosis Long term Opportuni es (>10 years) Short Term Opportuni es (5-10 years) Present Priority Research Areas Phenotype and Endotype Determine Risk Factors for Subclinical ILD Define Proxy Measures Risk-stra fica on Biomarkers Gene c Associa on Studies Func onal Imaging (MRI) Interven on- RCT Longitudinal Outcomes Focus Popula ons Families affected with pulmonary fibrosis Smokers undergoing screening for lung cancer Connec ve ssue disease (Ssc and RA) General popula on cohorts (FHS, MESA) Rosas Annals ATS 2014 28 NHLBI Funded Programs that Utilize Precision Medicine Tools for Early Detection and Intervention • Brigham and Women’s Hospital – Ivan Rosas • Columbia University – David Lederer • University of Colorado and National Jewish Health – David Schwartz • Vanderbilt University – Tim Blackwell 29 Summary Precision Medicine is a innovative multidisciplinary clinical strategy that aims to integrate key research teams and clinical practice to guide individualized patient care: • • • • Diagnosis and molecular classification Prediction of Clinical Outcomes Pharmacogenomics Prevention of Pulmonary Fibrosis 30 Acknowledgements Brigham and Women's Hospital Tetsuro Araki Bartolome Celli Sarah Chu Paul Dellaripa Souheil El-Chemaly Hiroto Hatabu Hilary Goldberg Matt Hunninghake Mizuki Nishino Avignat Patel Victor Pinto-Plata Tracy Doyle-Wanner George Washko NHLBI/NHGRI Joel Moss Bernadette Gochuico Jack Yao Gustavo Pacheco Eric Billings UPMC Ken Leader Jill Siegfried Joel Weissfeld David Wilson Yale Naftali Kaminski Guoying Yu Jose David Herazo P01 HL114501 RO1 HL15024 31 Peter Bent Brigham Hospital (circa 1920) BWH ILD Group ATS 2014