Transcript TRANSLATIONAL SCIENCE: PROGRESS TOWARDS

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
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The “Low-Cost Genome” is here…
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15 years after the Human Genome Project the
gradual reduction in cost has led to explosion in
genowide sequencing projects
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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
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Genome sequencing is generating ~ 40 petabytes
(40 million gigabytes) each year … not as big as
Google, Facebook or Utube
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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
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Patients and Translational Teams are Key
Stakeholders in Precision Medicine
Aronson Nature 2015
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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
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Precision Medicine and Phase lll Clinical Trials
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Industry Investment in Precision Medicine
Milne Nature Reviews –
Drug Discovery 2015
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How does “Big Data” become
Precision Medicine
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The long term goal is to integrate
genomics into the electronic medical
health care record (EMR)
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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
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Genomic Signatures that Predict Usual
Interstitial Pneumonia
Kim Lancet Respir Med 2015
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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
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Validated Genetic Variants Associated with
Idiopathic Interstitial Pneumonias
Chu Semin Respir Crit Care Med In Press
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Telomere Lengths Predict Survival for IPF
Patients
Stuart Lancet Respir Med 2014
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PBMC Gene Expression Profiles Predict
Poor Outcomes in IPF
Herazo Sci Transl Med 2013
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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
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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.
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MMP7 Serum Concentration (pg/ml)
Matrix Metallo-Proteinase 7 (MMP7)
Concentrations are not Modulated by CO
Rosas ATS 2015
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CO Modulates Relevant Biological Pathways in
PBMCs of IPF Patients
Garcia ATS 2015
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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
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PulmoGene™ Sequencing Panel
Short Telomeres, Telomeropathy, and Subclinical Extrapulmonary
Organ Damage in Patients With ILD
George Chest 2015
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Lymphocyte Telomere Length in Patients with ILD Disease
and Suspected Short Telomeres
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Telomere Length (kb)
Personalized Approaches to Lung Transplantation
for Pulmonary Fibrosis
Granulocytes
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51 y.o. female with fibrosis
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MCV 97.3
Gray patches in mid 20’s
Telomeres: 1st-10th percentile x 5 lines
PSP: c.XXXXG>A (p.ArgXXXHis)
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Age
Novel pathogenic variant
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Marrow dysfunction confirmed on BM biopsy (20%
cellularity) despite normal peripheral smears.
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Transplanted in early February with diagnosismotivated less aggressive immunosuppression
regimen
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No post-op myelosuppression or liver failure
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Discharged in late February in clinic last week doing
well
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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
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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
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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)
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Moyer Ann Intern Med 2014
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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
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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
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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
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Summary
Precision Medicine is a innovative multidisciplinary clinical
strategy that aims to integrate key research teams and
clinical practice to guide individualized patient care:
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Diagnosis and molecular classification
Prediction of Clinical Outcomes
Pharmacogenomics
Prevention of Pulmonary Fibrosis
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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
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Peter Bent Brigham Hospital (circa 1920)
BWH ILD Group ATS 2014