4/20/2018 Precision Medicine: A New Paradigm to Understand and Improve Outcomes in Pediatric PAH Vinicio A. de Jesus Perez, MD FAHA FCCP Assistant Professor of Medicine Stanford University Medical Center Updated Classification of Pulmonary Hypertension (2015) Questions • Does Precision Medicine in Pediatrics Mean the Same as in Adults? • What are the tools relevant to precision medicine? • Are Genetics of Pediatric PVD Different from Adult PVD? • Should different precision medicine approaches be prioritized in pediatrics vs. adults? • How can precision medicine help us improve drug discovery and clinical trial design? Galie N et al. EHJ 2016 5 th World Symposium on Pulmonary Hypertension, Nice 1
4/20/2018 Combination of Clinical Biomarkers Determines Mortality Risk in PAH Patients Abman S et al. Circulation 2017 Abman S et al. Circulation 2017 Survival Rates of PAH in the Modern Era: We Can Do Better! How can we improve our current clinical paradigm? Abman S et al. Circulation 2017 Ivy D et al, Children 2018 2
4/20/2018 Current Paradigm: “One-Size-Fits-All” Precision Medicine 101: But Only a Subset of Patients are True “Responders” Unique Patient=Unique Treatment Antman and Loscalzo, Nature Reviews 2016 Schork NJ, Nature 2015 Precision Medicine 101: Unique Patient=Unique Treatment 2013 2018 • Genetics Higher Level Evidence Lower Level Evidence Higher Level Evidence Lower Level Evidence BMPR2 SMAD4 BMPR2 SMAD4 ALK1 SMAD1 ALK1 SMAD1 • Preclinical Models ENG KLF2 ENG KLF2 SMAD9 BMPR1B SMAD9 BMPR1B TBX4 KCNA5 TBX4 GDF2 (BMP9) • Drug Screens KCNK3 AQP1 KCNK3 KCNA5 CAV1 CAV1 EIF2AK4 (PVOD EIF2AK4 /PAH) GDF2 (BMP9) ATP13A3 SOX17 3
4/20/2018 Gene Mutations are Present in Subsets of PAH Patients: Impact on Familial vs. Sporadic PAH TBX4 Circulation Genomics and Precision Medicine 2018 Girerd B et al, ERJ 2016 AJRCCM 2016 4
4/20/2018 AJRCCM 2017 Provencher S et al, Circ Research 2018 Inducible Pluripotent Stem Cells: Animal Models Do Not Recapitulate the Clinico-Pathological Complexity of PAH Ground Zero for Precision Medicine Dickinson MG et al, AJP Lung 2013 Gnechi et al, JACC 2012 5
4/20/2018 An iPSC based Platform can Accelerate Discovery of Lung on a Chip: A New Spin on in vitro Studies Novel Mechanisms and Therapeutic Approaches Next Gen Seq Fibroblasts PAH PBMCs Functional Patient studies Gene Editing Drug Screening https://wyss.harvard.edu/living-breathing-human-lung-on-a-chip-a-potential-drug- Gu M et al, Cell Stem Cell 2017 testing-alternative/ Sa S et al, AJRCCM 2016 Kiskin FN et al AJRCCM 2018 The Exposome Accounts for Environmental Effects PAH Linked to HIV and Methamphetamine Has a on Patient Health Worse Prognosis Compared to IPAH 6
4/20/2018 PAH is a Complication of Both HIV and METH: Is There a Common Genetic Susceptibility? First Hit Persistent Inflammation Smooth muscle Obliterative hyperplasia Pulmonary Vasculopathy ATVB 2013 Endothelial Injury HIV-Nef, Tat, gp120 Inflammation ATVB 2018 • Drugs of Abuse Second • Infections • Gene Susceptibility? Hit AJP-Lung 2017 Adapted from Morris and Gladwyn Proposed Model: Current Paradigm: “One Size Fits All” CES1 Increases Risk of PAH in METH and HIV Patients by But Only a Subset of Patients are True “Responders” Downregulation of BMPR2 Adverse Drug Reactions Healthy Healthy BMPR2 functional signaling pathway Vessel Integrity Injury! PAH No BMPR2 Dysfunctional BMPR2 pathway Vessel Loss PAH *Collaboration with Navneet Dhillon PhD Antman and Loscalzo, Nature Reviews 2016 Schork NJ, Nature 2015 7
4/20/2018 Pediatric Cardiology 2013 IV Epoprostenol AJRCCM 2015 8
4/20/2018 • Reduction in mPAP by at least 10 mmHg Positive • Must reduce to a mPAP of <40 mmHg. Vasoreactivity • Cardiac output must be maintained or improved. Roham Zamanian Circulation. 2015;131:401-409 Targeting BMPR2 Could Lead to Novel Therapies Targeting BMPR2 Can Lead to Novel Therapies… For Patients with Known BMPR2 Mutations But Are They Going to Work for Everyone with PAH? FK506 Tacrolimus Level Spiekerkoetter et al, AJRCCM 2015 Spiekerkoetter, JCI 2013 Low: <2ng/ml BMP-9 Medium: 2-3ng/ml High: 3-5ng/ml Long et al, Nature Medicine 2015 ERJ 2017 Ataluren Drake et al, AJRMB 2013 Thompson and Lawrie, 2016 9
4/20/2018 Wearables Are Here!!!!! (Whether You Like it or Not) Chen R et al, Cell 2012;148:1293-1307. Science Translational Medicine 2017 SNVs in SIRT3 and UCP2 Mike Snyder, PhD https://www.youtube.com/watch?v=d70Wm_-JDcA Ongoing Challenges for the Implementation of Precision Medicine Courtesy of Dr. Michael Snyder • It will take money. • Data storage and security risks • Acceptance by patients Also check: • Ethics Jamieson, NEJM 2015 • US medical system not incentivized for this. http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=741 10
4/20/2018 Precision Medicine: Precision Medicine 101: Success is Measured by Quality of Care Unique Patient=Unique Treatment ACKNOWLEDGEMENTS De Jesus Perez Collaborators Research Group Marlene Rabinovitch Mark Orcholski Mark Nicolls Ke Yuan Jeffrey Axelrod Ellen Hyung Joseph Wu Minzi Huang Roham Zamanian Elya Shamskhou Norbert Voelkel Halley Tsai Sebastian Bonnet Justin Lee Tim Lahm Erin Stewart Sushma Reddy Charlotte Rajasingh James Klinger Christian Westoo Corey Ventetuolo Navneet Dhillon Nils Patrick Nickel Alsu Zamaleeva Oscar Abilez Jair A. Tenorio Grazyna Kapieswka Christopher Rios Karin Tran Lundmark Alice Richter Utkan Demirci Abinaya Nathan Kurt Stenmark Ramon Ruiz III Halley Hedlin Kristy Red-Horse Andrea Frump 11
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