Questions Does Precision Medicine in Pediatrics Mean the Same as - - PowerPoint PPT Presentation

4/20/2018 1

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

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? Updated Classification of Pulmonary Hypertension (2015)

Galie N et al. EHJ 2016 5th World Symposium on Pulmonary Hypertension, Nice

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Abman S et al. Circulation 2017

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!

Ivy D et al, Children 2018

How can we improve our current clinical paradigm?

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Antman and Loscalzo, Nature Reviews 2016 Schork NJ, Nature 2015

Current Paradigm: “One-Size-Fits-All” But Only a Subset of Patients are True “Responders”

Precision Medicine 101: Unique Patient=Unique Treatment Precision Medicine 101: Unique Patient=Unique Treatment

• Genetics
• Preclinical Models
• Drug Screens

2013

Higher Level Evidence Lower Level Evidence

BMPR2 SMAD4 ALK1 SMAD1 ENG KLF2 SMAD9 BMPR1B TBX4 GDF2 (BMP9) KCNK3 KCNA5 CAV1 EIF2AK4

2018

Higher Level Evidence Lower Level Evidence

BMPR2 SMAD4 ALK1 SMAD1 ENG KLF2 SMAD9 BMPR1B TBX4 KCNA5 KCNK3 AQP1 CAV1 EIF2AK4 (PVOD /PAH) GDF2 (BMP9) ATP13A3 SOX17

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Girerd B et al, ERJ 2016

Gene Mutations are Present in Subsets of PAH Patients: Impact on Familial vs. Sporadic PAH

TBX4 Circulation Genomics and Precision Medicine 2018 AJRCCM 2016

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Provencher S et al, Circ Research 2018

AJRCCM 2017

Animal Models Do Not Recapitulate the Clinico-Pathological Complexity of PAH

Dickinson MG et al, AJP Lung 2013

Inducible Pluripotent Stem Cells: Ground Zero for Precision Medicine

Gnechi et al, JACC 2012

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Next Gen Seq Functional studies Gene Editing Drug Screening

An iPSC based Platform can Accelerate Discovery of Novel Mechanisms and Therapeutic Approaches

PAH Patient Fibroblasts PBMCs Gu M et al, Cell Stem Cell 2017 Sa S et al, AJRCCM 2016 Kiskin FN et al AJRCCM 2018

Lung on a Chip: A New Spin on in vitro Studies

https://wyss.harvard.edu/living-breathing-human-lung-on-a-chip-a-potential-drug- testing-alternative/

The Exposome Accounts for Environmental Effects

• n Patient Health

PAH Linked to HIV and Methamphetamine Has a Worse Prognosis Compared to IPAH

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PAH is a Complication of Both HIV and METH: Is There a Common Genetic Susceptibility?

HIV-Nef, Tat, gp120 Inflammation Pulmonary Endothelial Injury Persistent Inflammation Smooth muscle hyperplasia Obliterative Vasculopathy

First Hit

Second Hit

• Drugs of Abuse
• Infections
• Gene Susceptibility?

Adapted from Morris and Gladwyn

ATVB 2013 ATVB 2018 AJP-Lung 2017 Healthy

BMPR2 functional signaling pathway

Vessel Integrity

Injury!

Healthy

PAH Vessel Loss

Dysfunctional BMPR2 pathway

No BMPR2

PAH

Proposed Model: CES1 Increases Risk of PAH in METH and HIV Patients by Downregulation of BMPR2

*Collaboration with Navneet Dhillon PhD

Antman and Loscalzo, Nature Reviews 2016 Schork NJ, Nature 2015

Current Paradigm: “One Size Fits All” But Only a Subset of Patients are True “Responders”

Adverse Drug Reactions

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Pediatric Cardiology 2013

IV Epoprostenol

AJRCCM 2015

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• Reduction in mPAP by at least 10 mmHg
• Must reduce to a mPAP of <40 mmHg.
• Cardiac output must be maintained or improved.

Positive Vasoreactivity

Roham Zamanian

• Circulation. 2015;131:401-409

Targeting BMPR2 Could Lead to Novel Therapies For Patients with Known BMPR2 Mutations FK506

Spiekerkoetter et al, AJRCCM 2015 Spiekerkoetter, JCI 2013

BMP-9

Long et al, Nature Medicine 2015

Ataluren

Drake et al, AJRMB 2013

Thompson and Lawrie, 2016

Targeting BMPR2 Can Lead to Novel Therapies… But Are They Going to Work for Everyone with PAH?

Low: <2ng/ml Medium: 2-3ng/ml High: 3-5ng/ml Tacrolimus Level

ERJ 2017

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Science Translational Medicine 2017

SNVs in SIRT3 and UCP2

Wearables Are Here!!!!! (Whether You Like it or Not)

https://www.youtube.com/watch?v=d70Wm_-JDcA

Chen R et al, Cell 2012;148:1293-1307.

Mike Snyder, PhD http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=741 Also check:

Courtesy of Dr. Michael Snyder

• It will take money.
• Data storage and security risks
• Acceptance by patients
• Ethics
• US medical system not incentivized for this.

Ongoing Challenges for the Implementation

• f Precision Medicine

Jamieson, NEJM 2015

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Precision Medicine 101: Unique Patient=Unique Treatment

Precision Medicine: Success is Measured by Quality of Care

ACKNOWLEDGEMENTS

De Jesus Perez Research Group Mark Orcholski Ke Yuan Ellen Hyung Minzi Huang Elya Shamskhou Halley Tsai Justin Lee Erin Stewart Charlotte Rajasingh Christian Westoo Nils Patrick Nickel Alsu Zamaleeva Jair A. Tenorio Christopher Rios Alice Richter Abinaya Nathan Ramon Ruiz III Collaborators Marlene Rabinovitch Mark Nicolls Jeffrey Axelrod Joseph Wu Roham Zamanian Norbert Voelkel Sebastian Bonnet Tim Lahm Sushma Reddy James Klinger Corey Ventetuolo Navneet Dhillon Oscar Abilez Grazyna Kapieswka Karin Tran Lundmark Utkan Demirci Kurt Stenmark Halley Hedlin Kristy Red-Horse Andrea Frump