Jai Pal Singh Ph. D. Jai Pal Singh Ph. D. Chief Scientific Officer Chief Scientific Officer Vice President of ResearchVice President of Research

SJTRI Atlanta, GA, USASJTRI Atlanta, GA, USA

Vascular compatibility of polymers and Vascular compatibility of polymers and drugs in drug eluting stents drugs in drug eluting stents

• SJTRI is a research arm of the St. Joseph Hospital, Atlanta, GA

• Founded in 1999

• Non-profit, private institute

• Saint Joseph’s is one ofthe 32 hospitals in CHS• $4 billion in annualrevenue

Saint Joseph’s Translational ResearchInstitute ( SJTRI)

SJTRI Near Georgia Tech in theTechnology Enterprise Park

State-of-the-art preclinical facility• 32,000 sq feet, 12 flex labs

– Houses rodents, rabbits, swine,dogs, sheep, and goats

– Preclinical models• Cath labs, OR, imaging, cell and

molecular biology, histology,biomaterial, bio analytical labs andtraining center

• Full AAALAC accreditation, GLP

SJTRI: Open Access Translational Lab

SJTRI MissionTranslate scientific discoveriesinto modern therapeutics for

patient care

Achieve mission through collaboration withindustry, academic, governmental and

philanthropic organizations

Innovation Death Valley

>500,000 IP 2009

BasicResearch

Patients, Society

Basic Research

Clinical Applications

S J T R I

Translational Research at SJTRI

• Scientificknowledge

• Cell free• Cellular systems• MOA

• Preclinical Efficacy• PK/PD• Safety vs. standard of care• Differentiation

• FDAsubmission• Clinical plan• Enable

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VCPharma

GovBiotechVIC

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Biotech

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CHE clinical resource, tissues for genomics, proteomics -----

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Inventions:

• Device, drug

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• Antibody

• siRNA

Phase1 unitPhase1 unit

• Wireless sensing device thatis implanted usingminimally invasivetechniques and transmitscardiac output, bloodpressure and heart rate datathat are critical to themanagement of patients

• 5 million patients with heartfailure, $68 billion cost tosociety

Sensors have proven to save lives and hospitalization

Technology Translated at SJTRI

Heart patch implanted after bypass surgery

Products Developed at SJTRI

Drug delivery patch to prevent arrhythmia

SEM

Heart Patch Drug Coated Heart Patch

SJTRI - New Drug-Patch

Pre-clinical Research

•Interventional Cardiology -Development of interventional medical devices -Endothelial function and vascular disease

•Structural heart disease-Congestive heart failure-Heart valves-Ischemic heart disease

•Regenerative Medicine; Tissue Engineering-Adult stem cell therapy and enabling technologies-Cardiac and peripheral vascular disease-Islet cell transplantation-Vascular graft and heart patch engineering-Biopolymer based cells and drug delivery

•Orthopedic -Fracture healing drug- device research -Orthopedic device development

•Other areas: Neurology, genomics

Jai Pal Singh Ph. D. Jai Pal Singh Ph. D. Chief Scientific Officer Chief Scientific Officer Vice President of ResearchVice President of Research

SJTRI Atlanta, GA, USASJTRI Atlanta, GA, USA

Vascular compatibility of polymers and Vascular compatibility of polymers and drugs in drug eluting stents drugs in drug eluting stents

Metallic strutMetallic strut Cobalt-ChromiumCobalt-Chromium

Polymer Polymer coatingcoating

Drug DrugRapamycinRapamycin,,

Drug Eluting Stent (DES)Drug Eluting Stent (DES)

An interventional device used in more that 1 million patients An interventional device used in more that 1 million patients each year to restore blood flow in a blocked coronary arteryeach year to restore blood flow in a blocked coronary artery

stent

Coronary arteryAngiogram

BMS

Baseline After 1 month

DES

DES Reduces Restenosis

Vascular Pathophysiology of DES

• Late restenosis• Stent thrombosis• Malapposition• Aneurysm• Long term antiplatelet therapy• Poor efficacy in diabetics

Finn et al Eur Heart J 2009

SES ZESBMS

Stent Biocompatibility is Determinedby Vascular Histology

The molecular bases of DES pathopysiology is not well defined

• Determine gene expression changes in vessel wall in response to DES implantation

• Determine linkage of gene expression with pathways relevant to vascular pathophysiology

• To discern the changes attributed to the polymer or the drug

Objectives of the studies

• Juvenile Yorkshire swine received overlapping BMS,SES and ZES with S:A 1.1:1 and 4-6mm of overlap.

• All animals were terminated after one month• Histopathology and gene expression studies were

conducted

Experimental Strategy Experimental Strategy

• Use swine as a preclinical model for DES study

• Develop biomarkers to establish connectivity with human

Stent Groups For Micro-Array

Bare metal Zotarolimus Sirolimus

4746 RCA 4751 RCA 4745 LCX

4746 LAD 4751 LAD 4745 RCA

4747 LAD 4757 RCA 4750 LAD

4747 RCA 4757 LAD 4750 RCA

ZES BMS

Genes

SES

Gene Expression Analysis: Micro-ArrayGene Expression Analysis: Micro-Array

Gene Changes Relevant to Vascular Gene Changes Relevant to Vascular Physiological ResponsesPhysiological Responses

Genes Relevant to Vascular Pathophysiology

GS activator 2ACaviolinPRMT5ArginaseVEGFHIF1a, HiF2aEndothelin -1SODThioredoxinPON2HSP70

NFkB1AIL-1bIL-8CXCL2CCL5CCR2CCL3CCR9CXCL2CCL2CCR1ICAM-1

Tissue FactortPA DPP4L-selectinP-selectinvWF

Nitric Oxide NDNitric Oxide NDOxidative stressOxidative stress

InflammationInflammation ThrombosisThrombosisPathwayPathway

L-ArginineL-ArginineeNOS

cGMP

DES Induces NO Pathway Deficiencyand Endothelial Dysfunction

NO

Low Arginine

• Vasodilation• Anti-platelet• Anti-inflammation• Endothelial progenitor cell •AngiogenesisADMAADMA

O2

O ˙ 2－

Impaired Vasodilation in DES

Superoxide (O ˙ 2－ ) Production

P=0.044 P=0.032

n=5

n=9

n=7

n=4

n=7

n=60

5

10

15

20

25

30

35

40

proximal distal

Chemiluminiscence(RLU/s/mgoftissue)

BMS

SES

ZES

Both the Polymer and the Drug Contribute to Vascular Pathology

• Genes changes observed with both stents may represent a response to drug

• Differential gene changes in response may be related to differences in the polymer

• Gene expression profiling reveals unique pathological vascular responses to DES

• Changes in gene expression were associated with vascular pathophysiological responses

• Polymer biocompatibility and the drug contribute to vascular gene expression

• The molecular profiling can serve as a guide to differentiate/develop improved biocompatible DES.

Summary

AcknowledgementAcknowledgementDongming HouDongming HouJohn McDonald GTJohn McDonald GTAndrew Huang GTAndrew Huang GTNatarajan SelvamuthuNatarajan SelvamuthuJimmy LiJimmy LiNicolas ChronosNicolas ChronosSJTRI staffSJTRI staff