what‘s new: on classical and new adult cells? marc s. penn, md, phd, facc skirball laboratory for...
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What‘s New: On classical and new adult cells?
Marc S. Penn, MD, PhD, FACCSkirball Laboratory for
Cardiovascular Cellular Therapeutics
Director, Center for Cardiovascular Cell TherapyDirector, Bakken Heart-Brain InstituteDepartments of Cardiovascular Medicine,
Biomedical Engineering and Stem Cell BiologySenior Medical Director, Emerging Businesses
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Company Name Current RelationshipJuventas Therapeutics CSO, Equity, InventorIntellect, Inc. Equity, InventorCour Pharmaceuticals CMO, EquityPrognostix, Inc. CMO, Equity, InventorCardionomic, Inc. Equity, Inventor
BioHeart, Inc., SAB Member, Licensee
Oakwood Medical Ventures Venture Partner
Cardax Pharmaceuticals SAB Member
Athersys, Inc. Sponsored ResearchSDG, Inc. Sponsored ResearchCCO Technologies Sponsored ResearchCell Targeting Sponsored Research
Southwest Michigan Fund ConsultantMPI Research Consultant
DisclosuresDisclosures
03/2009
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Clinical Strategies for Stem Clinical Strategies for Stem Cell TherapyCell Therapy
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Cell Types of InterestCell Types of Interest
Embryonic Stem CellsTotipotent
Pluripotent
Hematopoietic SCCD117+, CD34+
Mesenchymal SCCD117-, CD34-, SH-1+
Monocytes, Neutrophils, . . . .Endothelial Cells, Hepatocytes
Cardiac Myocytes, Neurons
Umbilical Cord Stem CellsMAPCs
Skeletal Myoblasts
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Cell Types of InterestCell Types of Interest
Embryonic Stem CellsTotipotent
Pluripotent
Hematopoietic SCCD117+, CD34+
Mesenchymal SCCD117-, CD34-, SH-1+
Monocytes, Neutrophils, . . . .Endothelial Cells, Hepatocytes
Cardiac Myocytes, Neurons
Umbilical Cord Stem CellsMAPCs
Skeletal Myoblasts
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Direct Comparison of the Effects of Direct Comparison of the Effects of Allogeneic and Syngeneic MAPCAllogeneic and Syngeneic MAPC
• LAD ligation in Lewis Rat
• Genetically marked MAPC from– Lewis Rat (syngeneic)– SD Rat (allogeneic)
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Vascular Effects of MAPCVascular Effects of MAPC
PBSPBS
LewisLewis
SDSD
vWFvWF SMASMA OverlayOverlay
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MAPC into Lewis Rat at Time MAPC into Lewis Rat at Time of Acute MIof Acute MI
0
5
10
15
20
25
PBS Lewis SD
Sh
ort
en
ing
Fra
cti
on
(%
)
Source of MAPCSource of MAPC6 weeks after Acute MI6 weeks after Acute MI10 million MAPC or Saline at time of MI10 million MAPC or Saline at time of MI
75%51%
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Summary of PreclinicalSummary of PreclinicalMAPC StudiesMAPC Studies
• Administration of MAPC to the heart at the time of AMI results in decreased inflammation and improved cardiac function
• Improvement is despite– Loss of viable MAPC over time– No evidence of myocardial regeneration
• Suggests improvement due to paracrine effects of MAPC
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Clinical StrategyClinical Strategy
• Off the shelf cell product for allogeneic use
• Wanted easy to implement cell delivery strategy so that cells can be delivered at time of primary PCI
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Adventitial Delivery Catheters
2.5 – 3.0 mm treatment range
Cricket
Micro-Infusion Catheter™
Both 510(k) cleared for delivery to vessel wall or perivascular area
Bullfrog™
Micro-Infusion Catheter
3.0 – 6.0 mm treatment range
Adventitial Micro-Infusion Adventitial Micro-Infusion Catheter OperationCatheter Operation
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Adventitial Micro-Infusion Adventitial Micro-Infusion Catheter OperationCatheter Operation
Balloon shieldsmicroneedle
Needle is deployedwith inflation
Needle reachesadventitia for infusion
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Porcine ModelPorcine Model
• Anterior wall MI induced by 90 min balloon occlusion of LAD
• MAPC delivery 2 days post AMI to animals with EF < 40%
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Biodistribution Following Biodistribution Following Transarterial DeliveryTransarterial Delivery
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Biodistribution Following Biodistribution Following Transarterial DeliveryTransarterial Delivery
Circumferential Distribution of gal positive cells
Radial Distribution of -gal positive cells
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20
30
40
50
60
Baseline 1 Wk post-MI 4 Wk post MI
Eje
ctio
n F
ract
ion
%
***
MAPC 50MSaline
Acute MI Catheter-Based Acute MI Catheter-Based Delivery of MAPC Delivery of MAPC
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Improvements in Functional Improvements in Functional Performance in GLP StudyPerformance in GLP Study
At Risk Territory
Non-Risk Territory
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Summary of PreclinicalSummary of PreclinicalMAPC StudiesMAPC Studies
• Administration of MAPC to the heart at the time or 2 days after of AMI results in improved cardiac function
• Improvement is despite– Loss of viable MAPC over time– No evidence of myocardial regeneration
• Suggests improvement due to paracrine effects of MAPC
• Trans-arterial delivery of MAPC into infarcted myocardium is feasible
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MultiStem® in Patients With Acute Myocardial Infarction
• PI – Marc Penn, MD, PhD• Co-PI - Warren Sherman, MD
• Sponsors – Athersys/Angiotech
Clinical StudyClinical Study
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• Phase I study, open label, dose escalation– STEMI, LVEF between 30-45%
– Administration of MultiStem in coronary artery (via transarterial catheter) delivered on day 2-5 after Acute MI
– Multiple sites
• Objectives– Primary endpoints: safety: arrhythmias, acute toxicity,
hospitalization, death, mechanical complication
– Secondary endpoints: functionality measure
Clinical SynopsisClinical Synopsis
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Delivery of MultiStem in Post-AMI Delivery of MultiStem in Post-AMI PatientPatient
5 sec 30 sec 60 sec
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Advantage of the System Advantage of the System Approach Approach
• We have developed a clinically translatable system that allows for delivery of cell therapy to the myocardium at any time post primary PCI
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MAPC Reduces Inflammation MAPC Reduces Inflammation
PBS
MAPC
Elastase staining in infarcted hearts
Neutrophil count in infarcted hearts
Rat AMI Model•LAD ligation and direct MAPC injection in infarct zone
•Sacrifice after 3 days
0
10
20
30
40
50
PBS MAPC
**
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UpdateUpdate
• Cohort 1 with 20 million cells completed
• Cohort 2 with 50 million cells is enrolling
• Cohort 3 with 100 million cells is pending
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Where next?Where next?
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Stem Cell Based Tissue Stem Cell Based Tissue RepairRepair
• We proposed several years ago that:– Stem cell based repair of ischemic tissue in
mammals is a natural process but clinically inefficient due to dysregulation or short term expression of key molecular signals
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Stromal Cell-Derived Factor-1Stromal Cell-Derived Factor-1(SDF-1)(SDF-1)
• Chemokine – receptor CXCR4/CXCR7
• Induces stem cell homing to bone marrow
• Lethal knockout secondary to abnormal hematopoietic trafficking
• SDF-1:CXCR4 blocks apoptotic cell death
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Hypothesis: Hypothesis: Cell Therapy Induces Cell Therapy Induces Myocardial Repair by Temporally Aligning Myocardial Repair by Temporally Aligning
the SDF-1: CXCR4 axisthe SDF-1: CXCR4 axis
Time after Ischemic Injury
SDF-1
CXCR4
Exp
ress
ion
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Time after Ischemic Injury
SDF-1
CXCR4
Exp
ress
ion
Ischemic PreconditioningPretreat MSC with hypoxiaOver-express CXCR4Growth Factors: IGF-1 & FGF2Exogenous CD34+
SDF-1 DeliveryMSC EngraftmentBMMNC Infusion
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MSC Over-expressing SDF-1MSC Over-expressing SDF-1
0
200
400
600
0 6 12 18 24
T ime (h)
SD
F-1
Co
nce
ntr
atio
n in
Med
ia (
pg
/ml)
MSC
MSC:SDF-1
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SDF-1 Leads to Preservation of SDF-1 Leads to Preservation of Cardiac MyocytesCardiac Myocytes
MSC:SDF-1Saline MSC
Cardiac Myosin
5 weeks after AMI5 weeks after AMI
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SDF-1 Over-expression SDF-1 Over-expression Improves Cardiac FunctionImproves Cardiac Function
Eje
ctio
n F
ract
ion
(%
)
0
10
20
30
40
50
60
70
W eeks after AM I
0 1 2 3 4 5
S aline
MS C
MS C :S D F -1
78%
228%
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SDF-1 Efficacy in PigsSDF-1 Efficacy in Pigs
Saline or control plasmid delivered 3 month after AMI
Endoventricular injection using Biocardia Catheter
Echo 30 day after injection
AWMI model in Pig
90 min Balloon occlusion of LAD
EF ~35%
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SDF-1 Efficacy in PigsSDF-1 Efficacy in Pigs
-20
-10
0
10
20
30
% C
ha
ng
e in
EF
-30
-20
-10
0
10
20
30
40
PBS SDF-1 PBS SDF-1
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SDF-1 Efficacy in PigsSDF-1 Efficacy in Pigs
% C
ha
ng
e in
EF
30 d 60 dTime after Treatment
30 d 60 dTime after Treatment
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•SDF-1 Delivery 1 month after MI
•Baseline EF 31.2%
•N = 3-5 animals per dose
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Can we test this hypothesis?Can we test this hypothesis?
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CXCR4 is not required for Cardiac CXCR4 is not required for Cardiac Myocyte Development or FunctionMyocyte Development or Function
MCM-Cre: CXCR4f/f MLC-2v: CXCR4f/f
•No VSD
•No differences in EF, radial strain or circumferential strain compared to littermates lacking MLC-2v
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SummarySummary
• “Classical” bone marrow derived mononuclear cells are progressing through clinical trials
• Novel cell types and delivery systems are offering the flexibility to deliver cell therapy at any time after reperfusion– Testing of hypotheses directly in clinical populations
• Defining mechanisms of action may allow for the development of novel therapeutic targets
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Funding SourcesAmerican Heart AssociationNIHShalom FoundationSkirball FoundationState of OhioWilson Foundation
Commecial CollaborationsAthersys - MAPC studies
Bioheart Inc-SKMB:SDF-1 Preclinical and Clinical trials
Juventas Therapeutics- SDF-1 Clinical Development
AcknowledgementsAcknowledgements
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Maritza Mayorga, PhD Jing Bian, PhDIndu Deglurkar, MD Niladri Mal, MDArman Askari, MD Samuel Unzek, MDZoran Popovic, MD Soren Schenk, MDNikolai Vasilyev, MD Kai Wang, MD, PhDMing Zhang, MD, PhD Xiaorong Zhou, MDMazen Khalil, MD Dominik Wiktor, MDYu Peng, MD
Udit Agarwal Srividia SundararamanAmanda Finan Nikolai Sopko
Farhad Forudi, BSMatthew Kiedrowski, BSKristal Weber, BS
CCFStephen Ellis, MDRavi Nair, MDPhil Howe, PhDJames Thomas, MD
CWRUStan Gerson, MD
AcknowledgementsAcknowledgements