What‘s New: On classical and
new adult cells?
Marc S. Penn, MD, PhD, FACC
Skirball Laboratory for
Cardiovascular Cellular Therapeutics
Director, Center for Cardiovascular Cell Therapy
Director, Bakken Heart-Brain Institute
Departments of Cardiovascular Medicine,
Biomedical Engineering and Stem Cell Biology
Senior Medical Director, Emerging Businesses
Disclosures
Company Name
Juventas Therapeutics
Intellect, Inc.
Cour Pharmaceuticals
Prognostix, Inc.
Cardionomic, Inc.
Current Relationship
CSO, Equity, Inventor
Equity, Inventor
CMO, Equity
CMO, Equity, Inventor
Equity, Inventor
BioHeart, Inc.,
SAB Member, Licensee
Oakwood Medical Ventures
Venture Partner
Cardax Pharmaceuticals
SAB Member
Athersys, Inc.
SDG, Inc.
CCO Technologies
Cell Targeting
Sponsored Research
Sponsored Research
Sponsored Research
Sponsored Research
Southwest Michigan Fund
MPI Research
Consultant
Consultant
03/2009
Clinical Strategies for Stem
Cell Therapy
Cell Types of Interest
Totipotent
Embryonic Stem Cells
Pluripotent
Umbilical Cord Stem Cells
MAPCs
Mesenchymal SC
CD117-, CD34-, SH-1+
Cardiac Myocytes, Neurons
Skeletal Myoblasts
Hematopoietic SC
CD117+, CD34+
Monocytes, Neutrophils, . . . .
Endothelial Cells, Hepatocytes
Cell Types of Interest
Totipotent
Embryonic Stem Cells
Pluripotent
Umbilical Cord Stem Cells
MAPCs
Mesenchymal SC
CD117-, CD34-, SH-1+
Cardiac Myocytes, Neurons
Skeletal Myoblasts
Hematopoietic SC
CD117+, CD34+
Monocytes, Neutrophils, . . . .
Endothelial Cells, Hepatocytes
Direct Comparison of the Effects of
Allogeneic and Syngeneic MAPC
• LAD ligation in Lewis Rat
• Genetically marked MAPC from
– Lewis Rat (syngeneic)
– SD Rat (allogeneic)
Vascular Effects of MAPC
vWF
PBS
Lewis
SD
SMA
Overlay
Shortening Fraction (%)
MAPC into Lewis Rat at Time
of Acute MI
25
20
75%
15
51%
10
5
0
PBS
Lewis
SD
Source of MAPC
6 weeks after Acute MI
10 million MAPC or Saline at time of MI
Summary of Preclinical
MAPC 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
Clinical 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
Adventitial
Micro-Infusion
Adventitial Delivery Catheters
Catheter Operation
Cricket
™
Micro-Infusion Catheter
Bullfrog™
Micro-Infusion
Catheter
2.5 – 3.0 mm treatment range
Both 510(k) cleared for delivery to
vessel wall or perivascular area
3.0 – 6.0 mm
treatment range
Adventitial Micro-Infusion
Catheter Operation
Balloon shields
microneedle
Needle is deployed
with inflation
Needle reaches
adventitia for infusion
Porcine Model
• Anterior wall MI induced by 90 min
balloon occlusion of LAD
• MAPC delivery 2 days post AMI to
animals with EF < 40%
Biodistribution Following
Transarterial Delivery
Biodistribution Following
Transarterial Delivery
Circumferential Distribution of
b-gal positive cells
Radial Distribution of
b-gal positive cells
Acute MI Catheter-Based
Delivery of MAPC
60
Ejection Fraction %
MAPC 50M
Saline
**
*
50
40
30
20
Baseline
1 Wk post-MI
4 Wk post MI
Improvements in Functional
Performance in GLP Study
Circumferential Strain %
At Risk Territory
Non-Risk Territory
Summary of Preclinical
MAPC 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
Clinical Study
MultiStem® in Patients With Acute
Myocardial Infarction
• PI – Marc Penn, MD, PhD
• Co-PI - Warren Sherman, MD
• Sponsors – Athersys/Angiotech
Clinical Synopsis
• 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
Delivery of MultiStem in Post-AMI
Patient
5 sec
30 sec
60 sec
Advantage of the System
Approach
• We have developed a clinically translatable
system that allows for delivery of cell
therapy to the myocardium at any time post
primary PCI
MAPC Reduces Inflammation
Elastase staining in
infarcted hearts
Rat AMI Model
• LAD ligation and direct MAPC
injection in infarct zone
PBS
• Sacrifice after 3 days
Neutrophil count in infarcted hearts
Neutrophils / HPF
50
40
MAPC
30
**
20
10
0
PBS
MAPC
Update
• Cohort 1 with 20 million cells completed
• Cohort 2 with 50 million cells is enrolling
• Cohort 3 with 100 million cells is pending
Where next?
Stem Cell Based Tissue
Repair
• 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
Stromal Cell-Derived Factor-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
Expression
Hypothesis: Cell Therapy Induces
Myocardial Repair by Temporally Aligning
the SDF-1: CXCR4 axis
SDF-1
CXCR4
Time after Ischemic Injury
Ischemic Preconditioning
Pretreat MSC with hypoxia
Over-express CXCR4
Growth Factors: IGF-1 & FGF2
Exogenous CD34+
Expression
SDF-1 Delivery
MSC Engraftment
BMMNC Infusion
SDF-1
CXCR4
Time after Ischemic Injury
MSC Over-expressing SDF-1
SDF-1 Concentration in
Media (pg/ml)
600
MSC
MSC:SDF-1
400
200
0
0
6
12
T ime (h)
18
24
SDF-1 Leads to Preservation of
Cardiac Myocytes
Cardiac
Myosin
40
(% In fa rct Z o n e )
C ard ia c M yo s in + A rea
Saline
MSC
MSC:SDF-1
5 weeks after AMI
30
20
10
0
Saline
Ctrl
SDF-1
Expressing
MSC Cell Type
SDF-1 Over-expression
Improves Cardiac Function
Ejection Fraction (%)
70
S aline
MSC
60
M S C :S D F - 1
50
40
228%
30
78%
20
10
0
0
1
2
3
4
W ee k s after A M I
5
SDF-1 Efficacy in Pigs
AWMI model in Pig
Saline or control plasmid
delivered 3 month after AMI
90 min Balloon
occlusion of LAD
Endoventricular injection
using Biocardia Catheter
Echo 30 day after injection
EF ~35%
SDF-1 Efficacy in Pigs
30
40
30
% Change in EF
% Change in LVESV
20
10
0
-10
20
10
0
-10
-20
-30
-20
PBS SDF-1
PBS SDF-1
SDF-1 Efficacy in Pigs
30
50
Saline
SDF-1
% Change in EF
% Change in LVESV
40
20
10
0
-10
40
Saline
SDF-1
30
20
10
0
-10
-20
-20
30 d
60 d
Time after Treatment
30 d
60 d
Time after Treatment
40
•N = 3-5 animals
per dose
% Change ESV
•Baseline EF
31.2%
Relative to 1 mo after MI
60 day
30
20
10
0
10
Relative to 1 mo after MI
•SDF-1 Delivery 1
month after MI
% Change EF
30 day
Control
Low
Med
High
Control
Low
Med
High
0
-10
-20
-30
Can we test this hypothesis?
CXCR4 is not required for Cardiac
Myocyte 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
Summary
• “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
Acknowledgements
Funding Sources
American Heart Association
NIH
Shalom Foundation
Skirball Foundation
State of Ohio
Wilson Foundation
Commecial Collaborations
Athersys
- MAPC studies
Bioheart Inc
-SKMB:SDF-1 Preclinical and
Clinical trials
Juventas Therapeutics
- SDF-1 Clinical Development
Acknowledgements
Maritza Mayorga, PhD
Indu Deglurkar, MD
Arman Askari, MD
Zoran Popovic, MD
Nikolai Vasilyev, MD
Ming Zhang, MD, PhD
Mazen Khalil, MD
Yu Peng, MD
Udit Agarwal
Amanda Finan
Farhad Forudi, BS
Matthew Kiedrowski, BS
Kristal Weber, BS
Jing Bian, PhD
Niladri Mal, MD
Samuel Unzek, MD
Soren Schenk, MD
Kai Wang, MD, PhD
Xiaorong Zhou, MD
Dominik Wiktor, MD
Srividia Sundararaman
Nikolai Sopko
CCF
Stephen Ellis, MD
Ravi Nair, MD
Phil Howe, PhD
James Thomas, MD
CWRU
Stan Gerson, MD