Roberto Bolli, M.D.
Los Angeles, CA
c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy
Institute of Molecular Cardiology
University of Louisville
American Heart Association Scientific Sessions American Heart Association Scientific Sessions
Presenter Disclosure
information
FINANCIAL DISCLOSURE: None
UNLABELED/UNAPPROVED USES DISCLOSURE: None
c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy
Roberto Bolli, M.D.
SCIPIO (Study of Cardiac Stem Cells
Infusion in Patients with Ischemic
CardiOmyopathy)
• Phase I, open-label, randomized trial
• Single center
• 20 treated and 13 control patients
• http://clinicaltrials.gov/ct2/show/NCT00474461
Publius Cornelius Scipio Africanus
(235–183 BC)
SCIPIO (Study of Cardiac Stem Cells
Infusion in Patients with Ischemic
CardiOmyopathy)
Piero Anversa Annarosa Leri Jan Kajstura Domenico D’Amario
John Loughran Atul Chugh Brandon Elmore Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache
Institute of Molecular Cardiology
Brigham and Women’s Hospital
Primary Objective
1. To assess the feasibility and safety of infusing autologous
c-kitpos CSCs in patients with ischemic heart failure.
Secondary Objective
2. To obtain preliminary evidence for or against the efficacy
of CSCs in augmenting LV function, improving functional
status, and promoting myocardial regeneration.
The overall goal is to translate the discovery of CSCs
into clinically useful therapies.
SCIPIO: Objectives
SCIPIO: Time Line
A result of many years of preclinical work:
Trial opened to
enrollment in
February 2009
First CSC infusion
July 17, 2009
FDA contacted
in October
2004
2004 2012
IND application
submitted on
January 2006
2006
FDA
approval on
August 8,
2008
2008 2010
First patient
enrolled on
March 13,
2009
Last Patient
Enrolled
May 17,
2011
November 14, 2011
LVEF ≤ 40%
A history of Q-wave MI with a residual scar (as evidenced by ECG, cardiac MRI, low-dose dobutamine stress echo, and/or rest perfusion images on a sestamibi SPECT study)
Patient scheduled for CABG within 2 weeks of the initial screening.
SCIPIO
Inclusion Criteria
Enrollment CABG & Tissue
Harvesting
< 2 Weeks
SCIPIO: Protocol
At the time of CABG, the right atrial appendage is resected and
prepared for CSC isolation
CSC isolation and expansion
Enrollment CABG & Tissue
Harvesting
< 2 Weeks
SCIPIO: Protocol
4 ± 1 Months
•Cardiac MRI
•2-D & 3-D Echo • ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class
assessment
Follow-Up
2 Years
CSC
Infusion
SCIPIO: Protocol
CSC
Rx
• ECG x 3
• BMP, LFTs
•CBC
•Cardiac enzymes x
3
• Physical exam
•2-D & 3-D Echo • 24-h Holter monitor
• ECG
• BMP & LFTs
•CBC, & cardiac enzymes
• Physical Exam
•2-D & 3-D Echo • 24-h Holter monitor
• ECG
• BMP & LFTs
• CBC, & cardiac enzymes
• Physical Exam
Follow-up 24h Week 1 Week 2 Week 4 Month 4
• ECG
• BMP, LFTs
•CBC
•Cardiac enzymes
• Physical exam
•2-D & 3-D Echo
•Cardiac MRI • ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class
assessment
CSC
Rx
Follow-up Month 8 Year 1 Year 2
• 2-D & 3-D Echo
•Cardiac MRI
• ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class assessment
• ECG
• BMP, LFTs
•CBC
• 2-D & 3-D Echo
•Cardiac MRI • ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class assessment
SCIPIO: Protocol
SCIPIO
Phenotype of CSCs
SCIPIO: Phenotype of CSCs
SCIPIO: Phenotype of CSCs
SCIPIO
Phenotype of CSCs
SCIPIO: Phenotype of CSCs
SCIPIO: Phenotype of CSCs
SCIPIO:
Phenotype
of CSCs
Telomere Length
SCIPIO: Phenotype of CSCs
SCIPIO: Results
Ejection Fraction at 4 Months After CSCs
Absolu
te E
F U
nits
Baseline 4 months Pre-CSC 4 months
Controls (n=7) CSC-treated (n=14)
0
20
40
60
30.3±1.9
38.5±2.8
P=0.001
30.1±2.4 30.2±2.5
0
5
10
15
20
SCIPIO: Results
Change in Ejection Fraction After
CSC Treatment
4 months
P=0.001
8.2±2.0
12.3±2.1
Absolu
te E
F U
nits
P<0.001
12 months
n=14 n=8
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
Ejection Fraction (MRI) After CSC Therapy
4 months 12 months Pre-CSC
n=8 n=8 n=5
27.5
35.1
41.2
Absolu
te E
F u
nits
SCIPIO: MRI Results
P=0.004
P=0.013
0
5
10
15
20
25
Change in Ejection Fraction (MRI)
After CSC Therapy
n=5 n=8
P=0.004
7.7±1.8
P=0.013
13.6±3.2
ΔE
F (a
bsolu
te E
F u
nits)
4 months 12 months
0
5
10
15
20
25
0
5
10
15
20
25
SCIPIO: MRI Results
Baseline EF:
27.5%
0
10
20
30
40
0
10
20
30
40
-40
-20
0
20
40
60
80
-40
-20
0
20
40
60
80
-40
-20
0
20
40
60
80
-40
-20
0
20
40
60
80
-40
-20
0
20
40
60
80
-40
-20
0
20
40
60
80
Regional Ejection Fraction in Infarct-Related
Segments After CSC Therapy
n=8 n=8 n=5
10.3
24.5 21.5
Pre-CSC 4 months 12 months
Absolu
te E
F u
nits
4 months 12 months
n=5 n=8
P=0.008
14.2±3.9
P=0.085
17.9±7.9
ΔE
F (a
bsolu
te E
F u
nits)
SCIPIO: MRI Results
0
10
20
30
40
0
10
20
30
40
50P=0.008
n=8
24.5±6.4
10.3±6.9
Pre-CSC 4 months
P=0.085 n=5
21.5±7.3
3.5±6.7
Pre-CSC 12 months
Absolu
te E
F u
nits
Regional Ejection Fraction (MRI) in Infarct-
Related Segments After CSC Therapy
SCIPIO: MRI Results
0
20
40
60
80
-40
-20
0
20
40
Regional Ejection Fraction in Dyskinetic Segments
After CSC Therapy
4 months 12 months Pre-CSC
n=7 n=7 n=4
-20.6
3.9 7.9
Absolu
te E
F u
nits
ΔE
F (a
bsolu
te E
F u
nits)
n=4 n=7
P=0.014
24.5±7.1
P=0.030
35.7±9.1
4 months 12 months
SCIPIO: MRI Results
0
20
40
60
80
0
20
40
60
80
-100
-80
-60
-40
-20
0
20
40
60
80
Regional Ejection Fraction in the Least Functional
Segment After CSC Therapy
4 months 12 months Pre-CSC
n=8 n=8 n=5
-32.7
-7.1 2.7
Absolu
te E
F u
nits
ΔE
F (a
bsolu
te E
F u
nits)
n=5 n=8
P=0.020
25.6±8.5
P=0.023
40.2±11.3
4 months 12 months
SCIPIO: MRI Results
0.0
0.5
1.0
1.5
2.0
2.5
3.0
SCIPIO: Results
Global Wall Motion Score Index 4 Months
After CSC Treatment
Baseline 4 months Pre-CSC 4 months
Controls (n=7) CSC-treated (n=14)
P=0.005
1.91 1.73
1.89 1.88
0
1
2
3
4
5
Global WMSI After CSC Treatment in Patients
Who Have Completed 12 Month Follow-up
4 months Pre-CSC 12 months
P=0.010
P=0.008
n=8
1.99±0.08 1.73±0.10 1.68±0.12
SCIPIO: Results
SCIPIO:
Infarct Regression
Before CSCs 24 months after CSCs
-30
-25
-20
-15
-10
-5
0
10
20
30
40
50
0
10
20
30
40
50
0
10
20
30
40
50
0
10
20
30
40
50
0
10
20
30
40
50
SCIPIO: MRI Results
Change in Infarct Size by CMR Using a Semi-
automated (FWHM) Method After CSC
Treatment
0
10
20
30
40
50
-30
-25
-20
-15
-10
-5
-30
-25
-20
-15
-10
-5
n=6 n=9
P=0.003
-15.2±2.8
-44.8%
P<0.001
-13.3±2.3
-38.1%
4 months 12 months 4 months 12 months Pre-CSC
Mass
(g)
Change
in m
ass
(g) n=9 n=9 n=6
34.9
21.6 18.7
-30
-25
-20
-15
-10
-5
SCIPIO: MRI Results
Change in Non-Viable Tissue by CMR After
CSC Treatment
0
10
20
30
40
50
60
0
10
20
30
40
50
60
0
10
20
30
40
50
60
0
10
20
30
40
50
60
0
10
20
30
40
50
60
0
10
20
30
40
50
60
4 months 12 months Pre-CSC
Mass (
g)
n=9 n=9 n=6
24.1
12.1 10.4
Change in m
ass (
g)
-30
-25
-20
-15
-10
-5
-30
-25
-20
-15
-10
-5
-12.0±2.5
P=0.001
-49.7% -14.8±3.9
P=0.013
-58.6%
n=9 n=6
4 months 12 months
0
10
20
30
40
50
60
70
0
50
100
150
200
250
300
SCIPIO: MRI Results
4 months 12 months Pre-CSC
Mass (
g)
Change in m
ass (
g)
4 months 12 months
n=9 n=9 n=6
151.1 162.6 177.8
n=9 n=6
0
20
40
60
0
20
40
60
7.6% 11.6±5.2
P=0.055
21.5% 31.5±11.0
P=0.035
Change in Viable Tissue by CMR After CSC
Treatment
0
1
2
3
4
Baseline 4 months Pre-CSC 4 months
Controls (n=7) CSC-treated (n=16)
P=0.172 P=0.003
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
2.0±0.0 1.7±0.2
New York Heart Association Score 4
Months After CSC Treatment
2.2±0.2
1.6±0.2
SCIPIO: Results
0
1
2
3
4
5
6
NYHA Score After CSC Treatment in Patients
Who Have Completed 12 Month Follow-up
4 months Pre-CSC 12 months
P=0.024
P=0.004
n=10
2.4±0.22
1.8±0.20 1.5±0.17
SCIPIO: Results
0
20
40
60
80
0
20
40
60
80
0
20
40
60
80
0
20
40
60
80
0
20
40
60
80
Pre-CSC 4 months Baseline 4 months
Controls (n=7) CSC-treated (n=16)
P<0.001
MLHFQ Score 4 Months After
CSC Treatment
38.1±10.5
40.4±9.2 46.4±5.2
26.7±4.9
SCIPIO: Results
MLHFQ After CSC Treatment in Patients
Who Have Completed 12 Month Follow-up
0
20
40
60
80
0
20
40
60
80
0
20
40
60
80
0
20
40
60
80
4 months Pre-CSC 12 months
P<0.001
P=0.007 n=10
41.7±7.5
27.7±6.9 23.5±8.0
SCIPIO: Results
i) Feasibility and safety
The initial results of SCIPIO indicate that, in patients
with ischemic cardiomyopathy:
1. Isolation, expansion, and infusion of a highly pure
population of c-kitpos CSCs are feasible in virtually
all cases.
2. It is possible to obtain viable CSCs with high
telomerase activity and telomeres >7 kbp.
3. Intracoronary infusion of autologous CSCs is not
associated with appreciable adverse effects.
SCIPIO: Summary
ii) Efficacy
The initial results of SCIPIO indicate that:
4. Infusion of CSCs results, 4 months later, in a
reduction in infarct size, an increase in viable
myocardium, and a marked improvement in LV
EF, NYHA functional class, and quality of life
(MLHFQ).
5. These effects persist and are even more pronounced
at 1 year.
SCIPIO: Summary
The initial results of SCIPIO suggest that administration of
autologous c-kitpos CSCs is feasible and safe and produces
a sustained increase in viable myocardium, LV systolic
function, and functional capacity in patients with ischemic
cardiomyopathy.
Larger, Phase II studies are warranted.
SCIPIO: Conclusions
Acknowledgments Xian-Liang Tang Yiru Guo Gregg Rokosh Qianghong Li Atul Chugh John Loughran Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache Mark Slaughter
Boston group Piero Anversa Annarosa Leri Jan Kajstura
Institute of Molecular Cardiology
Thank You