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Governance of stem cell therapyConsequences of innovation
Prof. Dr. med. Gustav Steinhoff
Department of Cardiac Surgery
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Bergmann, O. et al. : Turnover after the fallout: Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102
Exchange of cardiomyocytes
Method: Integration of carbon-14, generated by nuclear bomb tests indicates age of cardiomyocytes
Results:1% turning over annually (age dependent)
Fewer than 50% of cardiomyocytesare exchanged at the age of 75
Conclusion: “… it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.”
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
LVEF Wall motion score index
5%
What are the effects of CABG surgery?
3
Knapp, M et. al.: Myocardial contractility improvement after coronary artery by-pass grafting in a 1-year observation: The role of myocardial viability assessment, Card. J., 2007, 246–251
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
mod. Dimmeler et al. JCI 2005
directapplication
mobilization
Cardiac Stem Cell Therapy
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Cell delivery
1.Mobilization (G-GSF)2.Systemic iv injection
3.Intracoronary injection4.Endocardial injection
NOGA
Local implantation imPatch TE
Heart valve TE
Action
HomingExtravasation
Stem / Progenitor Cell
Action
SurgeryCardiology
Problems observed
2001: First clinical stem cell application in heart disease (Strauer, Steinhoff)
Strauer, DüsseldorfIntravascular application MNC BM 3/2001
Steinhoff, RostockIntramyocardial application CD133 BMSC 6/2001
IntegrationMigration
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Combined Revascularization (Stent, CABG)• Acute myocardial infarction (immediately - days)• Early after myocardial infarction (< 2 weeks)• Chronic ischemia: Myocardial transition / remodeling
phase (2 weeks – several months)
Stand alone• Completed remodeling / scar postischemic
cardiomyopathy (>6 months)• Refractory angina• Chagas disease
Clinical indication – acute/chronic ischemia, post infarction
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Stem cell “homing” and vascular activity
8
*
Kaminski A et al. (Lab Investigation 2008)
Intravital fluorescence microscopy in murine cremaster muscle
Intravascular application
Role of endothelial NOS, SDF-1 alpha and local inflammation
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Aspects of ventricular remodeling after infarction
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Slezak et al. 2009
Connexin 43+ gap junctions
Control Hibernation
Myocardial infarction in a mouse heart
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
In vitro differentiation of endothelial cells from CD133-positive origin
Ong LL et al, Tissue engineering Part C, 2010
020406080
100120140160
CFU
-EC
(%)
0h 24h 48h 72h
P < 0.005 P < 0.005
Biological Interaction Network Effect of hypoxia on the differentiation of CD133
CD133+ cell product from human bone marrow
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1.5% [vol/vol] oxygen and 5% [vol/vol] carbon dioxide
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Hypothesis
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Intramyocardial CD133+ stem cell treatment
leads to
better recovery of hibernating myocardium
in addition to CABG surgery.
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
CD133+ stem cell preparation and transplantation
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
CD133+ stem cell preparation and transplantation
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Clinical setting: CD133+ Isolation with CliniMACS-unit Miltenyi Biotec
Direct injectioninto myocardium
150–200ml
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
LAD
Posteriorinterventricular
Lateral LV
viability / stress induced ischemia / reduced wall thickening
Target area for intramyocardial transepicardial injection
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
A
C
B
Analysis of stem cell related effects during CABG
Clinical case reports (CD133+, n= …)
Clinical trials Rostock Phase I (CABG + CD133+, n=15)
Rostock Phase II (CABG + CD133+, n=20)
Meta Analysis (CABG + stem cells, n=94)
Phase III Trial PERFECT
Clinical real world Rostock REGISTRY (CABG + CD133+, n=99)
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
74 y.o. ♂Stand-alonestem cell therapy2 monthsafter stentedLAD-infarction
EF 32% EF 47%
pre op 1 year
Case report stand alone CD133+ therapy
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A
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
-10
-5
0
5
10
15
20
25
30
diffe
renc
e in
LVEF
(%)
CABG & CD133+ cells CABG
9.7%
3.4%
p=0.0009
10
20
30
40
50
60
70
preop discharge 6 months 18 months
LVEF
(%)
39±947±6* 50±8*
48±6*
Phase I Trial / 18 months (n=15) Phase II Trial / 6months (n=20 vs. control)
25-35 25-40 25-45 >25
Abso
lute
LVE
F Im
prov
emen
t in
%
0
5
10
15
20
25
30Stem cell groupControl group
subgroup analysisn=35 vs. controln=20 at 6 months
Increase in myocardial
perfusionat 6 months
Rostock phase I/II study early follow-up
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B
Stamm et al. J Thorac Cardiov Surg, 133(3):717-25; 2007
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Myocardial perfusion after CD133 + CABG – 3years
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1 year 3 years
CABG+Stem cell Control
*
*p
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
CT-Scan B
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No cardiac malformation in all analyzed hearts! (MRI/CT)
One slight myocardial calcification without functional relevance in treatment group:
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Study No. of patientsTreatment Control
Age Treatment Control
Sex, male Treatment Control
Baseline LVEF Treatment Control
Follow-up LVEF Treatment Control
Change of LVEF Treatment Control
Stamm et al2007, Germany
20 20 62.0±10.2 63.5±8.4 75 80 37.4±8.4 37.9±10.3 47.1±8.3 41.3±9.1 9.7±8.8 3.4±5.5
Hendrikx et al2006, Belgium
10 10 63.2±8.5 66±9.2 100 70 42.9±10.3 39.5±5.5 48.9±9.5 43.1±10.9 6.1±8.6 3.6±9.1
Ahmadi et al2007, Iran
18 9 48.6±9.8 50.9±4.7 91.6 57.1 34.3±6.4 29.2±7.8 38.0±5.5 34.3±8.4 3.7±6.3 5.1±4.5
Mocini et al2005, Italy
18 18 64.4±8.6 66.9±4.5 94.4 94.4 46.0±6 48.0±8 51.0±9 49.0±9 5.0±8.3 1.0±4.8
Patel et al2005, USA
10 10 64.8±3.9 63.6±4.9 80 80 29.4±3.6 30.7±2.5 46.9±1.9 37.2±3.4 16.7±3.2 6.5±1.8
Zhao et al2008, China
18 18 60.3±10.4 59.1±15.7 83.3 83.3 35.8±7.3 36.7±9.2 49.1±9.7 40.6±8.4 13.3±9.2 3.9±4.9
Stamm et al. 2007
Hendrikx et al. 2006
Ahmadi et al. 2006
Moccini et al.2005
Patel et al. 2005
Zhao et al. 2006
Peter Donndorf et al., in review
B Meta analysis Intramyocardial bone marrow stem cell therapy during CABG
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
RR Cardiovascular Events.1 1 10
Combined
Zhao et al. 2008
Patel et al. 2005
Mocini et al. 2005
Ahmadi et al. 2006
Hendrikx et al. 2006
Stamm et al. 2007
Forrest Plot Fixed Effects
Major adverse cardiovascular eventsComposite of cardiac death, recurrent MI, revascularisation procedure and stroke
Favours BMSC Favours control
Combined
(95% CI)
Study
Stamm et al. 2007
Hendrikx et al. 2006
Ahmadi et al. 2006
Moccini et al.2005
Patel et al. 2005
Zhao et al. 2006
n=179
Meta analysis Intramyocardial bone marrow stem cell therapy during CABG
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B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Overall (I-squared = 81.7%, p = 0.000)
Ahmadi et al. 2006
Zhao et al. 2008
Hendrikx et al. 2006
ID
Study
Mocini et al. 2005
Patel et al. 2005
Stamm et al. 2007
6.94 (5.38, 8.51)
-1.40 (-5.57, 2.77)
9.40 (4.58, 14.22)
2.50 (-5.26, 10.26)
WMD (95% CI)
4.00 (-0.43, 8.43)
10.20 (7.92, 12.48)
6.30 (1.75, 10.85)
100.00
14.04
10.53
4.05
Weight
%
12.44
47.14
11.80
6.94 (5.38, 8.51)
-1.40 (-5.57, 2.77)
9.40 (4.58, 14.22)
2.50 (-5.26, 10.26)
WMD (95% CI)
4.00 (-0.43, 8.43)
10.20 (7.92, 12.48)
6.30 (1.75, 10.85)
100.00
14.04
10.53
4.05
Weight
%
12.44
47.14
11.80
Favours Control Favours BMSC
0-5.57 6.94 14.2
Forest Plot Fixed Effects
LVEF change (95%CI)
p=0,001)
Meta analysis Intramyocardial bone marrow stem cell therapy during CABG
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B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Overall ( I-squared = 0.0%, p = 0.715)
Stamm et al. 2007
ID
Patel et al. 2005
Study
Ahmadi et al. 2006
-14.28 (-28.87, 0.32)
-6.50 (-30.46, 17.46)
WMD (95% CI)
-18.00 (-39.11, 3.11)
-21.60 (-59.18, 15.98)
100.00
37.11
Weight
47.81
%
15.09
-14.28 (-28.87, 0.32)
-6.50 (-30.46, 17.46)
WMD (95% CI)
-18.00 (-39.11, 3.11)
-21.60 (-59.18, 15.98)
100.00
37.11
Weight
47.81
%
15.09
Favours BMSC Favours Control
0-59.2 -14.3 17.5
Forest Plot Fixed Effects
LVEDV follow-up (95%CI)
Stamm et al. 2007
Ahmadi et al. 2006
Patel et al. 2005
Overall (I-squared= 0.0%,p=0.715)
-6.50(-30.46,17.46) 37.11
-21.60(-59.18,15.99) 15.09
-18.00(-39.11,3.11) 47.81
-14.28(-28.87,0.32) 100.00
Study
WMD(95% CI)
%
Weight
-59,2 -14.3 0 17.5
Meta analysis Intramyocardial bone marrow stem cell therapy during CABG
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B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Conclusion and plans
A Phase-I clinical feasibility and safety study in 15 CABG patients showed that intramyocardial injection of autologous CD133+ bone marrow cells was not associated with cell-related complications in longterm analysis 1,2.
In a subsequent Phase-II randomized, controlled, and prospective clinical trial in 40 patients, CABG & intramyocardial injection of CD133+ bone marrow cells resulted in better LV ejection fraction and perfusion than CABG only 3. Longterm safety of the treatment couldbe confirmed 4.
Phase-III clinical study investigation (multicentre double-blindedrandomized trial) is planned to finish in 2012 for definitive clinicalintroduction in the treatment of chronic ischemia after myocardialinfarction.
1 Stamm et al. Autologous bone marrow stem-cell transplantation for myocardial regeneration. Lancet, 361(9351);45-6; 20032 Stamm et al. CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac Cardiov Surg, 52(3):152-8; 20043 Stamm et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart
disease: safety and efficacy sturdies. J Thorac Cardiov Surg, 133(3):717-25; 20074 Yerebakan et al. Safety of intramyocardial stem cell therapy for the ischemic myocardium: Results of the Rostock trial after five year
follow-up. Cell transplantation 2007; 16(9): 935-40.
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
PERFECT Phase III Studya controlled, prospective, randomized, double blinded multicenter
trial
PERFECTINTRAMYOCARDIAL TRANSPLANTATION OF BONE MARROW STEM CELLS FOR IMPROVEMENT OF POST-INFARCT MYOCARDIAL REGENERATION IN ADDITION TO
CABG SURGERY
Principal investigator: Prof. Dr. G. SteinhoffSponsor: Miltenyi-Biotec GmbH
German study centers: Berlin Heart CenterMedical School Hannover
University of Rostock
Approved (Phase III clinical trial) by Paul Ehrlich Institute June 2009First patient: October 2009
Recruitment: 24 monthsPlanned final evaluation: 2012
CLINICAL OUTCOME STUDY
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Inclusion:
Postinfarction (2w-6m), reduced LVEF (25-40%MRI), regional hibernation (MRI), indication CABG, 18-79y
Objectives:
Primary objective: To determine whether injection of autologously-derived bone marrow stem cells yields a functional benefit in addition to the coronary artery bypass graft (CABG) operation as determined by left ventricular heart function (LVEF-MRI).
Secondary objectives: To determine the effects of an injection of autologously-derived bone marrow stem cells on physical exercise capacity, cardiac function, safety and quality of life (QoL).
PERFECT Phase III Studya controlled, prospective, randomized, double blinded multicenter
trial
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
PERFECT Phase III Studya controlled, prospective, randomized, double blinded multicenter
trial 142 Patientsestimated drop-out rate
15%, randomized in an 1:1 ratio, bone marrow
aspiration prior to CABG surgery
71 Patientsto provide 60 evaluable
patientsfor stem cell group200 ml BM harvest
5ml CD133+ cells (1-10x106) suspended in
physiological saline + 10% autologous serumintramyocardially
71 Patientsto provide 60 evaluable
patientsfor placebo group200 ml BM harvest
5ml physiological saline + 10% autologous serum
intramyocardially
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
PERFECT study (pocket cards)
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Inclusion criteria Previous MI (2w–6m) CABG indicated LVEF 25–40%
Exclusion criteria Mitral regurgitation Emergency Cancer Claustrophobia Chronic Hepatitis
Secondary endpoints physical exercise capacity cardiac function safety and quality of life (QoL).
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
screening
6h 24h
discharge 6 month
72h
1. Cell-/Blood analysis: time points
post OPpre OP OP
BMaspiration
Concomitant research to PERFECT
29
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
max 10%of aspired bone marrow
2. Cell analysis
Isolation of CD133+ cells
miRNA profile Characterization (sub-populations, FACS) Parvo-Virus Vitality and proliferation (FACS, CFU-Assay) Angiogenesis in vitro und in vivo
Concomitant research to PERFECT
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B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
3. Blood analysis
All patients (Rostock, Hannover, Berlin): Angiogenesis (VEGF, FGF) Stem cell factors (SCF, SDF-1, GCSF) Heart failure (myoglobin) Inflammation reaction (IL-6, IL-8, TNFα) Immune suppression (IL-10) Endothelial activation (sE-Selectin) Monitoring (CMV, EBV, Parvo, HAMA, AFP) Identification of diagnostic markers
(miRNA, protein patterns)
ca 60 ml
Add. Rostock patients: ca. 90 ml blood
additional time points Angiogenesis in vivo Mobiliziation of endothelial
progenitor cells (FACS, CFU-Hill)
Concomitant research to PERFECT
31
B
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Clinical real world – the REGISTRY program
32
REGISTRY-program treatment of additional cardiovascular indications
long time FU
documentation at Rostock University since 2001
inclusion of further SC-therapy-centers in Germany
start national SC-register for cardiac application
C
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Content of the REGISTRY-Database
33
Database
Patient data
Follow-Up‘s(Laboratory, MRT, Scintigraphy, ECG)
Information about surgery / product
Indication
Screening (Laboratory, MRT, Scintigraphy, ECG)
Check lists, printed forms
C
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
34,1279069836,60869565
38,58461538
0
10
20
30
40
50
60
preop discharge 6 months
LVEF
Linear (LVEF)
REGISTRY / LVEF in CABG + CD133+
34
Improvement in LVEF 6 months after CD133 + CABG treatment: (n = 56)
mean 3.4±10.1 (50% change LVEF > 5%)
*
*p=0.005 vs. preop.
C
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
REGISTRY / Arrhythmia in CABG + CD133+
-10
-8
-6
-4
-2
0
2
4
6
8
preop postop follow-up
Mean change in VES / all beat percentage: -0.8%
CMedian change in number of ventricular ES / h
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
REGISTRY / Survival
Survival 93% in CABG + CD133+(93 out of 99)
vs. 88% in Control Phase II
patient 1 – 10 months (Phase II)patient 2 – 02 months (Registry)patient 3 – 74 months (Phase I)patient 4 – 07 months stroke (Phase I)patient 5 – 81 months (Phase I)patient 6 – 62 months (Registry)
36
C
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
1988 - 2009 Animal models, mechanism and safety research
2001: worldwide first application and phase I study of intramyocardialinjection of purified CD133+ bone marrow stem cells in coronary bypasspatients
2001 – 2006: Safety and efficacy approval in Phase I (2001-2003) andPhase II (2003-2005) clinical trials
Since 2006 Reimbursement by German health insurance companies(sDRG)
2008 Establishment of national reference center for cardiac stem celltherapy (RTC, Rostock)
2001-2009 Clinical safety and efficacy approval in longterm vigilancestudies
9/2009 Start of Phase III clinical outcome study (Sponsor: Miltenyi-BiotecGmbH)
37
Update 2010
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Intramyocardial CD133+ Bone Marrow Stem Cell Therapy,
38
Clinical research(I) (II) (III)
EMEA license
Preclinicalresearch
Standard therapy
2009200320011988
!
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Standardization of cardiac stem cell therapy
•Indication (ischemia/postinfarction/cardiomyopathy/Htx)•Safety (arrhythmia, tumor, calcification)•Dosage/Toxicity•Standardization of cell preparation•Efficacy (longterm, quality of life)•Biodistribution of cells (migration, survival)•Tumorogenicity•Mechanism of action (paracrine, cellular)•Comparison of different stem cell types
•CLINICAL OUTCOME (PE,MACE,QoL)
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Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Department of Cardiac Surgery, University of Rostock
40
This work was supported by the Helmholtz Gemeinschaft, Mecklenburg-Vorpommern (Nachwuchsgruppe Regenerative Medizin Regulation der Stammzellmigration 0402710), BMBF BioChance PLUS (0313191), Miltenyi Biotec, Sonderforschungs-bereich/Transregio 37, B5, B2 and A4; and BMBF Reference andTranslation Center of Cardiac Stem Cell Therapy (2008–2011).
www.cardiac-surgery-rostock.comwww.cardiac-stemcell-therapy.com Cardiac SurgeryA. Liebold / B. Westphal /
A. Kaminski / P. Donndorf /C. Nesselmann / C. Klopsch
Research Partners (RTC)N. Ma / P. Mark / W. Li / D. Furlani /R. Gäbel / W. Wang , C. Lux
Intenational PartnersNU Singapur, Beijing/Hefei/Nankai, ChinaAsahara, CDB/RIKEN, Kobe, JapanRenkeLiToronto, Kanada; Capogrossi, IDI, Rome, ItalyPompilio, Milano, Italy
R&D Partners:Miltenyi Biotec GmbHD-Trust GmbH, BerlinATP GmbH, RostockHelmholtz (GKSS/Teltow)
Clinical Development Partners:A. Haverich, MH HannoverR. Hetzer/C. Stamm, DHZ Berlin
Translation Management G. Tiedemann / J. Große / A. Wagner / J. Gabriel / B.E. Strauer
Governance of stem cell therapy�Consequences of innovationExchange of cardiomyocytesWhat are the effects of CABG surgery?Foliennummer 42001: First clinical stem cell application in heart disease (Strauer, Steinhoff)Foliennummer 6Foliennummer 7Stem cell “homing” and vascular activityAspects of ventricular remodeling after infarction CD133+ cell product from human bone marrow HypothesisCD133+ stem cell preparation and transplantationCD133+ stem cell preparation and transplantationTarget area for intramyocardial transepicardial injectionAnalysis of stem cell related effects during CABGCase report stand alone CD133+ therapyRostock phase I/II studyearly follow-upMyocardial perfusion after CD133 + CABG – 3years CT-Scan Meta analysis Intramyocardial bone marrow stem cell therapy during CABGMeta analysis Intramyocardial bone marrow stem cell therapy during CABGMeta analysis Intramyocardial bone marrow stem cell therapy during CABGMeta analysis Intramyocardial bone marrow stem cell therapy during CABGConclusion and plans�PERFECT Phase III Study�a controlled, prospective, randomized, double blinded multicenter trial PERFECT Phase III Study�a controlled, prospective, randomized, double blinded multicenter trial PERFECT Phase III Study�a controlled, prospective, randomized, double blinded multicenter trial PERFECT study (pocket cards)Concomitant research to PERFECT Concomitant research to PERFECT Concomitant research to PERFECT Clinical real world – the REGISTRY programContent of the REGISTRY-DatabaseREGISTRY / LVEF in CABG + CD133+REGISTRY / Arrhythmia in CABG + CD133+REGISTRY / SurvivalFoliennummer 37Intramyocardial CD133+ Bone Marrow Stem Cell Therapy, Foliennummer 39Foliennummer 40