Department of Cardiac Surgery
Governance of stem cell therapy Consequences of innovation Prof. Dr. med. Gustav Steinhoff
Exchange of cardiomyocytes Bergmann, O. et al. : Turnover after the fallout: Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102
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 cardiomyocytes are 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.”
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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What are the effects of CABG surgery? 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
LVEF
Wall motion score index 5%
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Cardiac Stem Cell Therapy
direct application
mobilization
mod. Dimmeler et al. JCI 2005
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Cell delivery
2001: First clinical stem cell application in heart disease (Strauer, Steinhoff) Stem / Progenitor Cell
Cardiology
Surgery
1.Mobilization (G-GSF) 2.Systemic iv injection 3.Intracoronary injection 4.Endocardial injection NOGA
Local implantation im Patch TE Heart valve TE
Homing Extravasation
Integration Migration
Action
Action
Strauer, Düsseldorf Intravascular application MNC BM 3/2001
Problems observed
Steinhoff, Rostock Intramyocardial application CD133 BMSC 6/2001
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Clinical indication – acute/chronic ischemia, post infarction
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 Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Stem cell “homing” and vascular activity Role of endothelial NOS, SDF-1 alpha and local inflammation
*
Intravascular application
Intravital fluorescence microscopy in murine cremaster muscle Kaminski A et al. (Lab Investigation 2008) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Aspects of ventricular remodeling after infarction
Myocardial infarction in a mouse heart
Control
Hibernation
Connexin 43+ gap junctions Slezak et al. 2009
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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CD133+ cell product from human bone marrow In vitro differentiation of endothelial cells from CD133-positive origin Ong LL et al, Tissue engineering Part C, 2010
P < 0.005
P < 0.005
160 CFU-EC (%)
140 120 100 80 60 40 20 0
Biological Interaction Network
0h
24h
48h
72h
Effect of hypoxia on the differentiation of CD133 1.5% [vol/vol] oxygen and 5% [vol/vol] carbon dioxide
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Hypothesis
Intramyocardial CD133+ stem cell treatment leads to better recovery of hibernating myocardium in addition to CABG surgery.
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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CD133+ stem cell preparation and transplantation
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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CD133+ stem cell preparation and transplantation 150–200ml
Clinical setting: CD133+ Isolation with CliniMACS-unit Miltenyi Biotec
Direct injection into myocardium
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Target area for intramyocardial transepicardial injection viability / stress induced ischemia / reduced wall thickening LAD
Lateral LV
Posterior interventricular
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Analysis of stem cell related effects during CABG A Clinical case reports
(CD133+, n= …)
B 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
C Clinical real world
Rostock REGISTRY (CABG + CD133+, n=99)
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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A
Case report stand alone CD133+ therapy
74 y.o. ♂ Stand-alone stem cell therapy 2 months after stented LAD-infarction
pre op
EF 32% Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
1 year
EF 47% 16
Rostock phase I/II study
B
Phase I Trial / 18 months (n=15)
early follow-up Phase II Trial / 6months (n=20 vs. control) 25
50
47±6*
50±8*
48±6*
39±9
40 30
difference in LVEF (%)
60
LVEF (%)
p=0.0009
30
70
20
20 15
9.7%
10 5
3.4%
0 -5 -10
10 preop
discharge
6 months
18 months
CABG & CD133+ cells
CABG
Absolute LVEF Improvement in %
Stamm et al. J Thorac Cardiov Surg, 133(3):717-25; 2007
Increase in myocardial perfusion at 6 months
30 Stem cell group Control group
25 20 15 10 5 0 25-35
25-40
25-45
>25
subgroup analysis n=35 vs. control n=20 at 6 months
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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B
Myocardial perfusion after CD133 + CABG – 3years
1,4
*
1,2 1
Preoperative value=1
0,8 0,6 0,4 0,2 0 1 year
3 years
CABG+Stem cell
Control
*p 5%) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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C
REGISTRY / Arrhythmia in CABG + CD133+ Median change in number of ventricular ES / h
8 6 4 2 0 -2
preop
postop
f ollow-up
-4 -6 -8 -10
Mean change in VES / all beat percentage: -0.8% Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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C
REGISTRY / Survival
Survival vs.
93% in CABG + CD133+(93 out of 99) 88% in Control Phase II patient 1 – patient 2 – patient 3 – patient 4 – patient 5 – patient 6 –
10 months (Phase II) 02 months (Registry) 74 months (Phase I) 07 months stroke (Phase I) 81 months (Phase I) 62 months (Registry)
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Update 2010
1988 - 2009 Animal models, mechanism and safety research 2001: worldwide first application and phase I study of intramyocardial injection of purified CD133+ bone marrow stem cells in coronary bypass patients 2001 – 2006: Safety and efficacy approval in Phase I (2001-2003) and Phase II (2003-2005) clinical trials Since 2006 Reimbursement by German health insurance companies (sDRG) 2008 Establishment of national reference center for cardiac stem cell therapy (RTC, Rostock) 2001-2009 Clinical safety and efficacy approval in longterm vigilance studies 9/2009 Start of Phase III clinical outcome study (Sponsor: Miltenyi-Biotec GmbH)
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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Intramyocardial CD133+ Bone Marrow Stem Cell Therapy,
Preclinical research
1988
Clinical research (I) (II) (III)
2001
2003
EMEA license
Standard therapy
2009
!
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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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) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
Department of Cardiac Surgery, University of Rostock www.cardiac-surgery-rostock.com www.cardiac-stemcell-therapy.com
Cardiac Surgery A. 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 Partners NU Singapur, Beijing/Hefei/Nankai, China Asahara, CDB/RIKEN, Kobe, Japan RenkeLiToronto, Kanada; Capogrossi, IDI, Rome, Italy Pompilio, Milano, Italy R&D Partners: Miltenyi Biotec GmbH D-Trust GmbH, Berlin ATP GmbH, Rostock Helmholtz (GKSS/Teltow) Clinical Development Partners: A. Haverich, MH Hannover R. Hetzer/C. Stamm, DHZ Berlin
This work was supported by the Helmholtz Gemeinschaft, Mecklenburg-Vorpommern (Nachwuchsgruppe Regenerative Medizin Regulation der Stammzellmigration 0402710), BMBF BioChance PLUS (0313191), Miltenyi Biotec, Sonderforschungsbereich/Transregio 37, B5, B2 and A4; and BMBF Reference and Translation Center of Cardiac Stem Cell Therapy (2008–2011).
Translation Management G. Tiedemann / J. Große / A. Wagner / J. Gabriel / B.E. Strauer
Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock
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