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Jozef Bartunek Cardiovascular Center, Aalst, Belgium

What’s New? On Adult Stem Cells?. Jozef Bartunek Cardiovascular Center, Aalst, Belgium Faculty of Biomedical Engineering, TU Eindhoven, NL. 5 th International Symposium on Stem Cell Therapy & Applied Biotechnology Madrid, April 2008.

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Jozef Bartunek Cardiovascular Center, Aalst, Belgium

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  1. What’s New? On Adult Stem Cells? Jozef Bartunek Cardiovascular Center, Aalst, Belgium Faculty of Biomedical Engineering, TU Eindhoven, NL 5th International Symposium on Stem Cell Therapy & Applied Biotechnology Madrid, April 2008 JB is a member of an institution which is a founding member of Cardio3 Biosciences

  2. Adult Stem Cells for Cardiac RepairFramework towards the optimization • PATIENT • Disease • Risk Profile • Bone Marrow • CELL PRODUCT • Type • Processing • Function and number STEM CELL THERAPY CELL DELIVERY • “MECHANISMS AT WORK” • Target organ – heart • Remote Homing • Arrhythmias • Coronary vasculature

  3. Two Clinically Applied Cell Types TX-Brazil/Houston Perin Repair-AMI, ASTAMI Janssens Steinhoff Lancet Diacrin Dib Siminiak EHJ Boost Lancet Bioheart Serruys Tse Lancet Myoblast Galinanes AHA Navarra Magic Menasche Seismic Serruys Zeiher Circulation MacLellan UCLA Strauer Circulation Menasché AHA Bone Marrow Stem Cells Steinhoff Anversa Nature 2000 2006 2008 2000

  4. Adult Stem Cells Therapy for Cardiac Repair Overall clinical safety demonstrated over 1 to 2 years period Abdel-Latif, Arch Intern Med 2007

  5. Adult Stem Cells for Cardiac RepairCell Type Hematopoetic stem cells C-kit+, CD34+, CD133+ CD31+ Endothelial progenitor cells CD34+, CD133+, CD31+, VEGFR 2+, VE-cadherin+ Mononuclear BM cells CD45+, CD14+ ~ 1-2% CD34/CD133+ Cardiac Repair Mesenchymal stem cells CD34-, CD45-, Adherent, CD90+ Skeletal Myoblasts

  6. Similar functional effects EPC vs MNC CD34+ superior to MNC Regional Wall Motion 0.0 -0.5 SD/chord -1.0 * * -1.5 -2.0 CPC BMC Baseline Follow-up Shachinger V, JACC 2004 Kawamoto A, Circulation 2006 Stem Cell Type and Therapeutic Effect Cell type • BM mononuclear fraction delivers functional response • No cell type omitted • Effect ~ cellular cross talk between multiple cell types Potential of enriched (hematopoietic) cell populations should be Investigated

  7. Markers Source Delivery Potential Pre-clinical experience Clinical Studies Hematopoietic stem cells CD133, CD34 CD31 Autologous Allogeneic (umbilical cord) Coronary Myocardial Angiogenic Paracrine Perfusion Function Rand-DB Ongoing BM mesenchymal stem cells CD166, Stro-1, CD44, CD106 Allogeneic Autologous Myocardial Systemic Multipotency Paracrine “Off-shelf” use Function Perfusion Rand-DB Ongoing Adipose-derived stem cells CD49D, Stro-1, CD166, CD44 Autologous Coronary Myocardial Pluripotency Angiogenic Perfusion Rand-DB Ongoing Resident cardiac stem cells C-kit, Sca1, MDR1, Isl1, Autologous Limited? Coronary Myocardial Cardio-myogenic Function Planned Selected/Enriched Adult Stem Cells for Cardiac Repair

  8. Stem Cell Type and Therapeutic EffectDirect Comparison MSCs vs BMNCs • Double-blinded, placebo controlled, randomized study • Direct comparison of autologous BM MNC and autologous culture expanded BM MSCs in the canine model of the chronic myocardial infarction • Multimodality functional and morphological assessment including, echocardiography, MRI and invasive pressure-volume loops • Histology and gene expression analyses Mathieu M, McEntee K, Erasmus, ULB Brussels, ACC 2008

  9. Stem Cell Type and Therapeutic EffectMSCs vs BMNCs • Superior effects of MNC vsMSCs in chronic MI: • Model specific? • Disease/remodelling specific? • Implications for the clinical trials? Mathieu M, Mc Entee K, Erasmus, ULB Brussels, ACC 2008

  10. Osteocalcin, Cy3 EGFP labeled stem cells Stem Cell Type and Therapeutic EffectWord of Caution on Safety? • Mice model of the myocardial infarction (cryoinjury, coronary ligation) • Injection of 2x105 MSCs (passage 3) or total BM from EGFP+ transgenic mice • Follow up from 29 to 268 days. Breitbach M et al, Blood 2007

  11. Adult Stem Cell Therapy Damaged adult heart may not be able to recapitulate necessary millieu to stimulate myocardial specification resulting in the limited efficacy or unwanted signalling/differentiation of “naive” or plastic stem cells Olson, Nat Medicine 2004; Chien, Nature 2004; Wang, J Thorac Cardiovasc Surg 2001, Yoon, Circulation 2004, Breitbach, Blood 2007

  12. From Non-modified Adult Stem Cells to“Second Generation Stem Cell Products” Goals: • to improve cell function • to increase engraftment • to increase integration • to increase cell survival • to guarantee safety • Strategies: • Pharmacological pretreatment • Genetic engineering • Tissue engineering • …..

  13. Improved Cell Function Enhanced Neovascularization “Second Generation Stem Cell Products” Increased efficacy after pretreatment with eNOS Enhancer Sasaki et al, PNAS 2006

  14. 50 40 30 Vascular Density (vessels/mm2) 20 10 0 SKMB AdSDF-1 + - + + Enhanced neovascularization and functional improvement Askari et al., JACC 2004 “Second Generation Stem Cell Products” SDF 1-engineered Skeletal Myoblasts

  15. “Second Generation Stem Cell Products” SCF-engineered MSCs • Stem cell factor binds to c-kit and leads to bone marrow stem cells activation and mobilization • SCF is upregulated in the myocardial tissue after the infarction • Hypothesis: Upregulation of SCF in MSCs leads to more efficient myocardial repair Fazel S et al, AHA 2007

  16. “Second Generation Stem Cell Products” SCF-engineered MSCs - Word of Caution? Stem cell therapy with engineered stem cells may enhance functional effects. However, outcome may be hindered by uncontrolled effect on proliferation and growth with risk of tumor formation if both techniques are combined in “plastic” cells. Fazel S et al, AHA 2007

  17. “Second Generation Stem Cell Products” Cardiomyogenic Specification? “clues” from embryonic development?

  18. “Second Generation Stem Cell Products” Cardiomyogenic Specification? Dog model of chronic myocardial infarction • Injection of culture expanded MSCs • Injection of modified MSCs (coctail of growth factors including BMP2, IGF-1 and bFGF) • Follow-up up to 12 weeks including histology Selected Cardiomyogenic Growth Factors Pretreatment

  19. % LV Wall Thickening % DiI + myosin+ cells/mm2 5 50 % 4 * 40 3 30 2 p=0.037 20 1 10 0 Non-modified BMSCs (n=3) Modified BMSCs (n=5) BL 1 BL 2 4 wks 8 wks 12 wks Modified MSC, n=7 Non-modified MSC, n=4 Non-modified vs Modified BMSCs in a Chronic Dog MI Model Regional LV function and Cell Retention Bartunek et al, AJP 2007

  20. “Second Generation Stem Cell ProductsSelected Cardiomyogenic Growth Factors Pretreatment • Problems encountered: • Only cytoplasmic expression, but no nuclear translocation of cardiac markers • “Terminal’ cardiac commitment (functional excitation-contraction coupling) in vitro was not achieved • Suboptimal reproducibility when treatment applied to mesenchymal stem cells from cardiac patients October 2006 Confidential 20

  21. “Second Generation Stem Cell ProductsHigh Throughput Genomic and Proteomic Technology A. Behfar & A. Terzic Behfar A et al , J Exp Med 2007; Arell et al Stem Cells 2008; Nelson TJ et al, Stem Cells 2008; Faustino RS et al , Genome Biol 2008; Behfar A et al, Nat Clin Pract Cardiovasc Med 2006

  22. “Second Generation Stem Cell ProductsHigh Throughput Genomic and Proteomic Technology Candidate effectors of cardiac differentiation were identified using the comparative proteomics and genomics on the secretome of murine visceral endoderm-like cells in response to TNF-α Behfar et al, J Exp Med 2007; Arell et al , Stem Cells 2008

  23. “Second Generation Stem Cell ProductsHigh Throughput Genomic and Proteomic Technology Cardiogenic Cocktail Mouse ESCs Guided mouse ESCs The cardiogenic coctail secured guided differentiation of mouse embyronic stem cells into cardiopoietic cells Behfar et al, 2007, J Exp Med 204: 405-420

  24. “Second Generation Stem Cell ProductsCardiogenic Coctail in Adult BM-MSCs from Cardiac Patients • Guided cardiopoietic BM mesenchymal stem cells: • upregulation and nuclear translocation of cardiac transcription factors, • sarcomeric organization and expression of the gap junction protein connexin 43 • rhythmic calcium transients. Behfar & Terizc, personnal communication

  25. “Second Generation Stem Cell ProductsGuided Cardiopoietic BM-MSCs in the Mice Model of the Chronic MI • Guided cardiopoietic BM mesenchymal stem cells: • superior effects on functional improvement in the chronically infarcted myocardium as compared to nonmodified MSCs • paralleled by the superior effects on neovascularization and cardiac differentiation • no toxicity observed Behfar & Terzic, personnal communication

  26. Cardio³ BioSciences C-Cure™ I Clinical TrialProtocol Number: C3BS-C-07-02EudraCT Number: 2007-007699-40 Goal: To test the safety and efficacy of guided, autologous bone marrow-derived cardiopoietic mesenchymal stem cells in ischemic cardiomyopathy Sponsor: Cardio3 Biosciences, Braine L’alleud, Belgium

  27. Cardio³ BioSciences C-Cure™ I Clinical Trial • A multicenter, prospective, open-label, sequential design with 2 parallel arms • Blinded core lab analyses • 2:1 randomization Stage B (n = 195) Stage A (n = 45) 2 Guided cells n = 30 Guided cells n =130 Ischemic Heart Failure Control group n = 65 Control group n = 15 1 ~12 sites ~ 25-30 sites

  28. Primary and Secondary Endpoints

  29. Major inclusion criteria • Patient has history of previous myocardial infarction • Patient on optimal and stable medical management (state-of-the-art treatment conform the guidelines) • Patient has congestive heart failure NYHA class II or III and LV ejection fraction ≥ 15% and ≤ 40%

  30. Treatment Procedure • All patients (Phase A) will receive an ICD • All patients under optimal medical management (CRT allowed if implanted > 6 months before randomization) • Mesenchymal stem cells culture expanded and treated with the cardiogenic coctail • Cardiomyogenic specification confirmed by the presence of the cardiac specific markers according to the release criteria • NOGA-guided cells injection into the dysfunctional and viable myocardium

  31. Trial Management • Prinicipal Investigators: J. Bartunek, A. Terzic • Steering Committee: J. Bartunek, A. Terzic, W. Wijns, M. Tendera, S. Henry • Clinical Event Committee: W. Shen, M. Bertrand, G. Breithardt, H. Klein • DSMB: S. Waldman, D. Meldrum, J. Thijssen • Trial monitoring: Cardio3Biosciences, Belgium • Independent core lab analyses: MUGA, Echocardiography, ECG/ICD

  32. Trial Sites/Investigators – Phase A

  33. Adult Stem Cells Therapy SWOT 2008 Weaknesses Strengths • Limited effects of naive stem cells • Fate of cells: survival, transdifferentiation and integration • Optimal cell type? • Mechanism? • Timing? Delivery? Homing? • What Patient? • Interplay between BM and heart after injury • Multipotency of BM stem cells • Variety of stem cell types • Promising functional effects on cardiac repair in experimental setting Opportunities Threats • “Hype” effect • Large scale randomized trials could be negative • Intellectual conflict of interest • Unforeseen safety problems • Proliferation of uncontrolled small trials “New age” in cardiac interventions: • “The” fundamental solution for the myocyte loss • Heart failure treatment and prevention

  34. Cardiovascular Center, Aalst Jozef Bartunek*, Marc Vanderheyden, William Wijns, Guy Heyndrickx, Mayo Clinic, Rochester, MN Andre Terzic Atta Behfar *Biomedical Engineering, TU Eindhoven, NL Birgit Faber Carlijn Van Bouten Anthal Smits Mark Post ULB Brussels, Belgium Kathleen McEntee Myreille Mathieu University of Gent, Belgium Bart Vandekerkhove Frank Timmermans Cardio3 Biosciences, Brussel Vincienne Gaussin Sophie Henry Christian Homsy Aurrore de Lavareille Naima Mazouz Phillipe Willemsen King’s College London, UK Jonathan Hill Ike W. Lee

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