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Hüseyin Ince MD, PhD University of Rostock Department for Internal Medicine, Cardiology

4th International Symposium on Stem Cell Therapy and Applied Cardiovascular Biology Madrid (Spain), April 26 – 27, 2007. Preclinical session. Hüseyin Ince MD, PhD University of Rostock Department for Internal Medicine, Cardiology hueseyin.ince@med.uni-rostock.de. What is stem cell therapy?.

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Hüseyin Ince MD, PhD University of Rostock Department for Internal Medicine, Cardiology

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  1. 4th International Symposium on Stem Cell Therapy and Applied Cardiovascular Biology Madrid (Spain), April 26 – 27, 2007 Preclinical session Hüseyin Ince MD, PhDUniversity of RostockDepartment for Internal Medicine, Cardiology hueseyin.ince@med.uni-rostock.de

  2. What is stem cell therapy?

  3. What is stem cell therapy?

  4. Stem cells in cardiomyopathy

  5. Antoni-Bayes Genís Ultrastructural findings of idiopathic dilated cardiomyopathy (IDCM): Myocyte atrophy and myofilament loss Main epicardial coronary arteries are shorter and smaller Microvascular density is reduced in the epicardium Moreover, this defective vascularization is associated with reduced myocardial expression of vascular -catenin, an important angiogenic regulator This study shows that both vasculogenesis and angiogenesis are altered in IDCM

  6. LC Guarita-Souza Simultaneous autologous transplantation of co-cultured stem cells (SC) and skeletal myoblasts (SM) in an experimental model of Chagas disease Seven Wistar rats received autologous transplant of 5,4x106 and 8,0x106 cells into the LV wall Control group (n=8) received culture medium After 4 weeks, cell transplantation significantly improved EF and reduced LVEDV No change has been observed in the control group. Conclusion: the co-transplant of SC and SM is functionally effective in Chagas disease (at least in Wistar rats)

  7. MiHeart The Multicenter Randomized Cell Therapy Trial in Cardiopathies (MiHeart) is composed of four independent clinical trials each one dealing with a specific cardiomyopathy: Chagasic cardiomyopathy Dilated cardiomyopathy Acute myocardial infarction Chronic ischemic heart disease

  8. MiHeart All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). The method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction six and twelve months after intervention in relation to the basal ejection fraction.

  9. MiHeart saftey endpoints Incidence of arrhythmias and conduction disturbances Number of ventricular extra systoles in six months and one year. Number of sustained ventricular tachycardia episodes in six months and one year. Number of non sustained ventricular tachycardia episodes in six months and one year. Incidence of atrial fibrillation in six months and one year. New-onset of atrioventricular or intraventricular conduction disturbances. Need for artificial pacemaker implantation.

  10. Wojciech Wojakowski SDF-1 (ligand of CXCR4 receptor) is a crucial factor involved in progenitor cell mobilization and homing There is an increase of SDF-1 production and release from ischemic myocardium generating the SDF-1 gradient towards the heart in AMI In patients with acute myocardial infarction the absolute number of CD34+CXCR4+, CD34+c-kit+ and c-met+ cells was significantly higher in comparison to patients with stable angina and healthy subjects Homing of tissue committed stem cells is also dependent on leukemia inhibitory factor (LIF) - LIF receptor and hepatocyte growth factor (HGF) - c-met axis

  11. G-CSF in AMI

  12. Firstline-AMI Direct effects of G-CSF on cardiac function after ischemia reperfusioninjury • Langendorff perfusion model w/wo 300 ng/ml G-CSF • early contraction with G-CSF in reperfusion • improved hemodynamics • less myocardial necrosis Harada et al., Nature Medicine 2005;11:305-11

  13. Angiographic and AMI related characteristics Firstline-AMI AMI = acute myocardial infarction; PCI = percutaneous coronary intervention; Ince et al. Circulation 2005; 112:3097-3106

  14. Functional echocardiographic parameters Firstline-AMI G-CSF (n=25) Control (n=25) LVEF LVEF (%) LVEF (%) p < 0.001 p < 0.002 p < 0.002 p < 0.001 59  7 56  4 54  8 54  5 53  5 51  5 51  4 51  8 48  4 47  5 46  4 43  5 Rest Low dose Dobutamine Ince et al. Circulation 2005; 112:3097-3106

  15. Firstline-AMI G-CSF (n=25) Control (n=25) 6 months angiographic results Restenosis parameters (in segments) Late lumen loss MLD Restenosis ns ns ns 20 16 0.61  0.18 0.60  0.23 1.96  0.50 1.95  0.38 Ince et al. Circulation 2005; 112:3097-3106

  16. G-CSF and Restenosis • Bone marrow mobilization strategies after the MAGIC trial. • No risk of restenosis

  17. G-CSF Control Delta-EF after G-CSF in AMI REVIVAL-2JAMA 2006 FIRSTLINE-AMICirculation 2005 Komuro et al.Circulation 2005 Valgimigli et al.EHJ 2006 Küthe et al.Am Heart J 2005 STEMMICirculation 2006 de Lezo et al.Rev Esp Cariol 2005

  18. Firstline-AMI G-CSF early after MI • G-CSF improves cardiac function • Dose and time sensitive effects Harada et al., Nature Medicine 2005;11:305-11

  19. Myoblasts in CHD

  20. Skeletal Myoblast Transplantation : Steps of the Procedure 10 g Biopsy GMP Cell Expansion

  21. Felipe Prosper Two months after induction of myocardial infarction (MI), Goettingen miniature pigs underwent autologous SkM transplant either by direct surgical injection (n=6) or percutaneous access (n=6) Control animals received media alone (n=4) Animals received a median of 407.55±115x106 BrdU labeled autologous SkM Functional analysis was performed by 2D echocardiography Myoblast transplant was associated with a significant increase in LVEF (p<0.01), increased vasculogenesis, decreased fibrosis (p<0.05) as compared with control animals No differences were found between groups receiving SkM by percutaneous or surgical access

  22. Herreros 12 221 x 106 + 3 mo. Eur Heart J 2003 EF : 35% to 53% at 3 mo. WMSI : 2.64 to 1.64 Siminiak 10 4 x 105 -5 x 107 + 12 mo. Am Heart J 2004 EF : 35% to 42% at 4 mo. 4/10 segments improved Dib 24 1 x 107 -3 x 108 + NA 45 mo. Circulation 2005 EF : 28% to 36% at 2 yrs Myoblast Tx : Phase I Surgical Trials Author No. Pts No. Cells CABG LV Function FU + cells Global Cell-Tx

  23. Smits 5 220 x 106 6 mo. JACC 2003 EF : 36% to 41% Ince 6 220 x 106 12 mo. JEVT 2004 EF : 24% to 32% Myoblast Tx : Phase I Interventional Trials Author No. Pts No. Cells LV Function FU Global Cell-Tx

  24. Lack of coupling between grafted myoblasts and host cardiomyocytes Impulse propagation Resting state Peak of action potentials No action potentials Embryonic myosin Connexin 43 Stretch activation by contracting myotubes Delayed cardiac repolarization Slowing of conduction, wave break & reentry Itabayashi et al.Cardiovasc Res 2005;67:561-70. Abraham et al. Circ Res 2005;97:159-67. Léobon et al. PNAS, 2003;100:7808-11. Patricia Lemarchand Possible Mechanisms of Myoblast-Related Arrhythmias

  25. Probability of Discharge of a First Shock in the ICD-Implanted Patients of the PATCH Trial Actuarial incidence of first discharges : 50% at 1 year and 57% at 2 years Bigger et al. New Engl J Med 1997;337:1569-75.

  26. Implantation of Skeletal Myoblasts : Lessons from Phase I Trials Efficacy Data Inability to draw meaningful conclusions from early studies because of : The small sample sizes The lack of control groups The confounding effect of associated CABG The dissociation between improved LV function and achievement of true myocardial regeneration Only randomized double-blind placebo-controlled adequately powered trials will provide a meaningful assessment of the risk-benefit ratio (In MAGIC the high dose cell group demonstrated a significant decrease in LV enddiastolic and endsystolic volumes)

  27. Concept of stent-induced “Aortic Reconstruction” Diagnosis Occlusion of proximal Entry Treatment Reconstruction of TL before stentgraft 1 year after stentgraft

  28. Antoine Lafont Aortic aneurysm formation is associated with matrix metalloproteinase-9 (MMP-9) activity Gingival healing is embryo-like in contrast to arterial healing This could be attributed to the gingival fibroblast Concept of using gingival fibroblast healing properties in arteries Gingival fibroblasts reduce MMP-9 expression by increasing TIMP-1 synthesis Vascular transfer of gingival fibroblasts could be a promising approach to treat aortic aneurysms

  29. Kai Pinkernell Preclinical evaluations of adipose derived stem and regenerative cells (ADRCs) have been carried out in acute and chronic cardiac diseases showing an improvement of cardiac function as well as a reduction in remodeling The PRECISE trial in patients with chronic myocardial ischemia has been started The APOLLO trial in patients with AMI is scheduled to follow soon in order to investigate the safety and feasibility of ADRC therapy in patients Both trials are designed as prospective, double blind, randomized, dose escalating trials

  30. Conclusions • Find the best stem cell types or cytokines for repair of cardiovascular disease. • Identify cardiovascular stem cells among circulating stem cells; adipose tissue; epithelial cells; bone marrow-derived stem cells and compare their capabilities in cardiovascular repair in relevant experimental animal models. • Identify roles of specific stem cell types or cytokines in reparative medicine and in cardiac regeneration and vascular repair.

  31. Conclusions • Identify optimal cell numbers and methods of administration of stem cells in cardiovascular repair. • Identify clinical problems most susceptible to stem cell or cytokine treatments.

  32. Thanks for your attention !

  33. Patients Acute Chronic MI IDCM Angina HF EPCs, CD34+, AC133+ Subsets Gender autologous allogeneic allogeneic Stroma (MSCs) MNC Team Composition Fat BM, Blood, UCB Muscle EMBRYONIC ADULT AGE Mb, Fb, SP cells CM (Parenchyma) Organ specific-Heart STEM CELLS

  34. ASTAMI REPAIR 140 * 120 100 + * 80 Invasion (x10E3) /10E6 BMC 60 40 20 0 SDF-1 basal basal Comparison of REPAIR-AMI versus ASTAMI Invasion activity Healthy Controls CAD-Patients REPAIR ASTAMI * 80 70 60 50 Invasion (x10E3) /10E6 BMC 40 + 30 20 10 0 SDF-1 basal SDF-1 basal SDF-1

  35. Phase I Study Design Phase I Trial Objectives • To determine the safety and tolerability of 3 different intravenous doses of Provacel compared to placebo in subjects with AMI • To evaluate the effect of Provacel on exploratory efficacy endpoints Design • Multi center study, randomized, double-blind, placebo-controlled, dose escalation study • 48 adult subjects with AMI (powered to show safety and preliminary efficacy) • 3 dose escalated cohorts and 1 safety cohort at the highest tolerated dose in a 2:1 ratio of active to placebo

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