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Stamceltechnologie: Mythe of Realiteit Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven Emeritiforum KULeuven, 26 april 2007.

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Presentatie over: "Stamceltechnologie: Mythe of Realiteit Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven Emeritiforum KULeuven, 26 april 2007."— Transcript van de presentatie:

1 Stamceltechnologie: Mythe of Realiteit Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven Emeritiforum KULeuven, 26 april 2007

2 Cardiale Regeneration in 2007: “the stem cell approach” Caulfield et al. Circ 1976 Infarct size (% LV mass) 48% 28% Shock, DeathCHF Pfeffer et al. NEJM years later: VALIANT study (14,703 post-MI pts with reduced EF or CHF ) -1 y mortality: 13% - 1 y death, reMI, rehosp CHF: 26%

3 Full Regeneration of Myocardium in Zebrafish Poss et al., Science 2002;298; 2188

4 Cardiac Regeneration in 2007: the (stem) cell paradox? - skeletal myoblasts ( ) - fibroblasts (2000) - smooth muscle cells (2003) - endothelial progenitor cells (2001) - mesenchymal stem cells (2005) - hematopoietic stem cells ( ) - other BM-derived cells (2005) - cardiac progenitor cells (2005) - ES cell-derived CMC (2005) ………. Different cell types with uniform benefit on cardiac function:

5 Cell Therapie voor AMI in 2007? 2.Toekomstperspectieven? Trial design: welke patiëntenpopulatie - eindpunten? 1. Lessen uit 4 RCT in 2006 met mononucleaire BM cellen en 6 RCT met mobilisatie strategieën? Is cardiale regeneratieve geneeskunde mogelijk?

6 Sca-1+ cells c-Kit + cells SP cells Endothelial Progenitor Cells Hematopoietic SCs Mesenchymal SCs Hemangioblasts SP cells MAPC Sca-1+ cells Myoblasts SP cells Mesenchymal SCs SPcells PLURIPOTENT Cel Types voor Cardiaal Herstel (adapted from Dimmeler et al., JCI 2005) Chronisch MI: MAGIC phase II Acuut MI Stabiele Ischemie

7 Sca-1+ cells c-Kit + cells SP cells Cardiospheres Future for Cardiac Resident (Stem) Cells?

8 Spontaneous Mobilization and Homing in Acute - Chronic Ischemia Mobilization: CD34+/CxCR4+/CD117+, c-met+ (Wojakowski, Circ 2004) CD133+ (Ott, EHJ 2006) CD34+ (Crea, EHJ 2005) Mes SC (Kastrup, EHJ 2006) EPC (Shintani, Circ 2001, George EHJ 2004, Massa, Blood 2005….) …………. ? VEGF, FGF2 SDF-1, IL-8,…. G-CSF

9 1.Kuethe et al. (Am Heart J 2005;150:115) 2.Ince et al. (FIRSTLINE-AMI, Circ 2005;112: 3097) 3.Valgimigli et al. (Eur Heart J 2005;26:1838) 4.Ripa et al. (STEMMI, Circ 2006;113:1983) 5.Zohlnhofer et al. (Revival 2, JAMA 2006;295:1003) ----> geruststellend veiligheidsprofiel -----> niet superieur tov placebo voor herstel LV functie -----> timing, dosis, directe versus indirecte cellulaire effecten? G-CSF RCT Trials in Acuut Myocard Infarct

10 BOOST: LV-Ejection Fraction after 6 and 18 Months (Circulation 2006;113: ) BMC-TransferControls LVEF [%] 0.7% 6.7% 2.4% -0.8%

11 UZ-Leuven Ervaring met BMC Transfer na AMI: design (2001) 2. Cel product? 1. Patiëntenpopulatie en Design van de Studie? 3. Timing voor Cel Transfer? 4. Primair eindpunt?

12 AMI + documented LV dysfunction post PCI Can BMSC Transfer Improve LV Recovery after Acute Myocardial Infarction? BMSC or placebo transfer in open IRA Informed consent TTE Acetate-PET scan Bone marrow aspiration + randomization 24 hours Admission (7 d) -cine MRI - LE -Echo / TDI Follow-up (4 mo) -cine MRI - LE -Acetate-PET scan -Echo / TDI Follow-up (1 y) - cine MRI - LE - Echo TDI

13 Bone Marrow Cell Transfer Post-AMI (randomized controlled trials 2006) LVEF - MRI (%) BMSC CON Leuven AMI (n=67) + 2.2%+ 3.4%  = +1.2% (P=NS) 4-mo (Lancet 2006; 367: ) LVEF - MRI (%) REPAIR-AMI (n=187) ASTAMI (n=87) + 3.0%+ 5.5%  = +2.5% (P<0.05) + 4.2%+ 1.2%  = -3% (P=NS) CON BMSC 4-mo 6-mo LVEF - angio (%) (NEJM 2006; 355: )

14 Bone Marrow Cell Transfer Post-AMI Does infarct size matter? BMCPlac Change EF (%) NEJM 2006; 355: Baseline EF <48.9% Baseline EF >48.9% P=0.002 P=0.81 (52)(41)(40)(54)

15 Bone Marrow Cell Transfer Post-AMI Does timing matter?  LV-EF (%) Time after PCI (days) 46 (8)47 (9) (n=36) LV-EF (%) P=NS 3-4 d4 mo LV-EDV (mL) P= (33)175 (43) 3-4 d4 mo >4 d<4 d

16 Coronary occlusion 20 min.60 min.3hrs.>3-6hrs. Reversible injury Irreversible injury Reperfusion LV Paracrine or autocrine effects of transferred cells? ? ? MRI and TDI Analysis Post-AMI: Infarct Transmurality & Segmental Contraction

17 BMSC Treatment Effect* on Infarct Size Infarct size (g) P=0.036 * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI. 28% treatment effect* ** Lancet 2006; 367:

18 BMSC Treatment Effect* on Infarct Size Infarct size (g) P=0.036 * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI. 28% treatment effect* ** 23%

19 Baseline5 d2 mo4 mo1 yr (n=232) Infarcted segments ** ES Strain (%) BMSC Control * p < Treatment Effect Time Profile Regional Function Analysis TDI: End-systolic Strain

20 Adverse Events during 1-year Follow-up BMSC Tx (n=31) Control group (n=34) Ventricular tachycardia (Holter) -1 Life threatening arrhythmia’s -1 (ICD) Death 1 (suicide)- Myocardial reinfarction 11 Recurrent ischemia, PCI 24 Congestive Heart Failure -1 Others: depression PAD (claudication)

21 Schachinger, V. et al. Eur Heart J : Kaplan-Meier event-free survival analysis

22 Conclusies IC transfer van autologe BMSCs is veilig en leidt niet tot laattijdige significante nevenwerkingen. Na tijdige reperfusie van een myocardinfarct met een matige graad van ventrikel schade hebben BMSCs variabele effecten op herstel van globale LV functie, doch verbeteren ze op significante wijze de regionale functie (waar schade is opgetreden). De uitdaging voor de toekomst bestaat erin om na te gaan hoe de geobserveerde paracriene effecten van BMSC kunnen vertaald worden tot een klinische meerwaarde voor AMI patienten met een ernstigere initiele linker ventrikel beschadiging.

23 Grote, multicenter studie in ernstig AMI - klinisch eindpunt -Centraal hematologie core faciltieit -SOPs cel bereiding -Q-control, financiele ondersteuning,…. Toekomstperspectieven: Optimaliseren van Stam Cel Transfer? Gefocuseerde klinische studies en parallele preklinische studies - Boost 2 - NL interuniversity study - Poland (cell comparison) - Leuven/Frankfurt meta-analysis - Leuven homing studies

24 Sca-1+ cells Myoblasts SP cells Cell Sources for Cardiac Repair (adapted from Dimmeler et al., JCI 2005) Ischemic Cardiomyopathy (EF<35%) MAGIC phase II

25 MAGIC Phase 1 Study To assess the feasibility and safety of autologous skeletal myoblasts in pts with ischemic heart failure. Single center (F): n=10 Suggestion of efficacy (EF, NYHA, WMSI) Cave: arrhythmogenicity

26 MAGIC Phase 2: Studie Procedures Biopsie GMP Cell Processing Cel suspensie 10 g

27 The MAGIC Trial Safety - MACE : All deaths, MI, congestive HF, resuscitated sudden death & stroke - Ventricular arrhythmias (ICD implanted in all patients before hospital discharge) End Points Efficacy - Primary : Recovery of contractility of previously akinetic segments & change from baseline to month 6 in LVEF as assessed by echocardiography (Core Labs) ± MUGA - Secondary : LV volumes

28 Skeletal Myoblast Transplantation Total of injections Injections in a grid with  5 mm between injections  equally divide in scar and in peri-infarct zone Injection volume 200 uL from 1 mL syringe Total injection volume 6 mL Total injection time: min X X X X X Infarct Zone (Scar) Peri-Infarct Zone

29 High dose group Low dose group Placebo group Summary of Time to First MACE p = 0.09 p = 0.43 Low dose vs placebo p = 0.87 p = 0.12 High dose vs placebo 6 months30 days High dose group Low dose group Placebo group

30 High dose group Low dose group Placebo group p = 0.23 p = 0.20 Low dose vs placebo p = 0.12 p = 0.30 High dose vs placebo 6 months30 days Death treated as censored event Summary of Time to First Ventricular Arrhythmia

31 The MAGIC Trial Regional Wall Motion Patients with Qualitative Echo Data at Baseline and Month 6 Number of patients Recovery in at least one segment Yes (%)12 (46)13 (46)18 (58) No (%)14 (54)15 (54)13 (42) Recovery in at least two segments Yes (%) 8 (31)10 (36)12 (39) No (%) 18 (69)18 (64)19 (61) High doseLow dosePlacebo

32 LV End-Diastolic Volume Data are given as median (interquartile range) n= (-42.0;0.0) n= (-33.0;25.0) n= (-21.0;28.0) p=0.006 p=0.62 mL

33 Sca-1+ cells c-Kit + cells SP cells Cardiospheres Isotype control Sca-1 Sca-1+ cells 60, ,000 Total %Sca Future for Cardiac Resident (Stem) Cells?

34 Smith, R. R. et al. Circulation 2007;115: Regenerative Potential of Biopsy-derived Human Cardiospheres

35 Cel Therapie voor Ischemische Dysfunctie in 2007: Droom of Realiteit? Isolatie, amplificatie en intramyocardiale administratie van Sca-1 positieve CSC (muis) en c-kit positieve CSC (rat, varken) en humane cardiospheren (RV biopsie) Intramyocardiale administratie van CSCs in geinfarceerd myocard verbetert regionale systolische functie (TTE) First in men (veiligheid, haalbaarheid per CABG): Q (US)

36 Stamcelbehandeling: Fontein van de Eeuwige Jeugd? Lucas Cranach (olie op canvas 1546)

37 - Departments of Cardiology, Hematology, Radiology, Nuclear Medicine, Radiopharmacy, Biostatistics - Leuven Coordinating Center (LCC) - Referring Cardiology Sites Acknowledgments Gasthuisberg University Hospital & CTG, VIB-3 University of Leuven, Belgium


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