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Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

Presenter Disclosure Information Valentin Fuster, M.D., Ph.D. Category of relationship Name of company Level of relationship Consulting fee Vasogen Modest

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Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

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  1. Presenter Disclosure InformationValentin Fuster, M.D., Ph.D. Category of relationship Name of company Level of relationship Consulting fee Vasogen Modest Consulting fee Merck & Co., Inc Modest Consulting fee Kereos Modest Chair of the GlaxoSmithKline Modest Foundation forCV Education & Research Chair HRP BG Medicine Significant

  2. Historical Notes – Feasibility, Disappoitments Observing the Protocols – Heterogeneity, End Points Stem Cells – Origin, Release, Homing, Target Function Imaging Technology - Large Experimental Animals Stimulating Future - Integration of gene / Cell Therapy Issues for Caution - Tumors, Ethics, Media CARDIOVASCULAR GENE AND CELL THERAPY“RISKY” AND “EXCITING”

  3. Late 1990’s

  4. EARLY 2000’sGENE THERAPY, USA TRIALS VECTORS AND TRANSGENES DNA Liposome PDGF 8% 8% FGF 8% HIF-f / DP16 14% Adenoviral 53% VEGF 64% Plasmid DNA 39% NOS 3% Del-1 3% JM Isner et al., Circ Res 2001; 89:389

  5. Therapeutic Angiogenesis for Limb Ischaemia Knee and upper tibia Angiographic analysis of collateral vessel formation Lower tibia, ankle and foot Before implantation 24 wks after implantation Yuyama, ET et. al. Lancet 2002; 360: 427.

  6. DELIVERY OPTIONS FOR IMPLANTING MYOCARDIAL GENE TRANSFER Nature 2002;415;234

  7. PROTEIN AND GENE BASED APPROACHES TO CORONARY ANGIOGENESIS – MID 2000’s Study Disease Therapy Agent Trial Phase Randomized Features Cardis Vasc-Grow CAD Protein FGF1 1 No Minithoracotomy Simons et al., CAD Protein FGF2 1 No Euro-Inject, Losordo et al CAD Gene VEGF2 1 / 2 Yes Endocardial Inj. AGENT, Grines et al. CAD Gene FGF4 1 No Genesis CAD Gene VEGF2 2b Yes Endocardial Inj. AnGes MC CAD Plasma HGF1 No Endocardial Inj. HC Herrmann et al., AHJ 2006; 151:S30

  8. Angiogenic Agents – 2005 • PHASE III CLINICAL TRIALS • 0

  9. DELIVERY / VECTOR ISSUES Route Immunity Pharmacokinetics of vector systems CONCEPTUAL ISSUES Single Growth Factor Approach Simplistic Persistent expression (VEGF) needed Heterogeneity of Responses Potential Reasons for Early Failures in Angiogenesis Study – Trials in the mid 2000’s

  10. The History of Regeneration – Early 2000’s

  11. Intracoronary Autologous BMC transfer after MI: Global LVEF at Baseline and 6 Months Follow-up. P< 0.003 BOOST (Wollert, KC et.al) Lancet 2004;364:141(Hanover,Mannheim)

  12. Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction Eighteen Months’ Follow-Up Data From the Randomized, Controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) In this study, a single dose of intracoronary BMCs did not provide long-term benefit on LV systolic function after AMI compared with a randomized control group, however, the study suggests an acceleration of LV ejection fraction recovery after AMI by BMC therapy. Circulation 2006; 113:1287

  13. AMI - INTRACORONARY BM - DPC INTERACTION BETWEEN BASELINE LVEF AND THE ABSOLUTE CHANGE IN LVEF (N=204, FU 4 Mo) Placebo BMC P=0.002 P=0.81 20 10 Absolute Change in Global LVEF (%) 0 -10 P for interaction = 0.02 -20 52 41 40 54 No. of patients Base LVEF at or below Median ( 48.9%) Base LVEF above Median (> 48.9%) At 1 y Reduction Death, MI, Revasc (p<0.01) REPAIR-MI (V Schachinger et al.) NEJM 2006; 355:1218

  14. AMI - LVEF AT BASELINE AT 2 TO 3 WEEKS AND AT 6 MONTHS Change between 2-3 wk and 6 Mo Mononuclear BMC Control P=0.29 P<0.001 80 10 70 8 60 P=0.054 50 6 40 LVEF (%) Percentage Points 4 30 20 2 10 0 0 2-3 Wk 6 Mo 2-3 Wk 6 Mo Mononuclear BMC Group Control Group Time after Myocardial Infarction ASTAMI (K Lenox et al.) NEJM 2006; 355:1199

  15. 1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY -  30 PATIENTS LVEF Outcome No. Days PtFUControlStem CellRx/Control SourceTrialPtsAMImoInfusionSourceComment Meluzin et al., 2006 Rand 66 5-9 3 None BM  5%/ 2% high dose Schachinger, 2006 REP-AMI204 3-7 4 Plac BM  5.5%/ 3.0% Schachinger, 2006 REP-AMI204 3-7 12 Plac BM  outcome of death reinfarction revasc Schaefer et al., 2006 BOOST 59 4-5 18 None BM NS Bartunek et al., 2005 Unbl 35 11.6 4 None CD133  infarct-related artery resten Chen et al., 2004 Rand 69 >18 6 Plac Mesench  18%/ 6% Schachinger, 2004 TOPC-AMI 54 3-7 12 None BM  3% for both bone or CPCs and CPCs at 4 mo Wolert et al., 2004 BOOST 60 4-8 6 None BM  6.7%/ 0.7% RK Burr et al., JAMA 2008; 299:925

  16. 1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY -  30 PATIENTS LVEF Outcome No.Days Pt FUContr.Stem CellRx/Control SourceTrialPtsAMImo InfusionSourceComment Onci et al.,2007 Unbl. 73 5-19 24 None Periph Bl NS Kang et al. 2007 MAGIC Cell 1 30 NA 24 G-CSF Periph Bl  Infusion comp G-CSF Li et al., 2007Unbl. 70 6 6 Untreat Periph Bl  7.1%/ 1.6% Tatsumi et al.,2007Unbl. 54 <5 6 None Periph Bl  13.4%/ 7.4% Janssens et al. 2006 Rand 67 1-2 4 Plac BM NS Kang et al., 2006 MAGICCell-3- 82 NA 6 AMI/old Periph Bl  5.1%/ -0.2% MI/untreat Lunde et al., 2006 ASTAMI 100 4-8 6 None BM NS Meyer et al., 2006 BOOST 50 4.8 18 None BM NS RK Burr et al., JAMA 2008; 299:925

  17. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) Trial First Randomized Study of Myoblast Transplantation This multicenter, randomized, placebo-controlled, double-blind study included patients with left ventricular (LV) dysfunction (ejection fraction  35%), myocardial infarction, and indication for coronary surgery. Each patient received either cells grown from a skeletal muscle biopsy or a placebo solution injected in and around the scar. All patients received an implantable cardioverter-defibrillator. Ninety-seven patients received myoblasts (400 or 800 million; n=33 and n=34, respectively) or the placebo (n=30). At 6 months myoblast transfer did not improve regional or global LV function beyond that seen in control patients. P Menasché et al., Circulation 2008; 117:1189

  18. 2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS No. FU Stem Cell Source Trial Type Pts, mo Route Source LVEF Outcome, Comment Gao et al., 2006 Unbl 26 3 Intrac BM  LVEF, improv. in CHF Hendrikx et al. 2006 Rand 20 4 Intram BM NS Mocini et al 2006 CABG + cells 36 12 Intram BM  LVEF & wall motion or CABG Erbs et al., 2005 Rand. 26 3 Intrac. CPCs  Patel et al., 2005 Rand. 20 6 Intram. CD34  Strauer et al.2005 IACT,No Cont 36 3 Intrac. BM  Perin et al., 2004 Seq enrollm. 20 12 Intramyoc BM NS Rx or contr Perin et al., 2003 Single gr 21 4 Intramyoc BM  RK Burr et al., JAMA 2008; 299:925

  19. 2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS No. FU Stem Cell LVEF Outcome Source Trial Type Pts mo Route Source Comment Assmus et al.,2007 TOPC CHD 121 19 Intrac. BM  mort. .high-order CFUs inj. Losardo et al.,2007 Rand 24 12 Intram. CD34 Not examined Manginas et al., 2007 Unbl. 24 28 Intrac CD133, CD34  LVEF Stamm et al., 2007 Unbli. 40 6 Intram. CD133  LVEF Assmus et al.,2006 TOPC-CHD 75 3 Intracor BM  with BM Rand. CPCs Beeres et al. 2006 Single gr. 26 12 Intram. BM  LVEF, ang. score, perfus. Chen et al., 2006 Unbl 45 12 Intrac. Mesench  isch NYHA cl. LVEF Fuchs et al., 2006 Single gr 27 12 Intram. CD34  CCS angina score RK Burr et al., JAMA 2008; 299:925

  20. Historical Notes – Feasibility, Disappoitments Observing the Protocols – Heterogeneity, End Points Stem Cells – Origin, Release, Homing, Target Function Imaging Technology - Large Experimental Animals Stimulating Future - Integration of gene / Cell Therapy Issues for Caution - Tumors, Ethics, Media CARDIOVASCULAR GENE AND CELL THERAPY“RISKY” AND “EXCITING”

  21. 1) Isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute MI ASTAMI REPAIR-AMI FH Seeger, A M. Zeiher, S Dimmeler et al. Eur Heart J. 2007;28:766.

  22. 1) Great Heterogeneity Time AMI-ther Nº Pts (ther/ctrl) CD34 (‰) Follow- Up LAD disease Nº Cells (X106) REF# 20 (10/10) 21 5-9d 3m 28 Strauer 40% 33 (20/13) 10 13.5 6m 78 Avilés 78% 20 (11/9) Chronic MI 24 12m 30 Perin --- 29 (29/0) 5 4.9d 12m 213 Zeiher 55% ? (77%) 60 (30/30) 4 4.8d 6m 2460 Booster Chronic MI 36 (18/18) ? 3m 360 Strauer 89% ? (68%) 67 (33/34) 16 1d 4m 172 Janss. 204 (101/103) Repair-AMI ? 3-6d 4m 236 Zeiher 64% 101 (52/49) 15 5-8d 6m 87 100% ASTAMI ASTAMI

  23. 2) EJECTION FRACTION - OVERVIEW OF CLINICAL TRIALS OF STEM-CELL OR PROGENITOR-CELL DELIVERY TO THE HEART Cell type Study No. of Mean FU No. cells Route of inj. Ejection fraction Source design pts mos. injected vs control (%) CPC Cohort 54 6 5 x 109 Intracoronary +6.0 (P=0.04) Tatsumi et al., (2007) Cohort 73 6 2 x 109 Intracoronary +2.8 (NS) Choi et al., (2007) R-SB 47 3 2 x 107 Intracoronary +0.8 (NS) Assmus et al., (2006) R 82 6 1.4 x 109 Intracoronary -0.2 (NS) Kang et al., (2006) Cohort 70 6 7.3 x 107 Intracoronary +5.5 (P=0.04) Li et al., (2006) SB 26 3 7 x 107 Intracoronary +7.2 (NS) Erbs et al., (2005) VFM Segers, RT Lee. Nature 2008; 451:937

  24. 2) EJECTION FRACTION - OVERVIEW OF CLINICAL TRIALS OF STEM-CELL OR PROGENITOR-CELL DELIVERY TO THE HEART Cell type Study No. Mean FU No. cells Route of inj. Ejection fraction Source design pts mos. injected vs control (%) BMMNC R-SB 60 12 108 Intracoronary +7.0 (P=0.03) Meluzin et al., (2007) R-SB 51 3 2 x 108 Intracoronary +4.1 (P=0.001) Assmus et al., (2006) R-SB 66 3 108 Intracoronary +3 (P=0.04) Meluzin et al., (2006) R-SB 204 12 2.4 x 108 Intracoronary  mortality Schächinger et al., (2006) R-SB 20 6 4 x 107 Intracoronary +6.7 (NS) Ge et al., (2006) R-SB 20 4 6 x 107 TEIM +2.5 (NS) Hendrikx et al., (2006) R-DB 67 4 1.7 x 108 Intracoronary +1.2 (NS) Jannsens et al., (2006) R-SB 100 6 8.7 x 107 Intracoronary -3.0 (P=0.05) Lunde et al., (2006) R-SB 60 18 2.5 x 109 Intracoronary +2.8 (NS) Meyer et al., (2006) Cohort 36 3 3 x 108 TEIM +4.0 (NS) Macini et al., (2006) R-SB 204 4 2.4 x 108 Intracoronary +2.5 (P=0.01) Schächinger et al., (2006) Cohort 36 3 9 x 107 Intracoronary +7.0 (P=0.02) Strauer et al., (2005) Cohort 20 12 2.6 x 107 TEIM +8.1 (NS) Perin et al., (2004) Cohort 20 3 2.8 x 107 Intracoronary +1.0 (NS) Strauer et al., (2002) VFM Segers, RT Lee. Nature 2008; 451:937

  25. Myocardial Cell Therapy At The Crossroads B Nadal-Ginard, V Fuster Nature CP Cardiov Med 2007; 4:1 Cardiac Cell Therapy: Bench or Bedside? Steering Committee NHLBI Cardiovascular Cell Therapy Research Network Nature CP Cardiov Med 2007; 4:403

  26. Historical Notes – Feasibility, Disappoitments Observing the Protocols – Heterogeneity, End Points Stem Cells – Origin, Release, Homing, Target Function Imaging Technology - Large Experimental Animals Stimulating Future - Integration of gene / Cell Therapy Issues for Caution - Tumors, Ethics, Media CARDIOVASCULAR GENE AND CELL THERAPY“RISKY” AND “EXCITING”

  27. 1)Stem cells origin and pathways - the bone marrow Interactive signaling pathways that regulate proliferation and differentiation of HSCs. K.A. Moore, I R Lemischka et. al. Science2006;311:1880.

  28. 2) Haematopoietic Stem Cell Release Is Regulated By Circadian Oscillations The cyclical release of HSCs and expression of Cxel12 are regulated by core genes of the molecular clock through circadian noradrenaline secretion by the sympathetic nervous system. These adrenergic signals are locally delivered by nerves in the bone marrow. These data indicate that a circadian, neurally driven release of HSC during the animal’s resting period may promote the regeneration of the stem cell niche and possibly other tissues. S Méndez-Ferrer et al., Nature 2008 (In Press)

  29. 3) Homing or tissue-committed (cardiac, endothelial, neural) stem cells (TCSC) Wojakowski W. et. al. Heart 2008;94:27.

  30. 3a) EVEN IF WE FIND THE RIGHT CELL, DOES IT MATTER? • Can Stem Cells Survive in the hostile environment of the ischemic myocardium without a known niche? • Can the end stage heart truly be reverse remodeled by stem cells? Even the liver, which is one of the most regenerative organs in the body, cannot be regenerated once it becomes cirrhotic.

  31. 3a) Cardiac Stem Cells in the Real World We prospectively screened 32 endomyocardial biopsies harvested from heart transplant recipients (off rejection episodes) and 18 right appendage biopsies collected during coronary artery bypass surgery, and processed the tissue specimens for the immunohistochemical detection of markers of stemness (c-kit, MDR-1, Isl-1), hematopoietic origin (CD45), mast cells (tryptase), endothelial cells (CD105), and cardiac lineage (Nkx2.5). These data raise a cautionary note on the therapeutic exploitation of cardiac stem cells in patients with ischemic cardiomyopathy, who may be the elective candidates for regenerative therapy. J Pouly, P Menasché et al., JTCS 2008; 135:673 (Paris)

  32. 3bc) Flow Reversal Mechanical & Biohumoral Risk Factors THROMBUS LDL b) TF MMPs CAMs c) PDGF ET Extracellular Matrix Fibroblasts Vasa Vasorum SMC contraction migration proliferation Fuster V et. al. J Am Coll Cardiol 2005;46:937.

  33. 3b) Early Structural-Functional Changes in the Endothelium for Vascular Disease Simionescu M. Arterioscler Thromb Vasc Biol. 2007;27:266.

  34. 3b) Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E-Deficient Mice Our findings provide the first quantitative data on endothelial turnover and repair (Evans Blue, Brd U) by progenitor cells that are, at least in part, derived from bone marrow (D31, CD144) during development of atherosclerosis in apoE-/- mice. G Foteinos, Q Xu et al., Circ 2008; 117:1856 (Insbr., Lond)

  35. 3b) Potential Origin and Differentiation of Endothelial Progenitor Cells Shantsila E et. al. J Am Coll Cardiol.2007;49:741.

  36. 3c) Contribution of BM-derived Sca-1Positive Progenitor Cells to Endothelium and Vasa Vasorum after Arterial Injury in Mice Hutter R, Fuster V, Badimon JJ et al 2007 (Subm)

  37. 4) PROPOSED FUNCTION OR ACTION OF STEM / PROGENITOR CELLS IN CARDIOVASCULAR REPAIR Cell homing and tissue integration EC Differentiation SMC Differentiation Cardiac Differentiation Fusion Paracrine Effects Attraction/ Activation of CSC Angiogenesis Vasculo- genesis Cardio- myogenesis Cardiomyocyte Proliferation Arteriogenesis Cardiomyocyte Apoptosis  Modulation of Inflammation Scar Remodelling Functional Improvement S Dimmeler, J Burchfield, AM Zeiher. ATVB 2008; 28:208 (Frankfurt)

  38. 4)Challenges for Cell-Based Therapy in Cardiac Repair Short and Long Term Function Dimmeler S, Zeiher AM, Schneider MD J Clin Invest2005:115;572.

  39. Historical Notes – Feasibility, Disappoitments Observing the Protocols – Heterogeneity, End Points Stem Cells – Origin, Release, Homing, Target Function Imaging Technology - Large Experimental Animals Stimulating Future - Integration of gene / Cell Therapy Issues for Caution - Tumors, Ethics, Media CARDIOVASCULAR CELL AND GENE THERAPY“RISKY” AND “EXCITING”

  40. 1) TRIALS OF CELL THERAPY OR G-CSF - MRI END POINT Author/Acronym Patients n FU Reference Result Lunde STEMI 47 6 mo LVEF, inf. size No diff. (2006) Ripa (STEMMI) STEMI 33 6 mo LVEF, inf. mass No diff. (2006) Kang (MAGIC) MI 25 acute 6 mo LVEF No diff. (2006) 16 old Hendrilox MI 10 4 mo LVEF No diff. (2006) Engleman STEMI 19 3 mo LVEF, inf. area No diff. G-CSF STEMI (2006) R Gibbons et al., JACC 2007; 50:988

  41. 2) MRI IN HUMANS - BIOLOGY AND OUTCOMES Author Population n MRI Predictor Outcomes FU Yan et al. MI (25% acute, 58% 144 % of MI with <1. All-Mortality. 29 mo (2006) chron., 17% ?age) intense DE2. CV Mortality(peri-infarct ) Assormull Dilated Cardiom. 101 Mid-wall DE1. All-Mort./Hp 22 ± 12 mo et al.,(2006) 2. SCD or sust. VT Barclay et al AMI s/p lysis 19 Transm ext. DEImproved in wall 8 weeks (2006) thickening Tarantini AMI s/p PCI 76 Transm. DE, Centr.Change LVE DV I 6 ± 1 mo et al. (2006) NE (Microv Obst)or LVEF White et al. CHF with 28 % DEClin. Resp. CRT 3 mo (2006) CRT Ypenburg Isch cardiom. 34 Segments for DE 1. LV vol./LVEF 6 mo et al. (2007) with CRT 2. Clin Resp. CRT Kaandorp AMI 29 % DE End-diast vol 9 mo et al. (2007) R Gibbons et al., JACC 2007; 50:988

  42. 2a) PREVALENCE OF ARRHYTHMIAS ON 24-H HOLTER ECG WITH RESPECT TO DE IN 177 HCM PATIENTS P=0.007 100 DE present DE absent 90 80 70 60 P=0.001 % Patients with Arrhythmia 50 P<0.0001 P=0.07 40 30 20 10 0 NSVT Complete PVCs SVT AS Adabag, BJ Maron et al., J Am Coll Cardiol 2008; 51:1369 (Minn)

  43. 2b)PMO or No Reflow Zone in Antero-apical infarction PMO = Persistent Microvascular Obstruction S Rajagopalan, V Fuster Nature CPCM 2006

  44. 2b) MI / HE - CHANGES IN CIRCUMFERENTIAL SHORTENING (%S) FROM EARLY ( WEEK 1) TO LATE (WEEK 8) FOLLOW UP - ROLE OF MO 30 Week 1 Week 8 25 20 %S 15 10 P=NS 5 P<0.001 P=NS 0 HE HE + MO Remote HE – Delayed Hyperenhancement MO – Microvascular Obstruction CJ Choi et al., JCMR 2004; 6:917 (Charlottesville, VA)

  45. 2b) Example of Myoc. Contr. Echo.(MCE) image in 4 Ch, 2 Ch and LAX view. Galiuto L, Crea F et. al. Heart2007;93:565.

  46. 2b) Reversible Microvascular Dysfunction Coupled With Persistent Myocardial Dysfunction: Implications For Post-Infarct Left Ventricular Remodelling In 39 patients with a first MI who underwent successful PCI, microvascular dysfunction was studied by myocardial contrast echocardiography (MCE) at 24 h, 1 week and 3 months after the procedure. Improvement in microvascular dysfunction occurs early after MI, although it is not associated with a parallel improvement in wall motion but is beneficial in preventing left ventricular remodelling. Accordingly, 1-week microvascular dysfunction is a powerful and independent predictor of left ventricular remodelling. L Galiuto, F Crea et al., Heart 2007; 93:565 (Rome)

  47. 2c) Impact of Collagen Type I Turnover on the Long-Term Response to Cardiac Resynchronization Rx Collagen type I turnover influences the long-term response to CRT. In addition, the ability of CRT to restore the balance between collagen type I synthesis and degradation is associated with a beneficial response. I García-Bolao, J Diez et al., Eur Heart J 2008; 29:898 (Pamplona, Spain)

  48. 3 Metoprolol Administration Pre-reperfusion. Direct CMR Visualization of Cardioprotection (Pig) T2W T1 T2W / T1 B Ibanez, S Prat, WS Spedl, V Fuster, J Sanz, JJ Badimon Circ 2007;115:2909 COMMIT Lancet 2005;366:1622 (China, N= 45852) – Within 24 Hours is too Late

  49. 3) Myocyte apoptosis at reperfusion can be diminished by different therapies. Swine infarct modelcaspase-3+ / Troponin T+ cells in border zone 24h after myocardial infarction B Ibanez, V Fuster, R Hutter, JJ Badimon. Submitted Focus on saving what is not already dead at reperfusion (but at risk of).

  50. Historical Notes – Feasibility, Disappoitments Observing the Protocols – Heterogeneity, End Points Stem Cells – Origin, Release, Homing, Target Function Imaging Technology - Large Experimental Animals Stimulating Future - Integration of gene / Cell Therapy Issues for Caution - Tumors, Ethics, Media CARDIOVASCULAR CELL AND GENE THERAPY“RISKY” AND “EXCITING”

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