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Presentation on theme: "Category of relationship Name of company Level of relationship Consulting fee Vasogen Modest Consulting fee Merck & Co., Inc Modest Consulting fee Kereos."— Presentation transcript:

1 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 for CV Education & Research Chair HRP BG Medicine Significant Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

2 CARDIOVASCULAR GENE AND CELL THERAPY “RISKY” AND “EXCITING” 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

3 Late 1990’s

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

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

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

7 PROTEIN AND GENE BASED APPROACHES TO CORONARY ANGIOGENESIS – MID 2000’s StudyDiseaseTherapy Agent Trial Phase RandomizedFeatures Cardis Vasc-GrowCADProteinFGF11 No Minithoracotomy Simons et al.,CADProteinFGF21No Euro-Inject, Losordo et alCADGeneVEGF21 / 2 Yes Endocardial Inj. AGENT, Grines et al.CADGeneFGF41No GenesisCADGeneVEGF22b Yes Endocardial Inj. AnGes MCCADPlasmaHGF1 No Endocardial Inj. HC Herrmann et al., AHJ 2006; 151:S30

8 Angiogenic Agents – 2005 PHASE III CLINICAL TRIALSPHASE III CLINICAL TRIALS0

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

10 The History of Regeneration – Early 2000’s

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

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) No. of patients Base LVEF at or below Median (  48.9%) Base LVEF above Median (> 48.9%) Absolute Change in Global LVEF (%) P for interaction = 0.02 Placebo BMC P=0.002P=0.81 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 LVEF (%) 2-3 Wk6 Mo2-3 Wk6 Mo Time after Myocardial Infarction Mononuclear BMCControl P<0.001P= Percentage Points Change between 2-3 wk and 6 Mo Mononuclear BMC Group Control Group P=0.054 ASTAMI (K Lenox et al.) NEJM 2006; 355:1199

15 LVEF Outcome No. Days PtFUControlStem Cell Rx/Control SourceTrialPtsAMI moInfusionSourceComment Meluzin et al., 2006Rand665-93NoneBM  5%/ 2% high dose Schachinger, 2006 REP-AMI PlacBM  5.5%/ 3.0% Schachinger, 2006 REP-AMI PlacBM  outcome of death reinfarction revasc Schaefer et al., 2006 BOOST NoneBM NS Bartunek et al., 2005 Unbl NoneCD133  infarct-related artery resten Chen et al., 2004 Rand69>186PlacMesench  18%/ 6% Schachinger, 2004 TOPC-AMI NoneBM  3% for both bone or CPCsand CPCs at 4 mo Wolert et al., 2004BOOST604-86NoneBM  6.7%/ 0.7% RK Burr et al., JAMA 2008; 299:925 1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY -  30 PATIENTS

16 LVEF Outcome No. Days Pt FU Contr. Stem Cell Rx/Control Source Trial Pts AMImo Infusion Source Comment Onci et al.,2007 Unbl NonePeriph Bl NS Kang et al MAGIC Cell 1 30 NA 24G-CSF Periph Bl  Infusion comp G-CSF Li et al., 2007 Unbl Untreat Periph Bl  7.1%/ 1.6% Tatsumi et al.,2007 Unbl. 54 <5 6None Periph Bl  13.4%/ 7.4% Janssens et al Rand PlacBM NS Kang et al., 2006 MAGIC Cell NA 6 AMI/oldPeriph Bl  5.1%/ -0.2% MI/untreat Lunde et al., 2006 ASTAMI NoneBM NS Meyer et al., 2006 BOOST NoneBM 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 RK Burr et al., JAMA 2008; 299:925 No. FU Stem Cell Source Trial Type Pts, mo RouteSource LVEF Outcome, Comment Gao et al., 2006 Unbl263Intrac BM  LVEF, improv. in CHF Hendrikx et al Rand204IntramBMNS Mocini et al 2006 CABG + cells3612IntramBM  LVEF & wall motion or CABG Erbs et al., 2005Rand.263Intrac.CPCs  Patel et al., 2005Rand.206Intram.CD34  Strauer et al.2005 IACT,No Cont 363Intrac.BM  Perin et al., 2004 Seq enrollm. 2012IntramyocBMNS Rx or contr Perin et al., 2003Single gr214IntramyocBM  2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS

19 2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS RK Burr et al., JAMA 2008; 299:925 No. FU Stem Cell LVEF Outcome SourceTrial Type Pts moRouteSource Comment Assmus et al.,2007 TOPC CHD12119Intrac.BM  mort..high-order CFUs inj. Losardo et al.,2007 Rand2412Intram.CD34Not examined Manginas et al., 2007 Unbl Intrac CD133, CD34  LVEF Stamm et al., 2007 Unbli.406Intram.CD133  LVEF Assmus et al.,2006 TOPC-CHD753IntracorBM  with BM Rand.CPCs Beeres et al Single gr.2612Intram.BM  LVEF, ang. score, perfus. Chen et al., 2006 Unbl4512Intrac.Mesench  isch NYHA cl. LVEF Fuchs et al., 2006 Single gr2712Intram.CD34  CCS angina score

20 CARDIOVASCULAR GENE AND CELL THERAPY “RISKY” AND “EXCITING” 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

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

22 Strauer Avilés Janss. Perin Zeiher Booster Zeiher ASTAMI REF# Nº Pts (ther/ctrl) CD34 (‰) Nº Cells (X10 6 ) LAD disease Follow- Up Time AMI-ther 20 (10/10) 33 (20/13) 20 (11/9) 101 (52/49) 29 (29/0) 60 (30/30) 36 (18/18) 67 (33/34) 204 (101/103) 40 % 89 % 78 % % ? (77 % ) 64 % 100 % ? (68 % ) ? ? d d Chronic MI 4.9d 4.8d 3-6d 5-8d Chronic MI 3m 6m 4m 12m 6m 4m 6m Repair -AMI ASTAMI 1) Great Heterogeneity

23 2) EJECTION FRACTION - OVERVIEW OF CLINICAL TRIALS OF STEM-CELL OR PROGENITOR-CELL DELIVERY TO THE HEART Cell type Study No. ofMean FUNo. cells Route of inj. Ejection fraction Source design ptsmos.injected vs control (%) CPCCohort54 65 x 10 9 Intracoronary +6.0 (P=0.04)Tatsumi et al., (2007) Cohort73 62 x 10 9 Intracoronary +2.8 (NS) Choi et al., (2007) R-SB47 32 x 10 7 Intracoronary +0.8 (NS) Assmus et al., (2006) R x 10 9 Intracoronary -0.2 (NS) Kang et al., (2006) Cohort x 10 7 Intracoronary +5.5 (P=0.04) Li et al., (2006) SB26 37 x 10 7 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 typeStudy No. Mean FUNo. cellsRoute of inj.Ejection fractionSource design ptsmos.injectedvs control (%) BMMNCR-SB Intracoronary+7.0 (P=0.03) Meluzin et al., (2007) R-SB5132 x 10 8 Intracoronary+4.1 (P=0.001) Assmus et al., (2006) R-SB Intracoronary+3 (P=0.04) Meluzin et al., (2006) R-SB x 10 8 Intracoronary  mortality Schächinger et al., (2006) R-SB2064 x 10 7 Intracoronary+6.7 (NS) Ge et al., (2006) R-SB2046 x 10 7 TEIM+2.5 (NS) Hendrikx et al., (2006) R-DB x 10 8 Intracoronary+1.2 (NS) Jannsens et al., (2006) R-SB x 10 7 Intracoronary-3.0 (P=0.05) Lunde et al., (2006) R-SB x 10 9 Intracoronary+2.8 (NS) Meyer et al., (2006) Cohort3633 x 10 8 TEIM+4.0 (NS) Macini et al., (2006) R-SB x 10 8 Intracoronary+2.5 (P=0.01) Schächinger et al., (2006) Cohort3639 x 10 7 Intracoronary+7.0 (P=0.02) Strauer et al., (2005) Cohort x 10 7 TEIM+8.1 (NS) Perin et al., (2004) Cohort x 10 7 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 CARDIOVASCULAR GENE AND CELL THERAPY “RISKY” AND “EXCITING” 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

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. Science 2006;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 TF MMPs CAMs Flow Reversal Mechanical & Biohumoral Risk Factors LDL ET Extracellular Matrix Fibroblasts Vasa Vasorum SMC contraction migration proliferation PDGF Fuster V et. al. J Am Coll Cardiol 2005;46:937. b) c) THROMBUS 3bc)

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-1 Positive Progenitor Cells to Endothelium and Vasa Vasorum after Arterial Injury in Mice 3c) Contribution of BM-derived Sca-1 Positive 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 S Dimmeler, J Burchfield, AM Zeiher. ATVB 2008; 28:208 (Frankfurt) Cell homing and tissue integration Paracrine Effects EC Differentiation SMC Differentiation Cardiac Differentiation Fusion Functional Improvement Angiogenesis Arteriogenesis Attraction/ Activation of CSC Cardiomyocyte Proliferation Scar Remodelling Modulation of Inflammation Cardiomyocyte Apoptosis  Cardio- myogenesis Vasculo- genesis

38 4) Challenges for Cell-Based Therapy in Cardiac Repair Short and Long Term Function Dimmeler S, Zeiher AM, Schneider MD J Clin Invest 2005:115;572.

39 CARDIOVASCULAR CELL AND GENE THERAPY “RISKY” AND “EXCITING” 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

40 1) TRIALS OF CELL THERAPY OR G-CSF - MRI END POINT Author/AcronymPatients n FUReference Result LundeSTEMI476 moLVEF, inf. sizeNo diff. (2006) Ripa (STEMMI) STEMI336 moLVEF, inf. massNo diff. (2006) Kang (MAGIC) MI25 acute6 moLVEFNo diff. (2006)16 old Hendrilox MI104 moLVEFNo diff. (2006) Engleman STEMI193 moLVEF, inf. areaNo diff. G-CSF STEMI (2006) R Gibbons et al., JACC 2007; 50:988

41 2) MRI IN HUMANS - BIOLOGY AND OUTCOMES AuthorPopulationnMRI PredictorOutcomes FU Yan et al. MI (25% acute, 58%144% of MI with <1. All-Mortality.29 mo (2006) chron., 17% ?age) intense DE 2. 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 lysis19Transm ext. DEImproved in wall 8 weeks (2006) thickening Tarantini AMI s/p PCI76Transm. DE, Centr.Change LVE DV I 6 ± 1 mo et al. (2006) NE (Microv Obst) or LVEF White et al. CHF with28% DEClin. Resp. CRT3 mo (2006) CRT Ypenburg Isch cardiom.34Segments for DE1. LV vol./LVEF6 mo et al. (2007) with CRT2. Clin Resp. CRT Kaandorp AMI 29% DE  End-diast vol9 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 NSVTCompletePVCsSVT AS Adabag, BJ Maron et al., J Am Coll Cardiol 2008; 51:1369 (Minn) % Patients with Arrhythmia P< P=0.001 P=0.007 P=0.07 DE present DE absent

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 %S HEHE + MORemote P<0.001 P=NS Week 1 Week 8 CJ Choi et al., JCMR 2004; 6:917 (Charlottesville, VA) HE – Delayed Hyperenhancement MO – Microvascular Obstruction

45 2b) Example of Myoc. Contr. Echo.(MCE) image in 4 Ch, 2 Ch and LAX view. Galiuto L, Crea F et. al. Heart 2007;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 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 3 Metoprolol Administration Pre-reperfusion. Direct CMR Visualization of Cardioprotection (Pig) T2W T1 T2W / T1

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

50 CARDIOVASCULAR CELL AND GENE THERAPY “RISKY” AND “EXCITING” 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

51 1)Turning skin into embryonic stem cells S Yamanaka, HY Chang, et. al. Nat Med. 2007;13:783. Cell, Nov 20, 2007 J Yu, JA Thomson et al., Science 2007; 318:1917

52 Anyone can do it ? Everyone can have their own custom-tailored cells ? To use custom-made cells “would take a ridiculous amount of money” Very expensive— a desire that some companies will no doubt try to capitalize on. Cyranoski D. Nature 2008;452:406. “Expertise in human embryonic stem- cell culture is absolutely critical.”

53 Cyranoski D. Nature 2008;452:406. The cures are on their way ? Status: Too soon to tell Embryonic stem cells are the same as iPS cells ? iPS cells, no ethical issues ? “maybe worse ones. Someone might use iPS cells to derive gametes— human reproductive cells”. “If you can’t tell a difference between iPS & embryonic stem cells, these will be a historical anomaly.”

54 2) Presence of Bona fide Cardiac Progenitors from Embryonic Stem Cells Is this the Ideal Cell For Regeneration?

55 3) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts Laflamme, MA et. al. Nat Biotech. 2007;25:1015. J-Y Hahn, H-S Kim et al., JACC 2008; 51:933(Seoul, Korea)

56 Lyon AR et. al. Heart 2008;94:89. 4) Nucleic acid processing steps required by gene therapy vectors for expression of their therapeutic gene

57 4) Vectors used in gene therapy trials International Gene Therapy Clinical Trial Registry 20 July 2007) Lyon AR et. al. Heart 2008;94:89. (up to Jan 2007)

58 4) POTENTIAL GENE THERAPY STRATEGIES FOR CARDIOVASCULAR DISEASES FieldDiseaseGeneMechanism HFDilated & Ischaemic CMSERCA2a Cardiac S100A1Calcium cycling IGF-1, Gr.Horm, HSP70iAntiapoptotic  TGF-1, thyr. Horm. Recept.Prev. of ventr. fibrosis Hypertrophic and famil. DCSarcom. or cytosk. prot, cell adh.Replac. of def. prot with. Arrhythmogenic RVD prot. (ARVC),  -galact. A (Fabry’s) normal wild-type prot. CADMyocardial ischaemiaVEGF, bFGF, HIF1  Angioneogenesis Plaque instabilityTIMPsInhibit MMP-mediat. plaq. Rupt. EPSAtrial fibrillationConnexin 43Stabilise conduction between cariomyocytes Ventric. ArrhythmiasSERCA2a, connexins LDTSNa+ or K+ channel subunitsNormalise ventr. APO repol. Sinus Node Dis. &/or CHBHCN4Novel pacem. Activi. HYPERT.Antis. or siRNA target. renin-angiot-Downreg. Neuroh. aldost. and/or endoth. systemspathways activ. in hypert. FAMILIAL PAPAbn. Pulm. Art. Remod.BMP receptor 2Replace mutated receptor Cardiac Transpl. RejectionPD-1.1g RANTES or MCP-1 antag. Reduce card. graft reject. AR Lyon, M Sato, RJ Hajjar et al., Heart 2008; 94:89

59 5) In Vivo Autologous Recellularization of a Tissue-engineered Porcine Pulmonary Heart Valve (In Lamb) A Vincentelli et. al. J Thorac Cardiovasc Surg. 2007;134:424 (Lille). AN Morrit et al Circ 2007;115:353 (Melbourne) – Vascularized Chamber

60 CARDIOVASCULAR GENE AND CELL THERAPY “RISKY” AND “EXCITING” 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

61 1) Long-Term Caution (Animals) Most preclinical studies only examined a limited time window of events in the foster millieu and hence may fail to detect insidious, potentially prohibitive side effects (i.e., Teratomas). Careful monitoring of transdifferentiation and fusion events as well as disruptive or neoplastic growth patterns will be critically important before ES cell-derived regenerative treatments can be realistically considered. S Janssens. Heart 2007; 93:1173 J Leor et al., Heart 2007; 93:1278 F Cao et al., Circ 2006; 113:1005

62 2) ETHICS AND ANIMAL-HUMAN HYBRID-EMBRYO RESEARCH There is a great difference between creating stem-cell lines for research or using cytoplasmic-hybrid embryos and bringing true animal-human hybrids to term. The promise of this research is significant. Somatic- cell nuclear transfer will allow the production of stem cells that will enable us to develop new treatments, but the ethical questions are inmense and deserve open discussion. The Lancet 2007; 370:909

63 Stem Cell Therapy is Available Now The Institute of Cellular Medicine (ICM) is currently accepting patients with the following conditions for stem cell therapy: 1) ALS 2)Autism 3) Autoimmune Diseases 4) Cardiovascular Disease 5) Cerebral Palsy 6) Diabetes Type 2 7) Multiple Sclerosis 8) Parkinson's Disease 9) Rheumatoid Arthritis 10)Stroke 3)


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