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Presenter Disclosure InformationValentin Fuster, M.D., Ph.D.

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

Late 1990’s

JM Isner et al., Circ Res 2001; 89:389

EARLY 2000’s GENE THERAPY, USA TRIALS VECTORS AND TRANSGENES

8%

Adenoviral53%

Plasmid DNA39%

PDGF8% FGF

8%

HIF-f / DP1614%

NOS3%

Del-13%

VEGF64%

DNA Liposome

Therapeutic Angiogenesis for Limb Ischaemia

Yuyama, ET et. al. Lancet 2002; 360: 427.

Angiographic analysis of collateral vesselformation

Knee and upper tibia

Lower tibia, ankle and foot

24 wks after implantationBefore implantation

DELIVERY OPTIONS FOR IMPLANTING MYOCARDIAL GENE TRANSFER

Nature 2002;415;234

PROTEIN AND GENE BASED APPROACHES TOCORONARY ANGIOGENESIS – MID 2000’s

Study DiseaseTherapy Agent Trial Phase RandomizedFeatures

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 HGF 1 No Endocardial Inj.

HC Herrmann et al., AHJ 2006; 151:S30

Angiogenic Agents – 2005

• PHASE III CLINICAL TRIALSPHASE III CLINICAL TRIALS

00

Potential Reasons for Early Failures in Angiogenesis Study – Trials in the mid 2000’s

DELIVERY / VECTOR ISSUESDELIVERY / VECTOR ISSUES

• RouteRoute

• ImmunityImmunity

• Pharmacokinetics of vector systemsPharmacokinetics of vector systems

CONCEPTUAL ISSUESCONCEPTUAL ISSUES

• Single Growth Factor Approach SimplisticSingle Growth Factor Approach Simplistic

• Persistent expression (VEGF) needed Persistent expression (VEGF) needed

• Heterogeneity of ResponsesHeterogeneity of Responses

The History of Regeneration – Early 2000’s

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

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

AMI - INTRACORONARY BM - DPCINTERACTION BETWEEN BASELINE LVEF AND THE ABSOLUTE

CHANGE IN LVEF (N=204, FU 4 Mo)

-20

-10

0

10

20

52 41 40 54No. of patients

Base LVEF at or below Median( 48.9%)

Base LVEF above Median(> 48.9%)

Ab

so

lute

Ch

an

ge

in

Glo

ba

l L

VE

F (

%)

P for interaction = 0.02

Placebo BMCP=0.002 P=0.81

At 1 y Reduction Death, MI, Revasc (p<0.01)

REPAIR-MI (V Schachinger et al.) NEJM 2006; 355:1218

AMI - LVEF AT BASELINE AT 2 TO 3 WEEKS AND AT 6 MONTHS

0

80

10

70

20

60

30

50

40

LV

EF

(%

)

2-3 Wk 6 Mo 2-3 Wk 6 Mo

Time after Myocardial Infarction

Mononuclear BMC ControlP<0.001P=0.29

0

2

4

6

8

10

Pe

rce

nta

ge

Po

ints

Change between 2-3 wk and 6 Mo

MononuclearBMC Group

ControlGroup

P=0.054

ASTAMI (K Lenox et al.) NEJM 2006; 355:1199

LVEF OutcomeNo. Days Pt FU Control Stem Cell Rx/Control

Source Trial Pts AMI mo Infusion Source Comment

Meluzin et al., 2006 Rand 66 5-9 3 None BM 5%/ 2% high dose

Schachinger, 2006 REP-AMI 204 3-7 4 Plac BM 5.5%/ 3.0% Schachinger, 2006 REP-AMI 204 3-7 12 Plac BM outcome of death

reinfarctionrevasc

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 boneor 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

1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY - 30 PATIENTS

1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY - 30 PATIENTS

LVEF Outcome No. Days Pt FU Contr. Stem Cell Rx/Control

Source Trial Pts AMI mo Infusion Source Comment

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., 2007 Unbl. 70 6 6 Untreat Periph Bl 7.1%/ 1.6%

Tatsumi et al.,2007 Unbl. 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 MAGIC Cell-3- 82 NA 6 AMI/oldPeriph 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


The Myoblast Autologous Grafting in IschemicCardiomyopathy (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


No. FU Stem CellSource 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

2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF - 20 PTS

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








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

Strauer

Strauer

Avilés

Janss.

Perin

Zeiher

Booster

Zeiher

ASTAMI

REF#Nº Pts

(ther/ctrl)CD34(‰)

Nº Cells(X106)

LAD disease

Follow-Up

TimeAMI-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%

---

55%

?(77%)

64%

100%

?(68%)

28

360

78

172

30

213

2460

236

87

21

?

10

16

24

5

4

?

15

5-9d

13.5

1d

Chronic MI

4.9d

4.8d

3-6d

5-8d

Chronic MI

3m

3m

6m

4m

12m

12m

6m

4m

6m

Repair-AMI

ASTAMI

1) Great Heterogeneity

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

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

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








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.

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)

3) Homing or tissue-committed (cardiac, endothelial, neural) stem cells (TCSC)

Wojakowski W. et. al. Heart 2008;94:27.

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.

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)

TFMMPs

CAMs

Flow ReversalMechanical & Biohumoral

Risk Factors

LDL

ET

Extracellular MatrixFibroblastsVasa Vasorum

SMC contractionmigration

proliferation

PDGF

Fuster V et. al.

J Am Coll Cardiol 2005;46:937.

b)

c)

THROMBUS

3bc)

3b) Early Structural-Functional Changes in the Endothelium for Vascular Disease

Simionescu M. Arterioscler Thromb Vasc Biol. 2007;27:266.

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)

3b) Potential Origin and Differentiation of Endothelial Progenitor Cells

Shantsila E et. al. J Am Coll Cardiol. 2007;49:741.

3c)3c) Contribution of BM-derived Contribution of BM-derived Sca-1Sca-1 Positive Progenitor Cells to Positive Progenitor Cells to

Endothelium and Vasa VasorumEndothelium and Vasa Vasorum after Arterial Injury in after Arterial Injury in MiceMice

3c)3c) Contribution of BM-derived Contribution of BM-derived Sca-1Sca-1 Positive Progenitor Cells to Positive Progenitor Cells to

Endothelium and Vasa VasorumEndothelium and Vasa Vasorum after Arterial Injury in after Arterial Injury in MiceMice

Hutter R, Fuster V, Badimon JJ et al 2007 (Subm)

4) PROPOSED FUNCTION OR ACTION OF STEM / PROGENITORCELLS IN CARDIOVASCULAR REPAIR

S Dimmeler, J Burchfield, AM Zeiher. ATVB 2008; 28:208 (Frankfurt)

Cell homingand tissue integration

Paracrine EffectsEC Differentiation

SMC DifferentiationCardiac Differentiation

Fusion

Functional Improvement

Angiogenesis

Arteriogenesis

Attraction/Activation

of CSC

CardiomyocyteProliferation

ScarRemodelling

Modulation ofInflammation

CardiomyocyteApoptosis

Cardio-myogenesis

Vasculo-genesis

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.

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







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

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 DE 2. CV Mortality (peri-infarct )

Assormull Dilated Cardiom. 101 Mid-wall DE 1. All-Mort./Hp 22 ± 12 moet al.,(2006) 2. SCD or sust. VT

Barclay et al AMI s/p lysis 19 Transm ext. DE Improved in wall 8 weeks(2006) thickening

Tarantini AMI s/p PCI 76 Transm. DE, Centr. Change LVE DV I 6 ± 1 moet al. (2006) NE (Microv Obst) or LVEF

White et al. CHF with 28 % DE Clin. Resp. CRT 3 mo(2006) CRT

Ypenburg Isch cardiom. 34 Segments for DE 1. LV vol./LVEF 6 moet al. (2007) with CRT 2. Clin Resp. CRT Kaandorp AMI 29 % DE End-diast vol 9 moet al. (2007)

R Gibbons et al., JACC 2007; 50:988

2a) PREVALENCE OF ARRHYTHMIAS ON 24-H HOLTER ECG WITHRESPECT TO DE IN 177 HCM PATIENTS

0

10

100

90

80

70

60

50

40

30

20

NSVT Complete PVCs SVT

AS Adabag, BJ Maron et al., J Am Coll Cardiol 2008; 51:1369 (Minn)

% P

atie

nts

wit

h A

rrh

yth

mia

P<0.0001

P=0.001

P=0.007

P=0.07

DE presentDE absent

2b) PMO or No Reflow Zone in Antero-apical infarction

PMO = Persistent Microvascular ObstructionS Rajagopalan, V Fuster Nature CPCM 2006

2b) MI / HE - CHANGES IN CIRCUMFERENTIAL SHORTENING (%S) FROM EARLY ( WEEK 1) TO LATE (WEEK 8) FOLLOW UP - ROLE OF MO

0

5

10

15

20

25

30

%S

HE HE + MO Remote

P<0.001

P=NS

P=NS

Week 1 Week 8

CJ Choi et al., JCMR 2004; 6:917 (Charlottesville, VA)

HE – Delayed Hyperenhancement MO – Microvascular Obstruction

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.

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)

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)

B Ibanez, S Prat, WS Spedl, V Fuster, J Sanz, JJ Badimon Circ 2007;115:2909COMMIT 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

Swine infarct modelcaspase-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).

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







1)Turning skin into embryonic stem cells

S Yamanaka, HY Chang, et. al. Nat Med. 2007;13:783. Cell, Nov 20, 2007J Yu, JA Thomson et al., Science 2007; 318:1917

Anyone can do it ?

Everyone can have their owncustom-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.”

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.”

2) Presence of Bona fide Cardiac Progenitors from Embryonic Stem Cells

Is this the Ideal Cell For Regeneratio

n?

3) Cardiomyocytes derived from human embryonic stemcells 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)

Lyon AR et. al. Heart 2008;94:89.

4) Nucleic acid processing steps required by gene therapy vectors for expression of their therapeutic gene

4) Vectors used in gene therapy trials International Gene Therapy Clinical Trial Registry

http://www.wiley.co.uk/genmed/clinicalaccessed 20 July 2007)Lyon AR et. al. Heart 2008;94:89. (up to Jan 2007)

4) POTENTIAL GENE THERAPY STRATEGIES FORCARDIOVASCULAR DISEASES

Field Disease Gene Mechanism

HF Dilated & Ischaemic CM SERCA2a Cardiac S100A1 Calcium cyclingIGF-1, Gr.Horm, HSP70i AntiapoptoticTGF-1, thyr. Horm. Recept. Prev. of ventr. fibrosis

Hypertrophic and famil. DC Sarcom. or cytosk. prot, cell adh. Replac. of def. prot with. Arrhythmogenic RVD prot. (ARVC), -galact. A (Fabry’s) normal wild-type prot.

CAD Myocardial ischaemia VEGF, bFGF, HIF1 AngioneogenesisPlaque instability TIMPs Inhibit MMP-mediat. plaq. Rupt.

EPS Atrial fibrillation Connexin 43 Stabilise conduction betweencariomyocytes

Ventric. Arrhythmias SERCA2a, connexinsLDTS Na+ or K+ channel subunits Normalise ventr. APO repol.Sinus Node Dis. &/or CHB HCN4 Novel pacem. Activi.

HYPERT. Antis. or siRNA target. renin-angiot- Downreg. Neuroh. aldost. and/or endoth. systems pathways activ. in hypert.

FAMILIAL PAP Abn. Pulm. Art. Remod. BMP receptor 2 Replace mutated receptor

Cardiac Transpl. Rejection PD-1.1g RANTES or MCP-1 antag. Reduce card. graft reject.

AR Lyon, M Sato, RJ Hajjar et al., Heart 2008; 94:89

5) In Vivo Autologous Recellularization of a Tissue-engineeredPorcine 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








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

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

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) ALS2)Autism3) Autoimmune Diseases4) Cardiovascular Disease5) Cerebral Palsy6) Diabetes Type 27) Multiple Sclerosis8) Parkinson's Disease9) Rheumatoid Arthritis10)Stroke

3)

Documents

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