Transcript “RISKY” AND “EXCITING”

Presenter Disclosure Information
Valentin 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
Foundation for
CV Education & Research
GlaxoSmithKline
Modest
Chair HRP
BG Medicine
Significant
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
EARLY 2000’s GENE THERAPY, USA TRIALS
VECTORS AND TRANSGENES
DNA Liposome
PDGF
8% FGF
8%
8%
Plasmid DNA
39%
Adenoviral
53%
VEGF
64%
HIF-f / DP16
14%
NOS
3%
Del-1
3%
JM Isner et al., Circ Res 2001; 89:389
Therapeutic Angiogenesis for Limb Ischaemia
Knee and upper tibia
Lower tibia, ankle and foot
Angiographic analysis of collateral vessel
formation
Before implantation
24 wks after implantation
Yuyama, ET et. al. Lancet 2002; 360: 427.
DELIVERY OPTIONS FOR IMPLANTING MYOCARDIAL GENE TRANSFER
Nature 2002;415;234
PROTEIN AND GENE BASED APPROACHES TO
CORONARY ANGIOGENESIS – MID 2000’s
Study
DiseaseTherapy
Agent Trial Phase Randomized
Cardis Vasc-Grow
CAD
Protein
FGF1
1
Simons et al.,
CAD
Protein
FGF2
1
Euro-Inject, Losordo et al CAD
Gene
VEGF2
1/2
AGENT, Grines et al.
CAD
Gene
FGF4
1
Genesis
CAD
Gene
VEGF2
2b
AnGes MC
CAD
Plasma
HGF
1
HC Herrmann et al., AHJ 2006; 151:S30
No
Features
Minithoracotomy
No
Yes
Endocardial Inj.
No
Yes
Endocardial Inj.
No
Endocardial Inj.
Angiogenic Agents – 2005
• PHASE III CLINICAL TRIALS
0
Potential Reasons for Early Failures in
Angiogenesis Study – Trials in the mid 2000’s
DELIVERY / VECTOR ISSUES
• Route
• Immunity
• Pharmacokinetics of vector systems
CONCEPTUAL ISSUES
• Single Growth Factor Approach Simplistic
• Persistent expression (VEGF) needed
• Heterogeneity of Responses
The History of Regeneration – Early 2000’s
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)
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 - DPC
INTERACTION BETWEEN BASELINE LVEF AND THE ABSOLUTE
CHANGE IN LVEF (N=204, FU 4 Mo)
Absolute Change in Global LVEF (%)
Placebo
BMC
P=0.002
P=0.81
20
10
0
-10
P for interaction = 0.02
-20
No. of patients
52
41
40
54
Base LVEF at or below Median
Base LVEF above Median
( 48.9%)
(> 48.9%)
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
80
Mononuclear BMC
Control
P=0.29
P<0.001
Change between 2-3 wk and 6 Mo
10
Percentage Points
70
LVEF (%)
60
50
40
30
20
10
0
2-3 Wk
6 Mo
2-3 Wk
6 Mo
Time after Myocardial Infarction
ASTAMI (K Lenox et al.) NEJM 2006; 355:1199
8
P=0.054
6
4
2
0
Mononuclear
BMC Group
Control
Group
1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY -  30 PATIENTS
LVEF Outcome
Source
Trial
No. Days Pt
Pts
AMI
FU Control
mo Infusion
Stem Cell
Source
Comment
Rx/Control
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
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
69
>18
6
Plac
Mesench
 18%/ 6%
Schachinger, 2004 TOPC-AMI
54
3-7
12
None
BM
or CPCs
 3% for both bone
and CPCs at 4 mo
Wolert et al., 2004 BOOST
60
4-8
6
None
BM
 6.7%/ 0.7%
Rand
RK Burr et al., JAMA 2008; 299:925
1) AMI - CLINICAL TRIALS OF STEM CELL THERAPY -  30 PATIENTS
LVEF Outcome
Source
Onci et al.,2007
Trial
No.
Pts
Unbl.
73
Days Pt
AMI
FU
mo
Contr.
Infusion
Stem Cell
Source
Rx/Control
Comment
5-19
24
None
Periph Bl
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
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
NS
 5.1%/ -0.2%
AMI/oldPeriph Bl
MI/untreat
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 cardioverterdefibrillator. 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
2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS
Trial Type
No.
Pts,
FU
mo
Unbl
26
3
Intrac
Hendrikx et al. 2006 Rand
20
4
Intram
BM
Mocini et al 2006 CABG + cells 36
or CABG
12
Intram
BM
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.
Rx or contr
20
12 Intramyoc
BM
NS
Perin et al., 2003 Single gr
21
4
BM

Source
Gao et al., 2006
RK Burr et al., JAMA 2008; 299:925
Stem Cell
Route
Source
Intramyoc
BM
LVEF Outcome, Comment
 LVEF, improv. in CHF
NS
 LVEF & wall motion
2) CHR. MYOC ISCH TRIALS OF STEM CELL Rx OR HF -  20 PTS
No.
Pts
FU
mo
Stem Cell
Route
Source
Assmus et al.,2007 TOPC CHD 121
19
Intrac.
BM
 mort. .high-order CFUs inj.
Losardo et al.,2007
CD34
Not examined
Source
Trial Type
LVEF Outcome
Comment
Rand
24
12
Intram.
Manginas et al., 2007 Unbl.
24
28
Intrac
Stamm et al., 2007
40
6
Intram.
CD133
 LVEF
Assmus et al.,2006 TOPC-CHD 75
Rand.
3
Intracor
BM
CPCs
 with BM
Beeres et al. 2006
26
12
Intram.
BM
 LVEF, ang. score, perfus.
Unbli.
Single gr.
CD133, CD34
 LVEF
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
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
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.
1) Great Heterogeneity
REF#
Strauer
Avilés
Perin
Zeiher
Booster
Strauer
Janss.
Repair
-AMI
Zeiher
ASTAMI
ASTAMI
Nº Pts
(ther/ctrl)
20
(10/10)
33
(20/13)
20
(11/9)
29
(29/0)
60
(30/30)
36
(18/18)
67
(33/34)
204
(101/103)
101
(52/49)
LAD
disease
Nº Cells
40%
28
21
5-9d
3m
78%
78
10
13.5
6m
---
30
24
Chronic
MI
12m
55%
213
5
4.9d
12m
(77%)
2460
4
4.8d
6m
89%
360
?
Chronic
MI
3m
(68%)
172
16
1d
4m
64%
236
?
3-6d
4m
100%
87
15
5-8d
6m
?
?
(X106)
CD34
(‰)
Time
AMI-ther
FollowUp
2) EJECTION FRACTION - OVERVIEW OF CLINICAL TRIALS
OF STEM-CELL OR PROGENITOR-CELL DELIVERY TO THE HEART
Cell type Study
design
No. of
pts
Mean FU
mos.
No. cells Route of inj.
injected
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
+7.2 (NS)
Erbs et al., (2005)
Intracoronary
VFM Segers, RT Lee. Nature 2008; 451:937
Ejection fraction
vs control (%)
Source
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
pts
mos.
injected
vs control (%)
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)
design
BMMNC
VFM Segers, RT Lee. Nature 2008; 451:937
Source
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
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
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)
3bc)
Flow Reversal
Mechanical & Biohumoral
Risk Factors
THROMBUS
LDL
b)
CAMs
TF
MMPs
c)
Fuster V et. al.
J Am Coll Cardiol 2005;46:937.
Extracellular Matrix
Fibroblasts
Vasa Vasorum
PDGF
ET
SMC contraction
migration
proliferation
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) 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)
4) PROPOSED FUNCTION OR ACTION OF STEM / PROGENITOR
CELLS IN CARDIOVASCULAR REPAIR
Cell homing
and tissue integration
EC Differentiation
SMC Differentiation
Vasculogenesis
Paracrine Effects
Cardiac Differentiation
Fusion
Angiogenesis
Attraction/
Activation
of CSC
Arteriogenesis
Cardiomyocyte
Proliferation
Cardiomyocyte
Apoptosis 
Modulation of
Inflammation
Cardiomyogenesis
Scar
Remodelling
Functional
Improvement
S Dimmeler, J Burchfield, AM Zeiher. ATVB 2008; 28:208 (Frankfurt)
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”
•
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
1) TRIALS OF CELL THERAPY OR G-CSF - MRI END POINT
Author/Acronym
Patients
n
FU
Lunde
(2006)
STEMI
47
6 mo
LVEF, inf. size
No diff.
Ripa (STEMMI)
(2006)
STEMI
33
6 mo
LVEF, inf. mass
No diff.
Kang (MAGIC)
(2006)
MI
25 acute
16 old
6 mo
LVEF
No diff.
Hendrilox
(2006)
MI
10
4 mo
LVEF
No diff.
Engleman
G-CSF STEMI
(2006)
STEMI
19
3 mo
LVEF, inf. area
No diff.
R Gibbons et al., JACC 2007; 50:988
Reference
Result
2) MRI IN HUMANS - BIOLOGY AND OUTCOMES
Author
Population
n
MRI Predictor
MI (25% acute, 58%
chron., 17% ?age)
Assormull
et al.,(2006)
Dilated Cardiom.
101
Mid-wall DE
1. All-Mort./Hp
2. SCD or sust. VT
Barclay et al
(2006)
AMI s/p lysis
19
Transm ext. DE
Improved in wall
thickening
8 weeks
Tarantini
et al. (2006)
AMI s/p PCI
76
Transm. DE, Centr.
NE (Microv Obst)
Change LVE DV I
or LVEF
6 ± 1 mo
White et al.
(2006)
CHF with
CRT
28
% DE
Clin. Resp. CRT
3 mo
Ypenburg
et al. (2007)
Isch cardiom.
with CRT
34
Segments for DE
1. LV vol./LVEF
2. Clin Resp. CRT
6 mo
29
% DE
 End-diast vol
9 mo
AMI
% of MI with <
intense DE
(peri-infarct )
R Gibbons et al., JACC 2007; 50:988
1. All-Mortality.
2. CV Mortality
FU
Yan et al.
(2006)
Kaandorp
et al. (2007)
144
Outcomes
29 mo
22 ± 12 mo
2a) PREVALENCE OF ARRHYTHMIAS ON 24-H HOLTER ECG WITH
RESPECT TO DE IN 177 HCM PATIENTS
P=0.007
% Patients with Arrhythmia
100
DE present
DE absent
90
80
70
60
50
P=0.001
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)
2b) PMO or No Reflow Zone
in Antero-apical infarction
PMO = Persistent Microvascular Obstruction
S 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
30
Week 1
Week 8
25
20
%S
15
10
5
P=NS
P<0.001
P=NS
0
HE
HE – Delayed Hyperenhancement
HE + MO
Remote
MO – Microvascular Obstruction
CJ Choi et al., JCMR 2004; 6:917 (Charlottesville, VA)
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 PostInfarct 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)
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
3) Myocyte apoptosis at reperfusion can be diminished
by different therapies.
Swine infarct model
caspase-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).
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
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
Anyone can do it ?
“Expertise in human embryonic stem- cell culture
is absolutely critical.”
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.
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 ?
Cyranoski D. Nature 2008;452:406.
“If you can’t tell a
difference
between iPS & embryonic
stem cells, these will
be a historical anomaly.”
“maybe worse ones.
Someone might use iPS
cells to derive gametes—
human reproductive cells”.
2) Presence of Bona fide Cardiac Progenitors
from Embryonic Stem Cells
Is this the Ideal
Cell For
Regeneration?
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)
4) Nucleic acid processing steps required by gene therapy vectors
for expression of their therapeutic gene
Lyon AR et. al. Heart 2008;94:89.
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 FOR
CARDIOVASCULAR DISEASES
Field
Disease
Gene
Mechanism
HF
Dilated & Ischaemic CM
SERCA2a Cardiac S100A1
IGF-1, Gr.Horm, HSP70i
TGF-1, thyr. Horm. Recept.
Calcium cycling
Antiapoptotic
Prev. of ventr. fibrosis
.
Hypertrophic and famil. DC
Arrhythmogenic RVD
Sarcom. or cytosk. prot, cell adh.
prot. (ARVC), -galact. A (Fabry’s)
Replac. of def. prot with
normal wild-type prot.
Myocardial ischaemia
Plaque instability
Atrial fibrillation
VEGF, bFGF, HIF1
TIMPs
Connexin 43
Angioneogenesis
Inhibit MMP-mediat. plaq. Rupt.
Stabilise conduction between
cariomyocytes
Ventric. Arrhythmias
LDTS
Sinus Node Dis. &/or CHB
SERCA2a, connexins
Na+ or K+ channel subunits
HCN4
Normalise ventr. APO repol.
Novel pacem. Activi.
FAMILIAL PAP
Abn. Pulm. Art. Remod.
Antis. or siRNA target. renin-angiotaldost. and/or endoth. systems
BMP receptor 2
Downreg. Neuroh.
pathways activ. in hypert.
Replace mutated receptor
Cardiac Transpl.
Rejection
PD-1.1g RANTES or MCP-1 antag.
Reduce card. graft reject.
CAD
EPS
HYPERT.
AR Lyon, M Sato, RJ Hajjar et al., Heart 2008; 94:89
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
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
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. Somaticcell 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
3)
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