stamceltechnologie: mythe of realiteit
DESCRIPTION
Stamceltechnologie: Mythe of Realiteit. Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven. Emeritiforum KULeuven, 26 april 2007. Infarct size (% LV mass). 40 years later: VALIANT study (14,703 post-MI pts with reduced EF or CHF ) 1 y mortality: 13% - PowerPoint PPT PresentationTRANSCRIPT
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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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Cardiale Regeneration in 2007: “the stem cell approach”
Caulfield et al . Circ 1976
0
10
20
30
40
50
60
Infarct size(% LV mass)
48% 28%
Shock, Death CHFPfeffer et al . NEJM 2003
40 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%
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Full Regeneration of Myocardium in Zebrafish
Poss et al., Science 2002;298; 2188Poss et al., Science 2002;298; 2188
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Cardiac Regeneration in 2007: the (stem) cell paradox?
- skeletal myoblasts (1998-2001)- fibroblasts (2000)- smooth muscle cells (2003)- endothelial progenitor cells (2001)- mesenchymal stem cells (2005)- hematopoietic stem cells (2001-04)- other BM-derived cells (2005)- cardiac progenitor cells (2005)- ES cell-derived CMC (2005) ……….
Different cell types with uniform benefit on cardiac function:
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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?
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Sca-1+ cellsc-Kit + cells
SP cells
Endothelial Progenitor Cells
Hematopoietic SCsMesenchymal SCs
HemangioblastsSP cellsMAPC
Sca-1+ cellsMyoblastsSP cells
Mesenchymal SCsSPcells
PLURIPOTENT
Cel Types voor Cardiaal Herstel(adapted from Dimmeler et al. , JCI 2005)
Chronisch MI:MAGIC phase II
Acuut MI
Stabiele Ischemie
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Sca-1+ cellsc-Kit + cells
SP cellsCardiospheres
Future for Cardiac Resident (Stem) Cells?
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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, FGF2SDF-1, IL-8,…. G-CSF
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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
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BOOST: LV-Ejection Fraction after 6 and 18 Months
(Circulation 2006;113:1287-94)
BMC-TransferControls
LV
EF
[%
]
0.7% 6.7%2.4% -0.8%
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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?
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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
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Bone Marrow Cell Transfer Post-AMI(randomized controlled trials 2006)
44
45
46
47
48
49
50
51
52
LVEF - MRI (%)
BMSCCON
Leuven AMI (n=67)
+ 2.2% + 3.4%
= +1.2% (P=NS)
4-mo 4-mo
(Lancet 2006; 367:113-121)
51
52
53
54
55
56
57
58
42
44
46
48
50
52
54
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 CON BMSCBMSC
4-mo 4-mo 6-mo 6-mo
LVEF - angio (%)
(NEJM 2006; 355:1199-1221)
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Bone Marrow Cell Transfer Post-AMIDoes infarct size matter?
BMCPlac
20
-20
10
-10
0
Change EF(%)
NEJM 2006; 355:1210-21
Baseline EF <48.9% Baseline EF >48.9%
P=0.002
P=0.81
(52) (41) (40) (54)
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Bone Marrow Cell Transfer Post-AMIDoes timing matter?
20
-20
10
-10
0
LV-EF (%)
Time after PCI (days)
46 (8) 47 (9)
(n=36)LV-EF (%)
P=NS
3-4 d 4 moLV-EDV
(mL)
P=0.014162 (33) 175 (43)
3-4 d 4 mo
>4 d <4 d
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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
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BMSC Treatment Effect* on Infarct Size
0
5
10
15
20
25
30
CONTROL BMSC
BASELINE4 Months
Infarct size (g)
P=0.036
* Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.
28% treatment effect*
**
**
Lancet 2006; 367:113-121
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BMSC Treatment Effect* on Infarct Size
0
5
10
15
20
25
30
CONTROL BMSC
BASELINE4 Months1 Year
Infarct size (g)
P=0.036
* Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.
28% treatment effect*
**
**
23%
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-20
-15
-10
-5
0
Baseline 5 d 2 mo 4 mo 1 yr
(n=232)
Infarcted segments
* *
ES Strain(%) BMSC
Control
* p < 0.001
Treatment Effect
Time Profile
Regional Function AnalysisTDI: End-systolic Strain
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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 1 1
Recurrent ischemia, PCI 2 4
Congestive Heart Failure - 1
Others: depression
PAD (claudication)
11
1-
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Schachinger, V. et al. Eur Heart J 2006 27:2775-2783
Kaplan-Meier event-free survival analysis
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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.
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• 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
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Sca-1+ cellsMyoblastsSP cells
Cell Sources for Cardiac Repair(adapted from Dimmeler et al. , JCI 2005)
Ischemic Cardiomyopathy
(EF<35%)MAGIC phase II
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MAGIC Phase 1 Study
To assess the feasibility and safety of autologous skeletal myoblasts in pts with
ischemic heart failure.
Single center (F): n=10Suggestion of efficacy (EF, NYHA, WMSI)
Cave: arrhythmogenicity
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MAGIC Phase 2: Studie Procedures
BiopsieBiopsie
GMP Cell ProcessingGMP Cell Processing Cel suspensieCel suspensie
10 g10 g
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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
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Skeletal Myoblast Transplantation
• Total of 30-35 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: 15-20 min
X X X X XX X X X XX X X X XX X X X XX X X X X
Infarct Zone(Scar)
Peri-InfarctZone
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High dose groupLow dose groupPlacebo group
Summary of Time to First MACE
12
0 1 6 12 18 2420
30
40
50
60
70
80
90
100
Months from CABG
MA
CE-f
rees
urv
ival(%
)
30 24 24 20 16 333 29 20 14 5 334 32 27 20 17 8#
at
risk
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 groupLow dose groupPlacebo group
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13
200 1 6 12 18 24
30
40
50
60
70
80
90
100
Ve
ntr
icu
lar
arr
hyth
mia
-fre
e su
rviv
al (%
)
Months from CABG
30 25 22 19 16 533 27 24 18 7 534 33 31 21 14 6#
at
ris
k
High dose groupLow dose groupPlacebo 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
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The MAGIC Trial
Regional Wall MotionPatients with Qualitative Echo Data at Baseline
and Month 6
Number of patients 26 28 31
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 dose Low dose Placebo
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LV End-Diastolic Volume
Data are given as median (interquartile range)
High dose Low dose Placebo-50
-40
-30
-20
-10
0
10
20
30
ED
V a
bs
olu
te c
ha
ng
e
n=26-23.0
(-42.0;0.0)
n=27-9.0
(-33.0;25.0)
n=30+9.0
(-21.0;28.0)
p=0.006
p=0.62
mL
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Sca-1+ cellsc-Kit + cells
SP cellsCardiospheres
10
010
110
210
310
40
150
pos isotype PE
Isotype control
Sca-1
Sca-1+ cells60,000 - 100,000
Total %Sca-1+
3500 89.97
Future for Cardiac Resident (Stem) Cells?
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Smith, R. R. et al. Circulation 2007;115:896-908
Regenerative Potential of Biopsy-derived Human Cardiospheres
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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): Q3 2007 (US)
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Stamcelbehandeling: Fontein van de Eeuwige Jeugd?
Lucas Cranach (olie op canvas 1546)
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- Departments of Cardiology, Hematology, Radiology, Nuclear Medicine, Radiopharmacy, Biostatistics- Leuven Coordinating Center (LCC) - Referring Cardiology Sites
AcknowledgmentsGasthuisberg University Hospital & CTG, VIB-3
University of Leuven, Belgium