How to mix technology with biology to improve cardiac function?

How to mix technology with biology to
improve cardiac function?
Pieter A. Doevendans
Chief of Div Heart & Lungs UMCU
Visiting Prof Yantai China; Boston US
ESC representative ATMP EMA
COI Founder: Leadpharma; DutchCardio (ICC).
March 2014
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Assist device: Heartmate II
58%
24%
Fang N Engl J Med 2009
Stem cell to product
•
•
•
•
•
•
•
Embryonic stem cell/iPS
cell/iPS
BMMNC
MSC
Cardiac stem cell (CSC; CMPC)
Exosomes
Pure factors/small molecules
Cells and scaffolds: TE
Cardiac repair:
• Angiogenesis; Ischemia
– Stem Cells;
Cells; Exosomes
Exosomes;; Growth factors
• Myocardial tissue: Cardiac Failure
– Stem Cells; Exosomes
Exosomes;; Growth factors
– Tissue engineering
Stem cells for MI/Cardiac Failure
• BM MNC
• MSC:
– Autologous
– Allogeneic
• CSC
Meta analysis
Total: 1340
Zimmet et al,
Eur J Heart Fail 2012;14:91-105
Trend to better outcome in the BMC group
Death
p=0.09
Cardiac Death
p=0.24
Death or MI
p=0.24
Death or Rehospitalization
for heart failure
p=0.08
Death, MI or Rehospitalization
for heart failure
p=0.14
Death, MI or Revascularization
p=0.03
0.2
BMC better
0.4
0.6
0.8
1.0
1.2
1.4
Placebo better
BAMI
protocol
Diagnosis of myocardial infarction
Primary Angioplasty <12 hours
Days 3-5
Echocardiogram EF<45%
BM Aspiration
100mls
Days 5-8
Repeat
Angiography
Standard care
BMMNC
infusion
2 years
Study end-point - mortality
 3000 patient outcome
study
 End
End–
–point = 25 %
reduction in death (all
cause at 2 years)
 STANDARDISATION of
cell processing technique
L UMC UU-HF trial
Design
• Randomized, double blinded, placebo controlled trial
Patients
• Ischemic Heart failure (EF<40%); no option (2x32 pts
pts))
Intervention
• NOGA guided intramyocardial injections of autologous
BMMNC (100x106) or placebo
Endpoints
• Primary: LVEF (SPECT) at 3 months
• Secondary (at 3, 6 and 12 months):
– Function: LVF regional, VO2 max, QoL
QoL,, myocardial
perfusion (incl. FDG SPECT)
– Safety: SAE, arrhythmias
Current Status
• 40 patients included
Sofar:: feasible and safe
Sofar
• Last inclusion expected: Q3 2014
• Primary endpoint (3 months): Q1 2015
PIs
• D. Atsma (LUMC, Leiden)
• S. Chamuleau Utrecht (UMCU,
Utrecht)
The next generation ….
1. MSC
2. CSC
3. iPS
Stem cells for MI/Cardiac Failure
• BM MNC
• MSC:
– Autologous
– Allogeneic
• CSC
The AMICI trial
• Allogeneic StroStro-3bright Mesenchymal Precursor
Stem Cells
• in the treatment of patients with an acute
STEMI
• FIM australia Q2 2013
• PI Eric Duckers UMC Utrecht
The AMICI clinical trial
• Multi-center, prospective, randomized, double-blinded phase IIa/IIb study with a sequential
design, with 3 parallel arms and blinded core lab analyses
• 1:1:1 randomization: 12.5/25.0 Mill allogeneic MPC vs placebo control
Phase A
FIM phase
(n = 30)
Stage B
(n = 96)
Stage C
(n = 225)
12.5 Mill MPC
n = 32
12.5 Mill MPC
n > 75
25.0 Mill MPC
n = 32
25.0 Mill MPC
n > 75
control group
n = 32
control group
n > 75
w 6 mo FU
w 1 mo FU
acute
STEMI
1:1:1
• all-comers anterior AMI
• de novo AMI
• successful PPCI
• ic infusion after PPCI
• FU CMR/ TTE/ SPECT 2 yrs
Safety
& Feasibility
Safety
& Feasibility
review by DSMB
& steering
Dose
Finding
Interim
Analysis
Power Analysis &
Adjustment of cohorts
AMICI clinical trial
collaborating centers in US/EU/Aus
45 EU centers projected
Belgium
UZ Brussels, Brussels
ZNA Middelheim, Antwerpen
Imelda Ziekenhuis, Bonheiden
Denmark
Rigshospitalet, Kopenhagen
Aalborg Sygehus, Aarhus University Hospital,
Aalborg
20 US centers projected
Minneapolis
Czech
Republik
Fakultni nemocnice u Sv. Anny, Brno
Minnesota Heart Institute, MN
IND will be submitted after first 30 EU pts
Vseobecna fakultni nemocnice v Praze, Praha
FNKV Prague, Prague
United
Kingdom
City Hospital NHS Trust, Birmingham
Leicester General Hospital, Leicester
West of Scotland Regional Heart Centre, Glasgow
Freeman Hospital, Newcastle
Netherlands
Erasmus Medical Center, Rotterdam
Maastricht UMC, Maastricht
Poland
10 Australian centers projected
Australia
St George Hospital, Kogarah NSW
University Medical Center Utrecht, Utrecht
John Hunter Hospital, New Lambton
OLVG Ziekenhuis, Amsterdam
Box Hill Hospital, Box Hill
HAGA Ziekenhuis, Den Haag
The Nothern Hospital, Epping
Pracownia Kardiologii Inwazyjnej, Lodz
Royal Perth Hospital, Perth
Pomorskie Centra Kardiologiczne Sp. Gdansk
Royal Adelaide Hospital, Adelaide
Klinika Zaburzen Rytmu Serca, Warszawa
Sir Charles Gairdner Hospital, Nedlands
Warszawski University, Warszawa
Royal Prince Alfred Hospital, Sidney
Stem cells for MI/Cardiac Failure
• BM MNC
• MSC:
– Autologous
– Allogeneic
• CSC
Human cardiomyocyte progenitor cells
CMPC
nucleus
endothelium
SMC
Goumans et al, Stem Cell Research, 2007
Bolli Lancet 2011 SCIPIO
Cardiac repair:
• Angiogenesis; Ischemia
– Stem Cells;
Cells; Exosomes
Exosomes;; Growth factors
• Myocardial tissue: Cardiac Failure
– Stem Cells;
Cells; Exosomes
Exosomes;; Growth factors
– Tissue engineering
Cardiac Tissue Engineering
Engineering:: porcine
Koudstaal, 2013 adv
biomaterials
Conclusion
Stem Cell studies Acute
Chronic
BM-MNC
BAMI
L UMC U trial
Autologous
ADVANCE
TAC-HFT
Allogeneic
AMICI
MPC helix
CSC
Fetal
SCIPIO
MSC
Exosomes
TE
Acknowledgements
Dept of Cardiology, Utrecht
Prof. Pieter Doevendans, MD PhD
Eric Duckers MD PhD
Steven Chamuleau, MD PhD
Roberto Gaetani, PhD
Hamid el Azzouzi, PhD
Jia Liu, MD PhD
Marish Oerlemans, MD
Krijn Vrijsen, MSc
Zhiyong Lei, MSc
Corina Metz
Esther van Eeuwijk
Krista den Ouden
Ben van Middelaar
Prof. Gerard Pasterkamp, MD PhD
Part of this research forms part of the Project P1.05 LUST of the
research
program of the BioMedical Materials institute, co-funded by the Dutch
Ministry of Economic Affairs, Agriculture and Innovation.
The financial contribution of the Nederlandse Hartstichting is gratefully
acknowledged.
Novel target identification
MGH:
Peter Paul Zwetsloot
Jan Willem Buikema
Ibrahim Domian
Loren Field
Mark Mercola
Molecular Cell Biology, Leiden
Prof. Marie-José Goumans,
PhD
Anke Smits, PhD
What are exosomes
exosomes?
?