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 Sotsji:: 2014 the tissue issue Sotsji Science and Engineering of the 2014 Olympic Winter Games NBC Learn and NBC Sports, in partnership with the National Science Foundation, explore the science, technology, engineering and math at the 2014 Olympic Winter Games. Lesson plans and activities provided by the National Science Teachers Association. Sotsji:: 2014 Sotsji 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? ?
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