Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial

Abstract

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%–50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887). Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%–50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887). Ischemic cardiovascular diseases remain the leading cause of morbidity and mortality worldwide,1Moran A.E. Forouzanfar M.H. Roth G.A. Mensah G.A. Ezzati M. Flaxman A. Murray C.J. Naghavi M. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study.Circulation. 2014; 129: 1493-1501Crossref PubMed Scopus (402) Google Scholar despite the success of revascularization therapy and medical treatments (e.g., statins and anti-hypertensive and anti-platelet drugs). Patients with myocardial infarction may suffer from impaired cardiac function owing to the loss of billions of cardiomyocytes, which normally do not regenerate following ischemic injury.2Foglia M.J. Poss K.D. Building and re-building the heart by cardiomyocyte proliferation.Development. 2016; 143: 729-740Crossref PubMed Scopus (138) Google Scholar Myocardial regions surrounding the core of a myocardial infarction are poorly perfused at rest or during stress. Although this myocardial tissue has reduced contractility, it remains viable and may be recoverable with revascularization therapy.3Ryan M.J. Perera D. Identifying and managing hibernating myocardium: what’s new and what remains unknown?.Curr. Heart Fail. Rep. 2018; 15: 214-223Crossref PubMed Scopus (12) Google Scholar Combining therapeutic angiogenesis with revascularization could improve outcomes in patients with myocardial infarction by promoting the growth of new blood vessels and regeneration of injured myocardium.4Hughes G.C. Annex B.H. Angiogenic therapy for coronary artery and peripheral arterial disease.Expert Rev. Cardiovasc. Ther. 2005; 3: 521-535Crossref PubMed Scopus (33) Google Scholar Modalities for targeted delivery of angiogenic factors include transplantation of ex vivo expanded cells, gene therapy with naked DNA plasmids or viral vectors, and administration of recombinant proteins.5Johnson T. Zhao L. Manuel G. Taylor H. Liu D. Approaches to therapeutic angiogenesis for ischemic heart disease.J. Mol. Med. (Berl.). 2019; 97: 141-151Crossref PubMed Scopus (33) Google Scholar Vascular endothelial growth factor (VEGF) family members are key regulators of angiogenesis and remain among the most promising candidates for therapeutic angiogenesis.6Ylä-Herttuala S. Baker A.H. Cardiovascular gene therapy: past, present, and future.Mol. Ther. 2017; 25: 1095-1106Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar VEGF-A has been tested in patients with myocardial infarction using gene therapy with plasmid DNA or adenoviral vectors, or administration of recombinant protein, but with inconclusive evidence of efficacy.7Giacca M. Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond.Gene Ther. 2012; 19: 622-629Crossref PubMed Scopus (158) Google Scholar,8Gaffney M.M. Hynes S.O. Barry F. O’Brien T. Cardiovascular gene therapy: current status and therapeutic potential.Br. J. Pharmacol. 2007; 152: 175-188Crossref PubMed Scopus (76) Google Scholar Clinical trials have, however, demonstrated the safety of epicardial injections in patients undergoing coronary artery bypass grafting.9Ahmadi H. Baharvand H. Ashtiani S.K. Soleimani M. Sadeghian H. Ardekani J.M. Mehrjerdi N.Z. Kouhkan A. Namiri M. Madani-Civi M. et al.Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction.Curr. Neurovasc. Res. 2007; 4: 153-160Crossref PubMed Scopus (84) Google Scholar, 10Ang K.L. Chin D. Leyva F. Foley P. Kubal C. Chalil S. Srinivasan L. Bernhardt L. Stevens S. Shenje L.T. Galiñanes M. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone.Nat. Clin. Pract. Cardiovasc. Med. 2008; 5: 663-670Crossref PubMed Scopus (85) Google Scholar, 11Katayama Y. Takaji K. Shao Z.Q. Matsukawa M. Kunitomo R. Hagiwara S. Moriyama S. Kawasuji M. The value of angiogenic therapy with intramyocardial administration of basic fibroblast growth factor to treat severe coronary artery disease.Ann. Thorac. Cardiovasc. Surg. 2010; 16: 174-180PubMed Google Scholar, 12Mocini D. Staibano M. Mele L. Giannantoni P. Menichella G. Colivicchi F. Sordini P. Salera P. Tubaro M. Santini M. Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting.Am. Heart J. 2006; 151: 192-197Crossref PubMed Scopus (83) Google Scholar, 13Patel A.N. Geffner L. Vina R.F. Saslavsky J. Urschel Jr., H.C. Kormos R. Benetti F. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study.J. Thorac. Cardiovasc. Surg. 2005; 130: 1631-1638Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 14Stamm C. Kleine H.D. Choi Y.H. Dunkelmann S. Lauffs J.A. Lorenzen B. David A. Liebold A. Nienaber C. Zurakowski D. et al.Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies.J. Thorac. Cardiovasc. Surg. 2007; 133: 717-725Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, S. B. R. M. J. S. M. G. of patients with ischemic with coronary artery bypass and intramyocardial bone marrow mononuclear cell follow-up PubMed Scopus Google Scholar, M. K. J.M. therapy for myocardial clinical with myocardial injection of as therapy for myocardial PubMed Scopus Google Scholar of efficacy may from gene expression of the protein, with and targeting of ischemic but viable S. C. P. Angiogenic gene therapy in cardiovascular or Heart J. 2017; Google Scholar targeting and delivery of VEGF therapy to regions of viable but myocardium could for improved cardiac function and clinical with therapeutic S. C. P. Angiogenic gene therapy in cardiovascular or Heart J. 2017; Google S. Myocardial therapeutic a of the of and Rev. Cardiovasc. Ther. PubMed Scopus Google Scholar in cardiac 15O-water positron emission tomography (PET) quantitative assessment of myocardial blood flow and which of ischemic but viable myocardium for targeted treatment with angiogenic M. M. C. T. T. M. P. A. T. et of myocardial with A study in myocardial 2019; PubMed Scopus Google Scholar, J. A. A. A. J. M. H. M. et intramyocardial gene myocardial in a study with Heart J. 2017; PubMed Scopus Google Scholar, S. P. et Cardiovascular of of of Myocardial of the Cardiovascular and the Med. 2018; PubMed Scopus Google Scholar mRNA VEGF-A expression and with gene therapy L. mRNA a new for cardiovascular and Med. 2014; 5: Google Scholar mRNA expression in vivo an innate immune and with for K. H. J.M. D. in with of mRNA Ther. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, K. H. J. H. S. D. of into mRNA with and Ther. 2008; 16: Full Text Full Text PDF PubMed Scopus Google Scholar, G. G. S. M. M. A. et of therapeutic after delivery of mRNA in PubMed Scopus Google Scholar, L. T. Y.H. H. F. A. et to and of cells with 2010; Full Text Full Text PDF PubMed Scopus Google Scholar A study in a of myocardial infarction injection of VEGF-A mRNA into cardiac expression of VEGF-A and to gene therapy with plasmid DNA in myocardial and L. A. D. H. M. R. et mRNA the of heart cells and vascular regeneration after myocardial PubMed Scopus Google Scholar AZD8601 is a VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for VEGF-A with minimal of innate immune B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google Scholar, L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar AZD8601 injection expression of VEGF-A in the and in B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google Scholar, L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar with or in and L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar of AZD8601 blood flow and blood vessel in the and heart in B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar epicardial injection of AZD8601 improved cardiac function in following myocardial L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar AZD8601 in with in a randomized, double-blind, M. C. A. M. A. J. et delivery of mRNA VEGF-A in patients with 2019; PubMed Scopus Google Scholar VEGF-A mRNA and to local VEGF-A expression after administration as as local of blood flow at and after M. C. A. M. A. J. et delivery of mRNA VEGF-A in patients with 2019; PubMed Scopus Google Scholar the of an ongoing safety study of epicardial injections of AZD8601 in patients with moderately impaired function are undergoing elective coronary artery bypass quantitative 15O-water PET is to and each of ischemic but viable myocardium for targeted epicardial injections of quantitative 15O-water PET is to in myocardial EPICCURE is a randomized, double-blind, clinical trial of the and exploratory efficacy of epicardial injections of AZD8601 in patients with coronary artery disease and moderately decreased left ventricular fraction are undergoing coronary artery bypass grafting surgery. The study in and is patients at in in in the and in and EPICCURE is as and to the of the of the Clinical the and and and the study and study A 10-min extension of to epicardial injections after of the peripheral The of EPICCURE is to the safety and of include efficacy 15O-water PET of myocardial blood flow as as clinical and and of AZD8601 of AZD8601 and global myocardial blood flow with 15O-water and global myocardial blood flow with 15O-water ventricular left ventricular and left ventricular fraction by myocardial by and function by in the left and in and from in and in coronary flow Heart positron emission vascular endothelial growth factor A. patients are and or are for elective coronary artery bypass grafting and left ventricular fraction is and Patients or be a for at be or using to in and be to or are in > or for for coronary artery bypass or of disease or the patient at or study 30 of ventricular cardiac for or of with of with of or or or of or coronary flow from the of the to the of the myocardial blood are randomized at coronary artery bypass grafting to AZD8601 3 mg, AZD8601 30 mg, or placebo in a of are into and randomized to AZD8601 or placebo with AZD8601 of 3 in the and 30 in the each are randomized to AZD8601 or by randomized to AZD8601 or by the randomized to to AZD8601 or from to after administration are by the safety the treatment of in the each and the treatment of in the and be 15O-water PET and are be reduced the and delivery of be a in the left artery to and and assessment during in coronary flow Heart positron emission vascular endothelial growth and each include with randomized to AZD8601 and randomized to 3 the and each include randomized to AZD8601 or placebo and the randomized to AZD8601 or placebo at is of the or and the study remain to treatment the remain to a treatment in a medical The safety is The placebo for injection the of the of the treatment be is by the using an by the a 15O-water PET to myocardial blood flow at rest and during stress. is with the coronary tomography to a combines coronary and myocardial blood The is to an injection of each injections during Ischemic regions are as with myocardial blood flow 2.3 or of the with myocardial blood flow 15O-water M. M. H. A. M. M. J. et value of of myocardial with in coronary artery Cardiovasc. 4: PubMed Scopus Google T. A. M. S. et assessment of myocardial in the of coronary artery disease: and of quantitative PET 2014; PubMed Scopus Google Scholar regions of ischemic but viable myocardium are as ischemic regions with resting myocardial blood flow 0.6 15O-water the injection 30 epicardial injection with are the The injection is in a the PET and from the study the from the PET core and at from The injection is a coronary and left ventricular myocardial blood flow during or myocardial blood flow < 2.3 The the left the of the left coronary artery for epicardial injections of AZD8601 (stress myocardial blood flow < 2.3 and resting myocardial blood flow > 0.6 mL/g/min). is the ischemic with injections for treatment of the left coronary left coronary artery coronary 30 epicardial injections of by injection to ischemic but viable myocardial Injections are after bypass grafting and treatment of AZD8601 3 injection AZD8601 30 injection or The injection is by or and the the injection the injection Injections are using a to a are the or of or at the injection and Patients remain in the for at after and follow-up at and after to safety and efficacy are by after surgery. outcomes include of and of and and assessment of and left ventricular are from coronary artery bypass grafting the of and are from the of are by the or for as as are to the medical and are to to study and to the injection and global myocardial blood flow and myocardial flow in myocardial blood be using 15O-water PET at and at and 3 after global and cardiac be using at and at and after surgery. follow-up 3 after surgery. at and after left ventricular function and coronary flow at rest and during at the study flow is the in flow in the left S. A. C. S. G. A. P. A. value of coronary flow in patients with myocardial undergoing myocardial Heart 2017; Scopus Google S. H. flow as a cardiac and J. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar Patients the J.A. and of the a new status for heart PubMed Scopus Google Scholar and the J.A. J.A. J. M. and of the a new status for coronary artery disease.J. 25: PubMed Scopus Google Scholar and Heart of the Heart and for of diseases of the heart and Scholar at and at and after in a and a at and at and after be to VEGF-A at during the and and after epicardial and at after to of AZD8601 be during the and and after be at during the and and after the epicardial and at and after for analysis of cardiovascular of are and The study is not patients be randomized for an patients be in randomized patients at injection of AZD8601 or efficacy be in randomized patients at injection of AZD8601 or placebo and for are at and at follow-up from in exploratory be tested using analysis of treatment as a and value as or and treatment and as and as not be for and be of and randomized to the patient and the follow-up in The EPICCURE study of AZD8601 is the clinical trial of mRNA in the high-efficiency VEGF-A expression from mRNA with quantitative treatment and EPICCURE a new and to for therapeutic angiogenesis in patients with cardiovascular EPICCURE is the therapeutic study to 15O-water PET not for targeting of VEGF-A mRNA injections to regions of ischemic but viable but for quantitative assessment of in myocardial blood flow during VEGF-A expression after injection of AZD8601 demonstrated in a with in B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google Scholar, L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar, M. C. A. M. A. J. et delivery of mRNA VEGF-A in patients with 2019; PubMed Scopus Google Scholar in local blood flow in and following AZD8601 together with local of VEGF-A B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google Scholar, L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar, M. C. A. M. A. J. et delivery of mRNA VEGF-A in patients with 2019; PubMed Scopus Google Scholar AZD8601 new blood vessel in and improved cardiac function in a of myocardial B. C. M. M. et VEGF-A mRNA and Rep. 2018; PubMed Scopus Google Scholar, L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar AZD8601 not innate immune in and in with minimal local L. C. F. T. M. et VEGF-A mRNA cardiac function after injection in Ther. Clin. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. G. R.F. L. of VEGF-A following injection of VEGF-A mRNA demonstrated by in the and in Res. 2019; PubMed Scopus Google Scholar, M. C. A. M. A. J. et delivery of mRNA VEGF-A in patients with 2019; PubMed Scopus Google Scholar Previous of VEGF-A gene therapy in patients with ischemic heart disease a evidence for but not S. Baker A.H. Cardiovascular gene therapy: past, present, and future.Mol. Ther. 2017; 25: 1095-1106Abstract Full Text Full Text PDF PubMed Scopus (69) Google S. C. P. Angiogenic gene therapy in cardiovascular or Heart J. 2017; Google Scholar A efficacy however, in the angiogenesis M. J. M. J. A. A. H. S. et al.Safety and of local intracoronary vascular endothelial growth factor gene in the of and and in the treatment of chronic myocardial of the PubMed Google Scholar of VEGF with in regional myocardial in patients coronary but the efficacy outcomes of or minimal M. J. M. J. A. A. H. S. et al.Safety and of local intracoronary vascular endothelial growth factor gene in the of and and in the treatment of chronic myocardial of the PubMed Google Scholar Previous not patients most to from therapeutic not gene delivery to ischemic but viable myocardial not VEGF-A expression and from plasmid or viral vectors, and not quantitative S. C. P. Angiogenic gene therapy in cardiovascular or Heart J. 2017; Google Scholar of are by the of A key of EPICCURE is the targeting of AZD8601 or placebo injections to regions of ischemic but viable myocardium using quantitative 15O-water PET regions a myocardial blood flow but resting myocardial blood flow which may function M. M. H. A. M. M. J. et value of of myocardial with in coronary artery Cardiovasc. 4: PubMed Scopus Google T. A. M. S. et assessment of myocardial in the of coronary artery disease: and of quantitative PET 2014; PubMed Scopus Google Scholar of the study include the randomized, double-blind, placebo-controlled study and the of quantitative and exploratory efficacy outcomes as as clinical and The with the to A key of the study is patients coronary artery bypass grafting to Injections be administered to of the ventricular or during most of the left is may be to to study administration or (e.g., and of patients with moderately reduced left ventricular fraction the of patients are to in most to from improved myocardial following coronary artery bypass of coronary artery bypass grafting with angiogenic may patients to from revascularization with with reduced left ventricular administration of AZD8601 in patients coronary the of AZD8601 with a cardiac has been The of placebo injections is a of the study but may to during surgery. placebo injections during coronary artery bypass grafting been in with safety Y. L. A. study of mononuclear bone marrow cell transplantation in patients with coronary Thorac. Surg. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, B. T. P. The of in the ischemic heart by the growth factor clinical Cardiovasc. Surg. Google Scholar, M. J.A. M.J. J.A. M. of surgical angiogenic therapy with fibroblast growth factor Thorac. Cardiovasc. Surg. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. et treatment with the efficacy of surgical angiogenesis in patients with severe coronary artery disease: the in Angiogenic randomized controlled Thorac. Cardiovasc. Surg. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. A. J. J. M. P. A. R. P. et bone marrow mononuclear cell transplantation in ischemic heart a randomized, study of cell transplantation with coronary Heart 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. Stevens S. K. 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P. et of regional but not global function by the intramyocardial autologous bone marrow transplantation: from a randomized controlled clinical 2006; Google Scholar intramyocardial injection of during coronary artery bypass grafting a safety to in H. Baharvand H. Ashtiani S.K. Soleimani M. Sadeghian H. Ardekani J.M. Mehrjerdi N.Z. Kouhkan A. Namiri M. Madani-Civi M. et al.Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction.Curr. Neurovasc. Res. 2007; 4: 153-160Crossref PubMed Scopus (84) Google Scholar, 10Ang K.L. Chin D. Leyva F. Foley P. Kubal C. Chalil S. Srinivasan L. Bernhardt L. Stevens S. Shenje L.T. Galiñanes M. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone.Nat. Clin. Pract. Cardiovasc. Med. 2008; 5: 663-670Crossref PubMed Scopus (85) Google Scholar, 11Katayama Y. Takaji K. Shao Z.Q. Matsukawa M. Kunitomo R. Hagiwara S. Moriyama S. Kawasuji M. The value of angiogenic therapy with intramyocardial administration of basic fibroblast growth factor to treat severe coronary artery disease.Ann. Thorac. Cardiovasc. Surg. 2010; 16: 174-180PubMed Google Scholar, 12Mocini D. Staibano M. Mele L. Giannantoni P. Menichella G. Colivicchi F. Sordini P. Salera P. Tubaro M. Santini M. Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting.Am. Heart J. 2006; 151: 192-197Crossref PubMed Scopus (83) Google Scholar, 13Patel A.N. Geffner L. Vina R.F. Saslavsky J. Urschel Jr., H.C. Kormos R. Benetti F. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study.J. Thorac. Cardiovasc. Surg. 2005; 130: 1631-1638Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 14Stamm C. Kleine H.D. Choi Y.H. Dunkelmann S. Lauffs J.A. Lorenzen B. David A. Liebold A. Nienaber C. Zurakowski D. et al.Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies.J. Thorac. Cardiovasc. Surg. 2007; 133: 717-725Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, S. B. R. M. J. S. M. G. of patients with ischemic with coronary artery bypass and intramyocardial bone marrow mononuclear cell follow-up PubMed Scopus Google Scholar The of a for intramyocardial injections in the study the of and at the injection EPICCURE combines VEGF-A delivery using mRNA with administration using quantitative 15O-water PET The study is not to the safety of but to angiogenic of VEGF-A mRNA therapy myocardial and cardiac function in patients with coronary artery disease bypass surgery. and and analysis and and and the and and of M.H. has from has and from and from to the has from has from and and from and and are of and may or the patients and study are in the study is by and treatments for cardiovascular AZD8601 is an medical with the of the and of medical by in study and of the study this the of the to medical and and to The to study the for and the the for the to the for

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