Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease

Focus Article

Yoav Hadas, Michael G. Katz, Charles R. Bridges, Lior Zangi

Published Online: Dec 02 2016

DOI: 10.1002/wsbm.1367

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality in developed countries. Current pharmacological and interventional therapies provide significant improvement in the life quality of patient; however, they are mostly symptom‐oriented and not curative. A high disease and economic burden of IHD requires the search for new therapeutic strategies to significantly improve patients’ prognosis and quality of life. One of the main challenges during IHD is the massive loss of cardiomyocytes that possess minimal regenerative capacity. Recent understanding of the pathophysiological mechanisms underlying IHD, as well as new therapeutic approaches provide new hope for patients suffering from IHD. Synthetic modified mRNA (modRNA) is a new gene delivery vector that is increasingly used in in vivo applications. modRNA is a relatively stable, non‐immunogenic, highly‐expressed molecule that has been shown to mediate high and transient expression of proteins in different type of cells and tissues including cardiomyocytes. modRNA properties, together with its expression kinetics in the heart make it an attractive option for the treatment of IHD, especially after myocardial infarction. In this review we discuss the role of gene therapy in cardiac regeneration as an approach to treat IHD; traditional and innovative gene delivery methods; and focus specifically on modRNA structure, mode of delivery, and its use for the induction of endogenous regenerative capacity, mainly in the context of IHD. WIREs Syst Biol Med 2017, 9:e1367. doi: 10.1002/wsbm.1367 This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Translational, Genomic, and Systems Medicine > Therapeutic Methods Translational, Genomic, and Systems Medicine > Translational Medicine

Ideal treatment for ischemic heart disease. Gene therapy goals in treating of IHD are in prevention of pathological heart remodeling by: (a) activation of adult cardiomyocytes proliferation (b) attenuating the innate and adaptive immune response (c) induction of angiogenesis (d) preventing cardiac cells apoptosis and necrosis.

[ Normal View | Magnified View ]

Main phases of Post‐MI myocardial remodeling in mouse. modRNA expression occurs during inflammatory and proliferative phases, when most of the changes in cardiac function take place.

[ Normal View | Magnified View ]

Routes of modRNA delivery to the myocardium. A current diagram of existing cardiac gene delivery techniques considers site and method of administration and, interventional approach. Methods for direct gene delivery include injection from epicardial or endocardial layers into myocardium. A global transduction of the myocardium can only be achieved with intravascular transfer, which includes simple intravenous injection, intracavitary administration and intracoronary arteries route of infusion.

[ Normal View | Magnified View ]

Possible modification of mRNA structure and delivery vehicle for optimal gene expression in the heart. Stability and expression level of proteins can be optimize by modifying the mRNA composition and structure. The modRNA can be delved naked or after complexing it with biomaterials to achieve optimal stability and penetration to the cardiac cells.

[ Normal View | Magnified View ]

References

Go, AS, Mozaffarian, D, Roger, VL, Benjamin, EJ, Berry, JD, Borden, WB, Bravata, DM, Dai, S, Ford, ES, Fox, CS, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013, 127:e6–e245.
Fox, K, Garcia, MA, Ardissino, D, Buszman, P, Camici, PG, Crea, F, Daly, C, De Backer, G, Hjemdahl, P, Lopez‐Sendon, J, et al. Guidelines on the management of stable angina pectoris: executive summary: the task force on the management of stable angina pectoris of the European Society of Cardiology. Eur Heart J 2006, 27:1341–1381.
Goldberg, RJ, Ciampa, J, Lessard, D, Meyer, TE, Spencer, FA. Long‐term survival after heart failure: a contemporary population‐based perspective. Arch Intern Med 2007, 167:490–496.
Lavu, M, Gundewar, S, Lefer, DJ. Gene therapy for ischemic heart disease. J Mol Cell Cardiol 2011, 50:742–750.
Hulot, JS, Ishikawa, K, Hajjar, RJ. Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J 2016, 37:1651–1658.
Anversa, P, Leri, A, Kajstura, J. Cardiac regeneration. J Am Coll Cardiol 2006, 47:1769–1776.
Bergmann, O, Bhardwaj, RD, Bernard, S, Zdunek, S, Barnabe‐Heider, F, Walsh, S, Zupicich, J, Alkass, K, Buchholz, BA, Druid, H, et al. Evidence for cardiomyocyte renewal in humans. Science 2009, 324:98–102.
Senyo, SE, Steinhauser, ML, Pizzimenti, CL, Yang, VK, Cai, L, Wang, M, Wu, TD, Guerquin‐Kern, JL, Lechene, CP, Lee, RT. Mammalian heart renewal by pre‐existing cardiomyocytes. Nature 2013, 493:433–436.
Senyo, SE, Lee, RT, Kuhn, B. Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res 2014, 13:532–541.
Urbanek, K, Torella, D, Sheikh, F, De Angelis, A, Nurzynska, D, Silvestri, F, Beltrami, CA, Bussani, R, Beltrami, AP, Quaini, F, et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci USA 2005, 102:8692–8697.
Beltrami, AP, Urbanek, K, Kajstura, J, Yan, SM, Finato, N, Bussani, R, Nadal‐Ginard, B, Silvestri, F, Leri, A, Beltrami, CA, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001, 344:1750–1757.
Porrello, ER, Mahmoud, AI, Simpson, E, Hill, JA, Richardson, JA, Olson, EN, Sadek, HA. Transient regenerative potential of the neonatal mouse heart. Science 2011, 331:1078–1080.
Katz, MG, Fargnoli, AS, Kendle, AP, Hajjar, RJ, Bridges, CR. The role of microRNAs in cardiac development and regenerative capacity. Am J Physiol Heart Circ Physiol 2016, 310:H528–H541.
Zhang, J, Wilson, GF, Soerens, AG, Koonce, CH, Yu, J, Palecek, SP, Thomson, JA, Kamp, TJ. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009, 104:e30–e41.
Wei, H, Tan, G, Manasi, QS, Kong, G, Yong, P, Koh, C, Ooi, TH, Lim, SY, Wong, P, et al. One‐step derivation of cardiomyocytes and mesenchymal stem cells from human pluripotent stem cells. Stem Cell Res 2012, 9:87–100.
Willems, E, Spiering, S, Davidovics, H, Lanier, M, Xia, Z, Dawson, M, Cashman, J, Mercola, M. Small‐molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell‐derived mesoderm. Circ Res 2011, 109:360–364.
Lian, X, Zhang, J, Azarin, SM, Zhu, K, Hazeltine, LB, Bao, X, Hsiao, C, Kamp, TJ, Palecek, SP. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta‐catenin signaling under fully defined conditions. Nat Protoc 2013, 8:162–175.
Balsam, LB, Wagers, AJ, Christensen, JL, Kofidis, T, Weissman, IL, Robbins, RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004, 428:668–673.
Nam, YJ, Song, K, Luo, X, Daniel, E, Lambeth, K, West, K, Hill, JA, DiMaio, JM, Baker, LA, Bassel‐Duby, R, et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci USA 2013, 110:5588–5593.
Qian, L, Huang, Y, Spencer, CI, Foley, A, Vedantham, V, Liu, L, Conway, SJ, Fu, JD, Srivastava, D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012, 485:593–598.
Spach, MS. Mounting evidence that fibrosis generates a major mechanism for atrial fibrillation. Circ Res 2007, 101:743–745.
Efe, JA, Hilcove, S, Kim, J, Zhou, H, Ouyang, K, Wang, G, Chen, J, Ding, S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011, 13:215–222.
Protze, S, Khattak, S, Poulet, C, Lindemann, D, Tanaka, EM, Ravens, U. A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte‐like cells. J Mol Cell Cardiol 2012, 53:323–332.
Hadas, Y, Etlin, A, Falk, H, Avraham, O, Kobiler, O, Panet, A, Lev‐Tov, A, Klar, A. A `tool box` for deciphering neuronal circuits in the developing chick spinal cord. Nucleic Acids Res 2014, 42:e148.
Tatsis, N, Ertl, HC. Adenoviruses as vaccine vectors. Mol Ther 2004, 10:616–629.
Schnell, MA, Zhang, Y, Tazelaar, J, Gao, GP, Yu, QC, Qian, R, Chen, SJ, Varnavski, AN, LeClair, C, Raper, SE, et al. Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Mol Ther 2001, 3:708–722.
Persons, DA. Lentiviral vector gene therapy: effective and safe? Mol Ther 2010, 18:861–862.
Schultz, BR, Chamberlain, JS. Recombinant adeno‐associated virus transduction and integration. Mol Ther 2008, 16:1189–1199.
Zincarelli, C, Soltys, S, Rengo, G, Rabinowitz, JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 2008, 16:1073–1080.
Boutin, S, Monteilhet, V, Veron, P, Leborgne, C, Benveniste, O, Montus, MF, Masurier, C. Prevalence of serum IgG and neutralizing factors against adeno‐associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010, 21:704–712.
Calcedo, R, Vandenberghe, LH, Gao, G, Lin, J, Wilson, JM. Worldwide epidemiology of neutralizing antibodies to adeno‐associated viruses. J Infect Dis 2009, 199:381–390.
Kawabata, K, Takakura, Y, Hashida, M. The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharm Res 1995, 12:825–830.
Wang, Z, Troilo, PJ, Wang, X, Griffiths, TG, Pacchione, SJ, Barnum, AB, Harper, LB, Pauley, CJ, Niu, Z, Denisova, L, et al. Detection of integration of plasmid DNA into host genomic DNA following intramuscular injection and electroporation. Gene Ther 2004, 11:711–721.
Wolff, JA, Malone, RW, Williams, P, Chong, W, Acsadi, G, Jani, A, Felgner, PL. Direct gene transfer into mouse muscle in vivo. Science 1990, 247:1465–1468.
Jirikowski, GF, Sanna, PP, Maciejewski‐Lenoir, D, Bloom, FE. Reversal of diabetes insipidus in Brattleboro rats: intrahypothalamic injection of vasopressin mRNA. Science 1992, 255:996–998.
Rittig, SM, Haentschel, M, Weimer, KJ, Heine, A, Muller, MR, Brugger, W, Horger, MS, Maksimovic, O, Stenzl, A, Hoerr, I, et al. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Ther 2011, 19:990–999.
Weide, B, Pascolo, S, Scheel, B, Derhovanessian, E, Pflugfelder, A, Eigentler, TK, Pawelec, G, Hoerr, I, Rammensee, HG, Garbe, C. Direct injection of protamine‐protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J Immunother 2009, 32:498–507.
Su, Z, Dan, J, Yang, BK, Dahm, P, Coleman, D, Yancey, D, Sichi, S, Niedzwiecki, D, Boczkowski, D, Gilboa, E, et al. Telomerase mRNA‐transfected dendritic cells stimulate antigen‐specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 2005, 174:3798–3807.
Heiser, A, Coleman, D, Dan, J, Yancey, D, Maurice, MA, Lallas, CD, Dahm, P, Niedzwiecki, D, Gilboa, E, Vieweg, J. Autologous dendritic cells transfected with prostate‐specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 2002, 109:409–417.
Fleeton, MN, Chen, M, Berglund, P, Rhodes, G, Parker, SE, Murphy, M, Atkins, GJ, Liljestrom, P. Self‐replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus. J Infect Dis 2001, 183:1395–1398.
Van Gulck, E, Vlieghe, E, Vekemans, M, Van Tendeloo, VF, Van De Velde, A, Smits, E, Anguille, S, Cools, N, Goossens, H, Mertens, L, et al. mRNA‐based dendritic cell vaccination induces potent antiviral T‐cell responses in HIV‐1‐infected patients. AIDS 2012, 26:F1–F12.
Hekele, A, Bertholet, S, Archer, J, Gibson, DG, Palladino, G, Brito, LA, Otten, GR, Brazzoli, M, Buccato, S, Bonci, A, et al. Rapidly produced SAM((R)) vaccine against H7N9 influenza is immunogenic in mice. Emerg Microbes Infect 2013, 2:e52.
Allard, SD, De Keersmaecker, B, de Goede, AL, Verschuren, EJ, Koetsveld, J, Reedijk, ML, Wylock, C, De Bel, AV, Vandeloo, J, Pistoor, F, et al. A phase I/IIa immunotherapy trial of HIV‐1‐infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption. Clin Immunol 2012, 142:252–268.
Dyer, KD, Rosenberg, HF. The RNase a superfamily: generation of diversity and innate host defense. Mol Divers 2006, 10:585–597.
Rigby, RE, Rehwinkel, J. RNA degradation in antiviral immunity and autoimmunity. Trends Immunol 2015, 36:179–188.
Diebold, SS, Massacrier, C, Akira, S, Paturel, C, Morel, Y, Reis e Sousa C. Nucleic acid agonists for Toll‐like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 2006, 36:3256–3267.
Heil, F, Hemmi, H, Hochrein, H, Ampenberger, F, Kirschning, C, Akira, S, Lipford, G, Wagner, H, Bauer, S. Species‐specific recognition of single‐stranded RNA via toll‐like receptor 7 and 8. Science 2004, 303:1526–1529.
Diebold, SS, Kaisho, T, Hemmi, H, Akira, S, Reis e Sousa C. Innate antiviral responses by means of TLR7‐mediated recognition of single‐stranded RNA. Science 2004, 303:1529–1531.
Alexopoulou, L, Holt, AC, Medzhitov, R, Flavell, RA. Recognition of double‐stranded RNA and activation of NF‐kappaB by Toll‐like receptor 3. Nature 2001, 413:732–738.
Pichlmair, A, Schulz, O, Tan, CP, Rehwinkel, J, Kato, H, Takeuchi, O, Akira, S, Way, M, Schiavo, G, Reis e Sousa C. Activation of MDA5 requires higher‐order RNA structures generated during virus infection. J Virol 2009, 83:10761–10769.
Schlee, M, Roth, A, Hornung, V, Hagmann, CA, Wimmenauer, V, Barchet, W, Coch, C, Janke, M, Mihailovic, A, Wardle, G, et al. Recognition of 5′ triphosphate by RIG‐I helicase requires short blunt double‐stranded RNA as contained in panhandle of negative‐strand virus. Immunity 2009, 31:25–34.
Yoneyama, M, Kikuchi, M, Matsumoto, K, Imaizumi, T, Miyagishi, M, Taira, K, Foy, E, Loo, YM, Gale, M Jr, Akira, S, et al. Shared and unique functions of the DExD/H‐box helicases RIG‐I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 2005, 175:2851–2858.
Yoneyama, M, Kikuchi, M, Natsukawa, T, Shinobu, N, Imaizumi, T, Miyagishi, M, Taira, K, Akira, S, Fujita, T. The RNA helicase RIG‐I has an essential function in double‐stranded RNA‐induced innate antiviral responses. Nat Immunol 2004, 5:730–737.
Kariko, K, Buckstein, M, Ni, H, Weissman, D. Suppression of RNA recognition by Toll‐like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005, 23:165–175.
Kariko, K, Muramatsu, H, Welsh, FA, Ludwig, J, Kato, H, Akira, S, Weissman, D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 2008, 16:1833–1840.
Anderson, BR, Muramatsu, H, Nallagatla, SR, Bevilacqua, PC, Sansing, LH, Weissman, D, Kariko, K. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 2010, 38:5884–5892.
Hemmi, H, Takeuchi, O, Kawai, T, Kaisho, T, Sato, S, Sanjo, H, Matsumoto, M, Hoshino, K, Wagner, H, Takeda, K, et al. A Toll‐like receptor recognizes bacterial DNA. Nature 2000, 408:740–745.
Machnicka, MA, Milanowska, K, Osman Oglou, O, Purta, E, Kurkowska, M, Olchowik, A, Januszewski, W, Kalinowski, S, Dunin‐Horkawicz, S, Rother, KM, et al. MODOMICS: a database of RNA modification pathways—2013 update. Nucleic Acids Res 2013, 41:D262–D267.
Anderson, BR, Muramatsu, H, Jha, BK, Silverman, RH, Weissman, D, Kariko, K. Nucleoside modifications in RNA limit activation of 2′‐5′‐oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res 2011, 39:9329–9338.
Uchida, S, Kataoka, K, Itaka, K. Screening of mRNA Chemical Modification to Maximize Protein Expression with Reduced Immunogenicity. Pharmaceutics 2015, 7:137–151.
Thess, A, Grund, S, Mui, BL, Hope, MJ, Baumhof, P, Fotin‐Mleczek, M, Schlake, T. Sequence‐engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 2015, 23:1456–1464.
Jemielity, J, Fowler, T, Zuberek, J, Stepinski, J, Lewdorowicz, M, Niedzwiecka, A, Stolarski, R, Darzynkiewicz, E, Rhoads, RE. Novel “anti‐reverse” cap analogs with superior translational properties. RNA 2003, 9:1108–1122.
Shaw, G, Kamen, R. A conserved AU sequence from the 3′ untranslated region of GM‐CSF mRNA mediates selective mRNA degradation. Cell 1986, 46:659–667.
Kariko, K, Kuo, A, Barnathan, E. Overexpression of urokinase receptor in mammalian cells following administration of the in vitro transcribed encoding mRNA. Gene Ther 1999, 6:1092–1100.
Mandal, PK, Rossi, DJ. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat Protoc 2013, 8:568–582.
Warren, L, Manos, PD, Ahfeldt, T, Loh, YH, Li, H, Lau, F, Ebina, W, Mandal, PK, Smith, ZD, Meissner, A, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010, 7:618–630.
Luni, C, Giulitti, S, Serena, E, Ferrari, L, Zambon, A, Gagliano, O, Giobbe, GG, Michielin, F, Knobel, S, Bosio, A, et al. High‐efficiency cellular reprogramming with microfluidics. Nat Methods 2016, 13:446–452.
Lui, KO, Zangi, L, Silva, EA, Bu, L, Sahara, M, Li, RA, Mooney, DJ, Chien, KR. Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA. Cell Res 2013, 23:1172–1186.
Kormann, MS, Hasenpusch, G, Aneja, MK, Nica, G, Flemmer, AW, Herber‐Jonat, S, Huppmann, M, Mays, LE, Illenyi, M, Schams, A, et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 2011, 29:154–157.
Zangi, L, Lui, KO, von Gise, A, Ma, Q, Ebina, W, Ptaszek, LM, Spater, D, Xu, H, Tabebordbar, M, Gorbatov, R, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 2013, 31:898–907.
Matsui, A, Uchida, S, Ishii, T, Itaka, K, Kataoka, K. Messenger RNA‐based therapeutics for the treatment of apoptosis‐associated diseases. Sci Rep 2015, 5:15810.
Nabhan, JF, Wood, KM, Rao, VP, Morin, J, Bhamidipaty, S, LaBranche, TP, Gooch, RL, Bozal, F, Bulawa, CE, Guild, BC. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich`s ataxia. Sci Rep 2016, 6:20019.
Zeyer, F, Mothes, B, Will, C, Carevic, M, Rottenberger, J, Nurnberg, B, Hartl, D, Handgretinger, R, Beer‐Hammer, S, Kormann, MS. mRNA‐mediated gene supplementation of toll‐like receptors as treatment strategy for asthma in vivo. PLoS One 2016, 11:e0154001.
Aini, H, Itaka, K, Fujisawa, A, Uchida, H, Uchida, S, Fukushima, S, Kataoka, K, Saito, T, Chung, UI, Ohba, S. Messenger RNA delivery of a cartilage‐anabolic transcription factor as a disease‐modifying strategy for osteoarthritis treatment. Sci Rep 2016, 6:18743.
Huang, CL, Leblond, AL, Turner, EC, Kumar, AH, Martin, K, Whelan, D, O`Sullivan, DM, Caplice, NM. Synthetic chemically modified mrna‐based delivery of cytoprotective factor promotes early cardiomyocyte survival post‐acute myocardial infarction. Mol Pharm 2015, 12:991–996.
Katz, MG, Swain, JD, White, JD, Low, D, Stedman, H, Bridges, CR. Cardiac gene therapy: optimization of gene delivery techniques in vivo. Hum Gene Ther 2010, 21:371–380.
Katz, MG, Fargnoli, AS, Williams, RD, Bridges, CR. The road ahead: working towards effective clinical translation of myocardial gene therapies. Ther Deliv 2014, 5:39–51.
Li de la Sierra‐Gallay, I, Zig, L, Jamalli, A, Putzer, H. Structural insights into the dual activity of RNase J. Nat Struct Mol Biol 2008, 15:206–212.
Escoffre, JM, Teissie, J, Rols, MP. Gene transfer: how can the biological barriers be overcome? J Membr Biol 2010, 236:61–74.
Islam, MA, Reesor, EK, Xu, Y, Zope, HR, Zetter, BR, Shi, J. Biomaterials for mRNA delivery. Biomater Sci 2015, 3:1519–1533.
Skold, AE, van Beek, JJ, Sittig, SP, Bakdash, G, Tel, J, Schreibelt, G, de Vries, IJ. Protamine‐stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets. Cancer Immunol Immunother 2015, 64:1461–1473.
Kedmi, R, Ben‐Arie, N, Peer, D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll‐like receptor 4 in immune activation. Biomaterials 2010, 31:6867–6875.
Li, L, Wei, Y, Gong, C. Polymeric Nanocarriers for Non‐Viral Gene Delivery. J Biomed Nanotechnol 2015, 11:739–770.
Turillazzi, E, Di Paolo, M, Neri, M, Riezzo, I, Fineschi, V. A theoretical timeline for myocardial infarction: immunohistochemical evaluation and western blot quantification for Interleukin‐15 and monocyte chemotactic protein‐1 as very early markers. J Transl Med 2014, 12:188.
Frangogiannis, NG. Regulation of the inflammatory response in cardiac repair. Circ Res 2012, 110:159–173.
Liehn, EA, Postea, O, Curaj, A, Marx, N. Repair after myocardial infarction, between fantasy and reality: the role of chemokines. J Am Coll Cardiol 2011, 58:2357–2362.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox