Cardiovascular Gene Therapy

  • Thomas J. LaRoccaEmail author
  • Roger J. Hajjar


Gene therapy is rapidly evolving as an effective therapeutic strategy for patients suffering from various forms of cardiovascular disease. Since the conceptualization of gene therapy, the scientific and clinical community has learned a great deal from the successes and, unfortunately, failures of previous gene therapy clinical trials over the past decades. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design and vector delivery modalities. Nonviral and viral vectors including plasmids, retrovirus, lentivirus, adenovirus, and adeno-associated virus each have unique cellular transduction mechanisms and expression profiles. Due to the exclusive qualities of each vector, the selection and development of vectors for cardiovascular gene therapy is critically dependent on the specific cardiac pathology. In addition, how these vectors are delivered to the heart greatly affects myocardial transduction and clinical outcomes. It is necessary to employ the proper vector and delivery modality that can safely and efficiently transduce the myocardium with well-validated transgenes shown to protect against acute ischemia, arrhythmias, hypertrophy, or ventricular failure. Gene therapies targeting the β-adrenergic pathway, calcium regulatory mechanisms, angiogenesis, or the CXCL12/CXCR4 axis have shown promise both preclinically and in human clinical trials. The current state of the art of cardiovascular gene therapy as well as clinically significant molecular targets is reviewed as this promising strategy enters the clinical realm.


Vascular Endothelial Growth Factor Gene Therapy Cardiac Myocyte Human Clinical Trial Equine Infectious Anemia Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Yockman JW et al. Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction. J Control Release. 2008;132(3):260–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Wasala NB, Shin JH, Duan D. The evolution of heart gene delivery vectors. J Gene Med. 2011;13(10):557–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Harraghy N, Gaussin A, Mermod N. Sustained transgene expression using MAR elements. Curr Gene Ther. 2008;8(5):353–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Girod PA et al. Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat Methods. 2007;4(9):747–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Ehrhardt A et al. Optimization of cis-acting elements for gene expression from nonviral vectors in vivo. Hum Gene Ther. 2003;14(3):215–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Argyros O et al. Development of S/MAR minicircles for enhanced and persistent transgene expression in the mouse liver. J Mol Med (Berl). 2011;89(5):515–29.CrossRefGoogle Scholar
  7. 7.
    Themis M et al. Mutational effects of retrovirus insertion on the genome of V79 cells by an attenuated retrovirus vector: implications for gene therapy. Gene Ther. 2003;10(19):1703–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat Immunol. 2010;11(6):457–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Hacein-Bey-Abina S et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Cavazzana-Calvo M et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288(5466):669–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Kraunus J et al. Self-inactivating retroviral vectors with improved RNA processing. Gene Ther. 2004;11(21):1568–78.PubMedCrossRefGoogle Scholar
  12. 12.
    Vodicka MA. Determinants for lentiviral infection of non-dividing cells. Somat Cell Mol Genet. 2001;26(1–6):35–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Levine BL et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA. 2006;103(46): 17372–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Kohn DB. Lentiviral vectors ready for prime-time. Nat Biotechnol. 2007;25(1):65–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Mortellaro A et al. Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects. Blood. 2006;108(9):2979–88.PubMedCrossRefGoogle Scholar
  16. 16.
    Lyle C, McCormick F. Integrin alphavbeta5 is a primary receptor for adenovirus in CAR-negative cells. Virol J. 2010;7:148.PubMedCrossRefGoogle Scholar
  17. 17.
    Matyas L et al. Arteriogenic gene therapy in patients with unreconstructable critical limb ischemia: a randomized, placebo-controlled clinical trial of adenovirus 5-delivered fibroblast growth factor-4. Hum Gene Ther. 2005;16(10):1202–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation. 2008;118(1):9–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Raper SE et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80(1–2):148–58.PubMedCrossRefGoogle Scholar
  20. 20.
    Becerra SP et al. Synthesis of adeno-associated virus structural proteins requires both alternative mRNA splicing and alternative initiations from a single transcript. J Virol. 1988;62(8):2745–54.PubMedGoogle Scholar
  21. 21.
    Pacak CA, Byrne BJ. AAV vectors for cardiac gene transfer: experimental tools and clinical opportunities. Mol Ther. 2011;19(9):1582–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Asokan A et al. Reengineering a receptor footprint of adeno-­associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol. 2010;28(1):79–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang J, Faust SM, Rabinowitz JE. The next step in gene delivery: molecular engineering of adeno-associated virus serotypes. J Mol Cell Cardiol. 2011;50(5):793–802.PubMedCrossRefGoogle Scholar
  24. 24.
    Mitchell AM et al. AAV’s anatomy: roadmap for optimizing vectors for translational success. Curr Gene Ther. 2010;10(5):319–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Li W et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther. 2008;16(7):1252–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Ying Y et al. Heart-targeted adeno-associated viral vectors selected by in vivo biopanning of a random viral display peptide library. Gene Ther. 2010;17(8):980–90.PubMedCrossRefGoogle Scholar
  27. 27.
    Jaski BE et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail. 2009;15(3):171–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Nonnenmacher M, Weber T. Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. Cell Host Microbe. 2011;10(6):563–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther. 2012;19(6):649–58.PubMedCrossRefGoogle Scholar
  30. 30.
    Boecker W et al. Cardiac-specific gene expression facilitated by an enhanced myosin light chain promoter. Mol Imaging. 2004;3(2):69–75.PubMedCrossRefGoogle Scholar
  31. 31.
    Prasad KM et al. Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution. Gene Ther. 2011;18(1):43–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Ruan H et al. A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy. Neoplasia. 2001;3(3):255–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Su H, Kan YW. Adeno-associated viral vector-delivered hypoxia-inducible gene expression in ischemic hearts. Methods Mol Biol. 2007;366:331–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Vanrell L et al. Development of a liver-specific Tet-on inducible system for AAV vectors and its application in the treatment of liver cancer. Mol Ther. 2011;19(7):1245–53.PubMedCrossRefGoogle Scholar
  35. 35.
    Ye X et al. Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer. Science. 1999;283(5398):88–91.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen ZY et al. Ultrasound- and liposome microbubble-mediated targeted gene transfer to cardiomyocytes in vivo accompanied by polyethylenimine. J Ultrasound Med. 2011;30(9):1247–58.PubMedGoogle Scholar
  37. 37.
    Mariani JA, Kaye DM. Delivery of gene and cellular therapies for heart disease. J Cardiovasc Transl Res. 2010;3(4):417–26.PubMedCrossRefGoogle Scholar
  38. 38.
    Parsa CJ et al. Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method. J Gene Med. 2005;7(5):595–603.PubMedCrossRefGoogle Scholar
  39. 39.
    Sasano T et al. Targeted high-efficiency, homogeneous myocardial gene transfer. J Mol Cell Cardiol. 2007;42(5):954–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Raake PW et al. Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Ther. 2008;15(1):12–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Karakikes I. Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts. Mol Ther. 2012;20:565–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Kaye DM et al. Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. J Am Coll Cardiol. 2007;50(3):253–60.PubMedCrossRefGoogle Scholar
  43. 43.
    Byrne MJ et al. Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals. Gene Ther. 2008;15(23):1550–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Fuchs S et al. A randomized, double-blind, placebo-controlled, multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial injection of AdVEGF121 in patients with refractory advanced coronary artery disease. Catheter Cardiovasc Interv. 2006;68(3):372–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Losordo DW et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109(4):428–36.PubMedCrossRefGoogle Scholar
  46. 46.
    Baldazzi F et al. Release of biomarkers of myocardial damage after direct intramyocardial injection of genes and stem cells via the percutaneous transluminal route. Eur Heart J. 2008;29(15):1819–26.PubMedCrossRefGoogle Scholar
  47. 47.
    Ishikawa K et al. Sterile abscess in the myocardium after direct intramyocardial injection related to gene therapy in a Swine model. ISRN Cardiol. 2011;2011:319453.PubMedGoogle Scholar
  48. 48.
    Ladage D et al. Delivery of gelfoam-enabled cells and vectors into the pericardial space using a percutaneous approach in a porcine model. Gene Ther. 2011;18(10):979–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Aragon JP et al. Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation. J Am Coll Cardiol. 2011;58(25):2683–91.PubMedCrossRefGoogle Scholar
  50. 50.
    Calvert JW et al. Exercise protects against myocardial ischemia-reperfusion injury via stimulation of beta(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ Res. 2011;108(12):1448–58.PubMedCrossRefGoogle Scholar
  51. 51.
    Morisco C et al. Beta-adrenergic cardiac hypertrophy is mediated primarily by the beta(1)-subtype in the rat heart. J Mol Cell Cardiol. 2001;33(3):561–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Woo AY, Xiao RP. beta-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin. 2012;33(3):335–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhu W. beta-adrenergic receptor subtype signaling in the heart: from bench to the bedside. Curr Top Membr. 2011;67:191–204.PubMedCrossRefGoogle Scholar
  54. 54.
    Patel PA, Tilley DG, Rockman HA. Physiologic and cardiac roles of beta-arrestins. J Mol Cell Cardiol. 2009;46(3):300–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Tilley DG. beta-Arrestin mediates beta1-adrenergic receptor-­epidermal growth factor receptor interaction and downstream ­signaling. J Biol Chem. 2009;284(30):20375–86.PubMedCrossRefGoogle Scholar
  56. 56.
    Noma T et al. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest. 2007;117(9):2445–58.PubMedCrossRefGoogle Scholar
  57. 57.
    Huang ZM, Gold JI, Koch WJ. G protein-coupled receptor kinases in normal and failing myocardium. Front Biosci. 2012;17:3047–60.CrossRefGoogle Scholar
  58. 58.
    Akhter SA et al. In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function. Circulation. 1999;100(6):648–53.PubMedCrossRefGoogle Scholar
  59. 59.
    Raake PW et al. AAV6.betaARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. Eur Heart J. 2013;34(19):1437–47.Google Scholar
  60. 60.
    Williams ML et al. Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts. Circulation. 2004;109(13):1590–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Hammond HK. Adenylyl cyclase gene transfer in heart failure. Ann N Y Acad Sci. 2006;1080:426–36.PubMedCrossRefGoogle Scholar
  62. 62.
    Okumura S et al. Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci USA. 2003;100(17):9986–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Rebolledo B et al. Adenylylcyclase gene transfer increases function of the failing heart. Hum Gene Ther. 2006;17(10):1043–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Gao MH, Hammond HK. Unanticipated signaling events associated with cardiac adenylyl cyclase gene transfer. J Mol Cell Cardiol. 2011;50(5):751–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Lai NC et al. Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation. 2004;110(3):330–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Hajjar RJ et al. Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation. 1997;95(2):423–9.PubMedCrossRefGoogle Scholar
  67. 67.
    del Monte F et al. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 1999;100(23):2308–11.CrossRefGoogle Scholar
  68. 68.
    Kawase Y et al. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol. 2008;51(11):1112–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Prunier F et al. Prevention of ventricular arrhythmias with sarcoplasmic reticulum Ca2+ ATPase pump overexpression in a porcine model of ischemia reperfusion. Circulation. 2008;118(6):614–24.PubMedCrossRefGoogle Scholar
  70. 70.
    Jessup M et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+−ATPase in patients with advanced heart failure. Circulation. 2011;124(3):304–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Kho C et al. SUMO1-dependent modulation of SERCA2a in heart failure. Nature. 2011;477(7366):601–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Ritterhoff J, Most P. Targeting S100A1 in heart failure. Gene Ther. 2012;19(6):613–21.PubMedCrossRefGoogle Scholar
  73. 73.
    Wright NT et al. S100A1: structure, function, and therapeutic potential. Curr Chem Biol. 2009;3(2):138–45.PubMedGoogle Scholar
  74. 74.
    Kiewitz R et al. Transcriptional regulation of S100A1 and expression during mouse heart development. Biochim Biophys Acta. 2000;1498(2–3):207–19.PubMedCrossRefGoogle Scholar
  75. 75.
    Remppis A et al. Altered expression of the Ca(2+)-binding protein S100A1 in human cardiomyopathy. Biochim Biophys Acta. 1996;1313(3):253–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Remppis A et al. The small EF-hand Ca2+ binding protein S100A1 increases contractility and Ca2+ cycling in rat cardiac myocytes. Basic Res Cardiol. 2002;97 Suppl 1:I56–62.PubMedGoogle Scholar
  77. 77.
    Yamasaki R et al. Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J. 2001;81(4):2297–313.PubMedCrossRefGoogle Scholar
  78. 78.
    Brinks H et al. S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes. J Am Coll Cardiol. 2011;58(9):966–73.PubMedCrossRefGoogle Scholar
  79. 79.
    Pleger ST. Cardiac AAV9-S100A1 gene therapy rescues post-­ischemic heart failure in a preclinical large animal model. Sci Transl Med. 2011;3(92):92ra64.PubMedCrossRefGoogle Scholar
  80. 80.
    Mikroulis D et al. Angiogenic growth factors in the treatment of peripheral arterial disease. Curr Vasc Pharmacol. 2007;5(3):195–209.PubMedCrossRefGoogle Scholar
  81. 81.
    Henry TD et al. Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study. Gene Ther. 2011;18(8):788–94.PubMedCrossRefGoogle Scholar
  82. 82.
    Yang ZJ et al. Hepatocyte growth factor plays a critical role in the regulation of cytokine production and induction of endothelial progenitor cell mobilization: a pilot gene therapy study in patients with coronary heart disease. Clin Exp Pharmacol Physiol. 2009;36(8):790–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Kastrup J et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol. 2005;45(7):982–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Gyongyosi M et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation. 2005;112(9 Suppl):I157–65.PubMedGoogle Scholar
  85. 85.
    Stewart DJ et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther. 2009;17(6):1109–15.PubMedCrossRefGoogle Scholar
  86. 86.
    Zou YR et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393(6685):595–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Askari AT et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet. 2003;362(9385):697–703.PubMedCrossRefGoogle Scholar
  88. 88.
    Penn MS et al. Role of stem cell homing in myocardial regeneration. Int J Cardiol. 2004;95 Suppl 1:S23–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Zhang M et al. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J. 2007;21(12):3197–207.PubMedCrossRefGoogle Scholar
  90. 90.
    Saxena A et al. Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction. Circulation. 2008;117(17):2224–31.PubMedCrossRefGoogle Scholar
  91. 91.
    Tang J et al. Adenovirus-mediated stromal cell-derived factor-1 alpha gene transfer improves cardiac structure and function after experimental myocardial infarction through angiogenic and antifibrotic actions. Mol Biol Rep. 2010;37(4):1957–69.PubMedCrossRefGoogle Scholar
  92. 92.
    Sundararaman S et al. Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure. Gene Ther. 2011;18(9):867–73.PubMedCrossRefGoogle Scholar
  93. 93.
    Pyo RT et al. CXCR4 modulates contractility in adult cardiac myocytes. J Mol Cell Cardiol. 2006;41(5):834–44.PubMedCrossRefGoogle Scholar
  94. 94.
    LaRocca TJ. β2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4. J Cardiovasc Pharmacol. 2010;56(5):548–59.PubMedCrossRefGoogle Scholar
  95. 95.
    LaRocca TJ, Jeong D, Chen J, Kohlbrenner E, Lee A, Hallar RJ, et al. CXCR4 gene transfer prevents pressure overload induced heart failure. J Mol Cell Cardiol. 2012;53(2):223–32.PubMedCrossRefGoogle Scholar

Recommended Reading

  1. Asokan A, Schaffer DV, Samulski RJ. The AAV vector toolkit: poised at the clinical crossroads. Mol Ther. 2012;20(4):699–708.PubMedCrossRefGoogle Scholar
  2. Kotin RM. Large-scale recombinant adeno-associated virus production. Hum Mol Genet. 2011 Apr 15;20(R1):R2–6.PubMedCrossRefGoogle Scholar
  3. Rosas LE, et al. Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther. 2012 Nov;20(11):2098–110. doi:10.1038/mt.2012.197.PubMedCrossRefGoogle Scholar
  4. Merlet E, et al. A calcium-sensitive promoter construct for gene therapy. Gene Ther. 2012 Mar 29. doi:10.1038/gt.2012.30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA
  2. 2.Cardiovascular Research CenterMount Sinai School of MedicineNew YorkUSA

Personalised recommendations