Gene therapy for cardiovascular disease: Advances in vector development, targeting, and delivery for clinical translation

Cardiovascular Research

Volumn 108, Issue 1, 2015, Pages 4-20

  Rincon, Melvin Y ^a,b   VandenDriessche, Thierry ^a,c   Chuah, Marinee K ^a,c  

^a VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

^b FUNDACIÓN CARDIOVASCULAR DE COLOMBIA   (Colombia)

^c UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Adeno associated viral vector; Adenylate cyclase; Cardiovascular disease; Clinical trials; CRISPR; Gene therapy; Heart failure; miRNA; S100A1; SERCA2a

Indexed keywords

ADENO ASSOCIATED VIRAL VECTOR; ADENOVIRUS VECTOR; ADENYLATE CYCLASE 6; ANGIOGENIC FACTOR; CALCIUM ION; COMPLEMENT; CYCLIC AMP DEPENDENT PROTEIN KINASE; LENTIVIRUS VECTOR; MICRORNA; MYOSIN HEAVY CHAIN ALPHA; MYOSIN LIGHT CHAIN; NEUTRALIZING ANTIBODY; PLASMID DNA; PROTEIN S 100; PROTEIN S 100A1; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE 2; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN A; VIRUS VECTOR; CALCIUM; S100A1 PROTEIN;

CARDIOVASCULAR DISEASE; CELLULAR IMMUNITY; CRISPR CAS SYSTEM; GENE TARGETING; GENE THERAPY; GENETIC TRANSDUCTION; HEART FAILURE; HEART FUNCTION; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; VIRAL GENE THERAPY; ADENOVIRIDAE; ANIMAL; CARDIOVASCULAR DISEASES; CLINICAL TRIAL (TOPIC); DEPENDOPARVOVIRUS; GENE TRANSFER; GENE VECTOR; GENETICS; HEART CONTRACTION; LENTIVIRINAE; METABOLISM;

ADENOVIRIDAE; ANIMALS; CALCIUM; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; DEPENDOVIRUS; GENE TRANSFER TECHNIQUES; GENETIC THERAPY; GENETIC VECTORS; HUMANS; LENTIVIRUS; MYOCARDIAL CONTRACTION; S100 PROTEINS; SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES;

EID: 84943370744     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvv205     Document Type: Review

References (172)

1. Bleumink GS, Knetsch AM, Sturkenboom MCJM, Straus SMJM, Hofman A, Deckers JW, Witteman JCM, Stricker BHC. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 2004; 25: 1614-1619
2. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53: 557-573
3. Tilemann L, Ishikawa K, Weber T, Hajjar RJ. Gene therapy for heart failure. Circ Res 2012; 110: 777-793
4. Kay MA. State-of-The-Art gene-based therapies: the road ahead. Nat Rev Genet 2011; 12: 316-328
5. Yerevanian A, Yerevanian A, Hajjar RJ. Progress in gene therapy for heart failure. J Cardiovasc Pharmacol 2014; 63: 95-106
6. Gao MH, Lai NC, Miyanohara A, Schilling JM, Suarez J, Tang T, Guo T, Tang R, Parikh J, Giamouridis D, Dillmann WH, Patel HH, Roth DM, Dalton ND, Hammond HK. Intravenous adeno-Associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice. Hum Gene Ther 2013; 24: 777-785
7. Lai NC, Tang T, Gao MH, Saito M, Miyanohara A, Hammond HK. Improved function of the failing rat heart by regulated expression of insulin-like growth factor I via intramuscular gene transfer. Hum Gene Ther 2012; 23: 255-261
8. Ding Q, Strong A, Patel KM, Ng S-L, Gosis BS, Regan SN, Cowan CA, Rader DJ, Musunuru K. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014; 115: 488-492
9. Olson EN. MicroRNAs as Therapeutic Targets and Biomarkers of Cardiovascular Disease. Sci Transl Med 2014; 6: 239ps3
10. Su C-H, Wu Y-J, Wang H-H, Yeh H-I. Nonviral gene therapy targeting cardiovascular system. Am J Physiol Heart Circ Physiol 2012; 303: H629-H638
11. Gyöngyö si M, Khorsand A, Zamini S, Sperker W, Strehblow C, Kastrup J, Jorgensen E, Hesse B, Tägil K, Bøtker HE, Ruzyllo W, Teresiñ ska A, Dudek D, Hubalewska A, Rück A, Nielsen SS, Graf S, Mundigler G, Novak J, Sochor H, Maurer G, Glogar D, Sylven C. 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: I157-I165
12. Scimia MC, Cannavo A, Koch WJ. Gene therapy for heart disease: molecular targets, vectors and modes of delivery to myocardium. Expert Rev Cardiovasc Ther 2013; 11: 999-1013
13. Mali B, Jarm T, Corovic S, Paulin-Kosir MS, Cemazar M, Sersa G, Miklavcic D. The effect of electroporation pulses on functioning of the heart. Med Biol Eng Comput 2008; 46: 745-757
14. Ferrara K, Pollard R, Borden M. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng 2007; 9: 415-447
15. Fujii H, Sun Z, Li S-H, Wu J, Fazel S, Weisel RD, Rakowski H, Lindner J, Li R-K. Ultrasound-Targeted gene delivery induces angiogenesis after a myocardial infarction in mice. JACC Cardiovasc Imaging 2009; 2: 869-879
16. Fujii H, Li S-H, Wu J, Miyagi Y, Yau TM, Rakowski H, Egashira K, Guo J, Weisel RD, Li R-K. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. Eur Heart J 2011; 32: 2075-2084
17. Gill S-L, ONeill H, McCoy RJ, Logeswaran S, OBrien F, Stanton A, Kelly H, Duffy GP. Enhanced delivery of microRNA mimics to cardiomyocytes using ultrasound responsive microbubbles reverses hypertrophy in an in-vitro model. Technol Health Care Off J Eur Soc Eng Med 2014; 22: 37-51
18. Petrus I, Chuah M, VandenDriessche T. Gene therapy strategies for hemophilia: benefits versus risks. J Gene Med 2010; 12: 797-809
19. Schneider CK, Salmikangas P, Jilma B, Flamion B, Todorova LR, Paphitou A, Haunerova I, Maimets T, Trouvin JH, Flory E, Tsiftsoglou A, Sarkadi B, Gudmundsson K, ODonovan M, Migliaccio G, Ancans J, Maciulaitis R, Robert JL, Samuel A, Ovelgönne JH, Hystad M, Fal AM, Lima BS, Moraru AS, Turcáni P, Zorec R, Ruiz S, Akerblom L, Narayanan G, Kent A, Bignami F, Dickson JG, Niederwieser D, Figuerola-Santos MA, Reischl IG, Beuneu C, Georgiev R, Vassiliou M, Pychova A, Clausen M, Methuen T, Lucas S, Schüssler-Lenz M, Kokkas V, Buzás Z, MacAleenan N, Galli MC, Lin-e A, Gulbinovic J, Berchem G, Fraczek M, Menezes-Ferreira M, Vilceanu N, Hrubisko M, Marinko P, Timón M, Cheng W, Crosbie GA, Meade N, di Paola ML, VandenDriessche T, Ljungman P, DApote L, Oliver-Diaz O, Büttel I, Celis P. Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov 2010; 9: 195-201
20. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 2013; 122: 23-36
21. Wasala NB, Shin J-H, Duan D. The evolution of heart gene delivery vectors. J Gene Med 2011; 13: 557-565
22. Parker AL, Nicklin SA, Baker AH. Interactions of adenovirus vectors with blood: implications for intravascular gene therapy applications. Curr Opin Mol Ther 2008; 10: 439-448
23. Du L, Dronadula N, Tanaka S, Dichek DA. Helper-dependent adenoviral vector achieves prolonged, stable expression of interleukin-10 in rabbit carotid arteries but does not limit early atherogenesis. Hum Gene Ther 2011; 22: 959-968
24. Hajjar RJ. Potential of gene therapy as a treatment for heart failure. J Clin Invest 2013; 123: 53-61
25. Wright MJ, Wightman LM, Lilley C, de Alwis M, Hart SL, Miller A, Coffin RS, Thrasher A, Latchman DS, Marber MS. In vivo myocardial gene transfer: optimization, evaluation and direct comparison of gene transfer vectors. Basic Res Cardiol 2001; 96: 227-236
26. Kilian EG, Sadoni S, Vicol C, Kelly R, van Hulst K, Schwaiger M, Kupatt C, Boekstegers P, Pillai R, Channon K, Hetzer R, Reichart B. Myocardial transfection of hypoxia inducible factor-1alpha via an adenoviral vector during coronary artery bypass grafting. A multicenter phase I and safety study. Circ J Off J Jpn Circ Soc 2010; 74: 916-924
27. Muona K, Mäkinen K, Hedman M, Manninen H, Ylä-Herttuala S. 10-year safety followup in patients with local VEGF gene transfer to ischemic lower limb. Gene Ther 2012; 19: 392-395
28. Gahéry-Ségard H, Farace F, Godfrin D, Gaston J, Lengagne R, Tursz T, Boulanger P, Guillet JG. Immune response to recombinant capsid proteins of adenovirus in humans: antifiber and anti-penton base antibodies have a synergistic effect on neutralizing activity. J Virol 1998; 72: 2388-2397
29. Krause A, Joh JH, Hackett NR, Roelvink PW, Bruder JT, Wickham TJ, Kovesdi I, Crystal RG, Worgall S. Epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity. J Virol 2006; 80: 5523-5530
30. Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, Graham FL, Beaudet AL, Kochanek S. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet 1998; 18: 180-183
31. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao G, Wilson JM, Batshaw ML. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003; 80: 148-158
32. Kaski JC, Consuegra-Sanchez L. Evaluation of ASPIRE trial: a Phase III pivotal registration trial, using intracoronary administration of Generx (Ad5FGF4) to treat patients with recurrent angina pectoris. Expert Opin Biol Ther 2013; 13: 1749-1753
33. Chuah MKL, Collen D, VandenDriessche T. Biosafety of adenoviral vectors. Curr Gene Ther 2003; 3: 527-543
34. Gao MH, Lai NC, McKirnan MD, Roth DA, Rubanyi GM, Dalton N, Roth DM, Hammond HK. Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data. Hum Gene Ther 2004; 15: 574-587
35. Ylä-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 2003; 9: 694-701
36. Vassalli G, Büeler H, Dudler J, von Segesser LK, Kappenberger L. Adeno-Associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors. Int J Cardiol 2003; 90: 229-238
37. Williams PD, Ranjzad P, Kakar SJ, Kingston PA. Development of viral vectors for use in cardiovascular gene therapy. Viruses 2010; 2: 334-371
38. Dakin RS, Parker AL, Delles C, Nicklin SA, Baker AH. Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector. Hum Gene Ther 2015; 26: 312-319
39. Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 2011; 12: 341-355
40. Vandendriessche T, Thorrez L, Acosta-Sanchez A, Petrus I, Wang L, Ma L, DE Waele L, Iwasaki Y, Gillijns V, Wilson JM, Collen D, Chuah MKL. Efficacy and safety of adeno-Associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy. J Thromb Haemost JTH 2007; 5: 16-24
41. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, Wilson JM. Clades of Adeno-Associated viruses are widely disseminated in human tissues. J Virol 2004; 78: 6381-6388
42. Zincarelli C, Soltys S, Rengo G, Koch WJ, Rabinowitz JE. Comparative cardiac gene delivery of adeno-Associated virus serotypes 1-9 reveals that AAV6 mediates the most efficient transduction in mouse heart. Clin Transl Sci 2010; 3: 81-89
43. Inagaki K, Fuess S, Storm TA, Gibson GA, Mctiernan CF, Kay MA, Nakai H. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 2006; 14: 45-53
44. Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, Lewis MA, Cloutier DE, Zolotukhin I, Tarantal AF, Byrne BJ. Recombinant adeno-Associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006; 99: e3-e9
45. Di Pasquale G, Chiorini JA. AAV transcytosis through barrier epithelia and endothelium. Mol Ther 2006; 13: 506-516
46. Prasad K-MR, Smith RS, Xu Y, French BA. A single direct injection into the left ventricular wall of an adeno-Associated virus 9 (AAV9) vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction. J Gene Med 2011; 13: 333-341
47. Gao G, Bish LT, Sleeper MM, Mu X, Sun L, Lou Y, Duan J, Hu C, Wang L, Sweeney HL. Transendocardial delivery of AAV6 results in highly efficient and global cardiac gene transfer in rhesus macaques. Hum Gene Ther 2011; 22: 979-984
48. Chuah MK, Petrus I, De Bleser P, Le Guiner C, Gernoux G, Adjali O, Nair N, Willems J, Evens H, Rincon MY, Matrai J, Di Matteo M, Samara-Kuko E, Yan B, Acosta-Sanchez A, Meliani A, Cherel G, Blouin V, Christophe O, Moullier P, Mingozzi F, VandenDriessche T. Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates. Mol Ther 2014; 22: 1605-1613
49. Nicklin SA, Buening H, Dishart KL, de Alwis M, Girod A, Hacker U, Thrasher AJ, Ali RR, Hallek M, Baker AH. Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Mol Ther 2001; 4: 174-181
50. White SJ, Nicklin SA, Büning H, Brosnan MJ, Leike K, Papadakis ED, Hallek M, Baker AH. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-Associated virus vectors. Circulation 2004; 109: 513-519
51. Work LM, Büning H, Hunt E, Nicklin SA, Denby L, Britton N, Leike K, Odenthal M, Drebber U, Hallek M, Baker AH. Vascular bed-Targeted in vivo gene delivery using tropism-modified adeno-Associated viruses. Mol Ther 2006; 13: 683-693
52. Yue Y, Ghosh A, Long C, Bostick B, Smith BF, Kornegay JN, Duan D. A single intravenous injection of adeno-Associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. Mol Ther 2008; 16: 1944-1952
53. 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: 793-802
54. Ying Y, Mü ller OJ, Goehringer C, Leuchs B, Trepel M, Katus HA, Kleinschmidt JA. Heart-Targeted adeno-Associated viral vectors selected by in vivo biopanning of a random viral display peptide library. Gene Ther 2010; 17: 980-990
55. Yang L, Jiang J, Drouin LM, Agbandje-McKenna M, Chen C, Qiao C, Pu D, Hu X, Wang D-Z, Li J, Xiao X. A myocardium tropic adeno-Associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc Natl Acad Sci USA 2009; 106: 3946-3951
56. Asokan A, Conway JC, Phillips JL, Li C, Hegge J, Sinnott R, Yadav S, DiPrimio N, Nam H-J, Agbandje-McKenna M, McPhee S, Wolff J, Samulski RJ. Reengineering a receptor footprint of adeno-Associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 2010; 28: 79-82
57. Pulicherla N, Shen S, Yadav S, Debbink K, Govindasamy L, Agbandje-McKenna M, Asokan A. Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol Ther 2011; 19: 1070-1078
58. Wang B, Li J, Fu FH, Chen C, Zhu X, Zhou L, Jiang X, Xiao X. Construction and analysis of compact muscle-specific promoters for AAV vectors. Gene Ther 2008; 15: 1489-1499
59. Sanbe A, Gulick J, Hanks MC, Liang Q, Osinska H, Robbins J. Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res 2003; 92: 609-616
60. Bostick B, Yue Y, Long C, Marschalk N, Fine DM, Chen J, Duan D. Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice. Mol Ther 2009; 17: 253-261
61. Phillips MI, Tang Y, Schmidt-Ott K, Qian K, Kagiyama S. Vigilant vector: heart-specific promoter in an adeno-Associated virus vector for cardioprotection. Hypertension 2002; 39: 651-655
62. Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W, Kan YW. Adeno-Associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Proc Natl Acad Sci USA 2004; 101: 16280-16285
63. Choi S-C, Shim W-J, Lim D-S. Specific monitoring of cardiomyogenic and endothelial differentiation by dual promoter-driven reporter systems in bone marrow mesenchymal stem cells. Biotechnol Lett 2008; 30: 835-843
64. Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, Zarzoso M, Ramirez RJ, Sener MF, Mundada LV, Klos M, Devaney EJ, Vikstrom KL, Herron TJ, Jalife J. Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res 2013; 11: 1335-1347
65. Boecker W, Bernecker OY, Wu JC, Zhu X, Sawa T, Grazette L, Rosenzweig A, del Monte F, Schmidt U, Hajjar RJ. Cardiac-specific gene expression facilitated by an enhanced myosin light chain promoter. Mol Imaging 2004; 3: 69-75
66. Rincon MY, Sarcar S, Danso-Abeam D, Keyaerts M, Matrai J, Samara-Kuko E, Acosta-Sanchez A, Athanasopoulos T, Dickson G, Lahoutte T, De Bleser P, VandenDriessche T, Chuah MK. Genome-wide computational analysis reveals cardiomyocyte-specific transcriptional cis-regulatory motifs that enable efficient cardiac gene therapy. Mol Ther 2015; 23: 43-52
67. Nair N, Rincon MY, Evens H, Sarcar S, Dastidar S, Samara-Kuko E, Ghandeharian O, Man Viecelli H, Thöny B, De Bleser P, VandenDriessche T, Chuah MK. Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy. Blood 2014; 123: 3195-3199
68. Geisler A, Schön C, Gröbl T, Pinkert S, Stein EA, Kurreck J, Vetter R, Fechner H. Application of mutated miR-206 target sites enables skeletal muscle-specific silencing of transgene expression of cardiotropic AAV9 vectors. Mol Ther 2013; 21: 924-933
69. Geisler A, Jungmann A, Kurreck J, Poller W, Katus HA, Vetter R, Fechner H, Müller OJ. microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Gene Ther 2011; 18: 199-209
70. Wu Z, Yang H, Colosi P. Effect of genome size on AAV vector packaging. Mol Ther 2010; 18: 80-86
71. Lai Y, Yue Y, Liu M, Ghosh A, Engelhardt JF, Chamberlain JS, Duan D. Efficient in vivo gene expression by trans-splicing adeno-Associated viral vectors. Nat Biotechnol 2005; 23: 1435-1439
72. Ghosh A, Yue Y, Shin J-H, Duan D. Systemic Trans-splicing adeno-Associated viral delivery efficiently transduces the heart of adult mdx mouse, a model for duchenne muscular dystrophy. Hum Gene Ther 2009; 20: 1319-1328
73. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Rasko J, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342-347
74. Kwon I, Schaffer DV. Designer gene delivery vectors: molecular engineering and evolution of adeno-Associated viral vectors for enhanced gene transfer. Pharm Res 2008; 25: 489-499
75. Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, OBeirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CYC, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, et al. Adenovirus-Associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357-2365
76. Martino AT, Basner-Tschakarjan E, Markusic DM, Finn JD, Hinderer C, Zhou S, Ostrov DA, Srivastava A, Ertl HCJ, Terhorst C, High KA, Mingozzi F, Herzog RW. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 2013; 121: 2224-2233
77. European Society of Gene and Cell Therapy. French Society of Cell and Gene Therapy Collaborative Congress 2012 October 25-29, 2012 Palais des Congrés de Versailles Versailles, France. Hum Gene Ther 2012; 23: A1-A173
78. Cooray S, Howe SJ, Thrasher AJ. Retrovirus and lentivirus vector design and methods of cell conditioning. Methods Enzymol 2012; 507: 29-57
79. Mátrai J, Chuah MKL, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol Ther 2010; 18: 477-490
80. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 2013; 341: 1233151
81. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NAL, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341: 1233158
82. VandenDriessche T, Thorrez L, Naldini L, Follenzi A, Moons L, Berneman Z, Collen D, Chuah MKL. Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. Blood 2002; 100: 813-822
83. Bonci D, Cittadini A, Latronico MVG, Borello U, Aycock JK, Drusco A, Innocenzi A, Follenzi A, Lavitrano M, Monti MG, Ross J, Naldini L, Peschle C, Cossu G, Condorelli G. Advanced generation lentiviruses as efficient vectors for cardiomyocyte gene transduction in vitro and in vivo. Gene Ther 2003; 10: 630-636
84. Niwano K, Arai M, Koitabashi N, Watanabe A, Ikeda Y, Miyoshi H, Kurabayashi M. Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats. Mol Ther 2008; 16: 1026-1032
85. Cherqui S, Kingdon KM, Thorpe C, Kurian SM, Salomon DR. Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Mol Ther 2007; 15: 1264-1272
86. VandenDriessche T, Chuah MK. Targeting endothelial cells by gene therapy. Blood 2013; 122: 1993-1994
87. Abel T, El Filali E, Waern J, Schneider IC, Yuan Q, Münch RC, Hick M, Warnecke G, Madrahimov N, Kontermann RE, Schüttrumpf J, Mü ller UC, Seppen J, Ott M, Buchholz CJ. Specific gene delivery to liver sinusoidal and artery endothelial cells. Blood 2013; 122: 2030-2038
88. Witting SR, Vallanda P, Gamble AL. Characterization of a third generation lentiviral vector pseudotyped with Nipah virus envelope proteins for endothelial cell transduction. Gene Ther 2013; 20: 997-1005
89. Papayannakos C, Daniel R. Understanding lentiviral vector chromatin targeting: working to reduce insertional mutagenic potential for gene therapy. Gene Ther 2013; 20: 581-588
90. Sasano T, Kikuchi K, McDonald AD, Lai S, Donahue JK. Targeted high-efficiency, homogeneous myocardial gene transfer. J Mol Cell Cardiol 2007; 42: 954-961
91. Karakikes I, Hadri L, Rapti K, Ladage D, Ishikawa K, Tilemann L, Yi G-H, Morel C, Gwathmey JK, Zsebo K, Weber T, Kawase Y, Hajjar RJ. Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts. Mol Ther 2012; 20: 565-571
92. Vera Janavel GL, De Lorenzi A, Cortés C, Olea FD, Cabeza Meckert P, Bercovich A, Criscuolo M, Laguens R, Crottogini A. Effect of vascular endothelial growth factor gene transfer on infarct size, left ventricular function and myocardial perfusion in sheep after 2 months of coronary artery occlusion. J Gene Med 2012; 14: 279-287
93. Ferrarini M, Arsic N, Recchia FA, Zentilin L, Zacchigna S, Xu X, Linke A, Giacca M, Hintze TH. Adeno-Associated Virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs. Circ Res 2006; 98: 954-961
94. Tao Z, Chen B, Tan X, Zhao Y, Wang L, Zhu T, Cao K, Yang Z, Kan YW, Su H. Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci 2011; 108: 2064-2069
95. Post MJ, Sato K, Murakami M, Bao J, Tirziu D, Pearlman JD, Simons M. Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Am J Physiol Regul Integr Comp Physiol 2006; 290: R494-R500
96. del Monte F, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW, Gwathmey JK, Rosenzweig A, Hajjar RJ. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 1999; 100: 2308-2311
97. Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, Hajjar RJ. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA 2000; 97: 793-798
98. Beeri R, Chaput M, Guerrero JL, Kawase Y, Yosefy C, Abedat S, Karakikes I, Morel C, Tisosky A, Sullivan S, Handschumacher MD, Gilon D, Vlahakes GJ, Hajjar RJ, Levine RA. Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricular remodeling in ischemic mitral regurgitation. Circ Heart Fail 2010; 3: 627-634
99. del Monte F, Lebeche D, Guerrero JL, Tsuji T, Doye AA, Gwathmey JK, Hajjar RJ. Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling. Proc Natl Acad Sci USA 2004; 101: 5622-5627
100. Hadri L, Bobe R, Kawase Y, Ladage D, Ishikawa K, Atassi F, Lebeche D, Kranias EG, Leopold JA, Lompré A-M, Lipskaia L, Hajjar RJ. SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells. Mol Ther 2010; 18: 1284-1292
101. Pleger ST, Most P, Boucher M, Soltys S, Chuprun JK, Pleger W, Gao E, Dasgupta A, Rengo G, Remppis A, Katus HA, Eckhart AD, Rabinowitz JE, Koch WJ. Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. Circulation 2007; 115: 2506-2515
102. Pleger ST, Shan C, Ksienzyk J, Bekeredjian R, Boekstegers P, Hinkel R, Schinkel S, Leuchs B, Ludwig J, Qiu G, Weber C, Raake P, Koch WJ, Katus HA, Mü ller OJ, Most P. Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci Transl Med 2011; 3: 92ra64
103. Shah AS, Lilly RE, Kypson AP, Tai O, Hata JA, Pippen A, Silvestry SC, Lefkowitz RJ, Glower DD, Koch WJ. Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-Adrenergic receptor in the heart : prospects for molecular ventricular assistance. Circulation 2000; 101: 408-414
104. Kawahira Y, Sawa Y, Nishimura M, Sakakida S, Ueda H, Kaneda Y, Matsuda H. In vivo transfer of a beta 2-Adrenergic receptor gene into the pressure-overloaded rat heart enhances cardiac response to beta-Adrenergic agonist. Circulation 1998; 98: II262-II267; discussion II267-II268
105. Rengo G, Zincarelli C, Femminella GD, Liccardo D, Pagano G, de Lucia C, Altobelli GG, Cimini V, Ruggiero D, Perrone-Filardi P, Gao E, Ferrara N, Lymperopoulos A, Koch WJ, Leosco D. Myocardial b(2)-Adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure. Br J Pharmacol 2012; 166: 2348-2361
106. Roth DM, Lai NC, Gao MH, Drumm JD, Jimenez J, Feramisco JR, Hammond HK. Indirect intracoronary delivery of adenovirus encoding adenylyl cyclase increases left ventricular contractile function in mice. Am J Physiol Heart Circ Physiol 2004; 287: H172-H177
107. Takahashi T, Tang T, Lai NC, Roth DM, Rebolledo B, Saito M, Lew WYW, Clopton P, Hammond HK. Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction. Circulation 2006; 114: 388-396
108. Guellich A, Gao S, Hong C, Yan L, Wagner TE, Dhar SK, Ghaleh B, Hittinger L, Iwatsubo K, Ishikawa Y, Vatner SF, Vatner DE. Effects of cardiac overexpression of type 6 adenylyl cyclase affects on the response to chronic pressure overload. Am J Physiol Heart Circ Physiol 2010; 299: H707-H712
109. Lai NC, Roth DM, Gao MH, Tang T, Dalton N, Lai YY, Spellman M, Clopton P, Hammond HK. Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation 2004; 110: 330-336
110. Rissanen TT, Ylä-Herttuala S. Current status of cardiovascular gene therapy. Mol Ther 2007; 15: 1233-1247
111. Taimeh Z, Loughran J, Birks EJ, Bolli R. Vascular endothelial growth factor in heart failure. Nat Rev Cardiol 2013; 10: 519-530
112. Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda T, Chimenti S, Baker M, Limana F, Nurzynska D, Torella D, Rotatori F, Rastaldo R, Musso E, Quaini F, Leri A, Kajstura J, Anversa P. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-Term survival. Circ Res 2005; 97: 663-673
113. Autiero M, Luttun A, Tjwa M, Carmeliet P. Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 2003; 1: 1356-1370
114. Zachary I, Morgan RD. Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects. Heart Br Card Soc 2011; 97: 181-189
115. Xiao N, Qi X-Y, Tang L-N, Tan L-L, Chen Y-Q, Zhao H-M. VEGF promotes cardiac stem cells differentiation into vascular endothelial cells via the PI3K/Akt signaling pathway. Artif Cells Nanomedicine Biotechnol 2014; 42: 400-405
116. Giacca M, Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 2012; 19: 622-629
117. Itoh N, Ohta H. Pathophysiological roles of FGF signaling in the heart. Front Physiol 2013; 4. http: //www.ncbi.nlm.nih.gov/pmc/articles/PMC3764331/ (30 April 2015, date last accessed)
118. Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, West A, Rade JJ, Marrott P, Hammond HK, Engler RL. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105: 1291-1297
119. Detillieux KA, Sheikh F, Kardami E, Cattini PA. Biological activities of fibroblast growth factor-2 in the adult myocardium. Cardiovasc Res 2003; 57: 8-19
120. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307
121. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10: 417-427
122. Ylä-Herttuala S. Cardiovascular gene therapy with vascular endothelial growth factors. Gene 2013; 525: 217-219
123. Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-Arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006; 8: 1223-1234
124. Rissanen TT, Korpisalo P, Markkanen JE, Liimatainen T, Ordén M-R, Kholová I, de Goede A, Heikura T, Gröhn OH, Ylä-Herttuala S. Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis. Circulation 2005; 112: 3937-3946
125. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000; 102: 898-901
126. Kapur NK, Rade JJ. Fibroblast growth factor 4 gene therapy for chronic ischemic heart disease. Trends Cardiovasc Med 2008; 18: 133-141
127. Sarkar N, Rück A, Källner G, Y-Hassan S, Blomberg P, Islam KB, van der Linden J, Lindblom D, Nygren AT, Lind B, Brodin LA, Drvota V, Sylvén C. Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease-12-month follow-up: angiogenic gene therapy. J Intern Med 2001; 250: 373-381
128. Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N, Schatz RA, Asahara T, Isner JM, Kuntz RE. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012-2018
129. Favaloro L, Diez M, Mendiz O, Janavel GV, Valdivieso L, Ratto R, Garelli G, Salmo F, Criscuolo M, Bercovich A, Crottogini A. High-dose plasmid-mediated VEGF gene transfer is safe in patients with severe ischemic heart disease (Genesis-I). A phase I, open-label, two-year follow-up trial. Catheter Cardiovasc Interv Off J Soc Card Angiogr Interv 2013; 82: 899-906
130. Stewart DJ, Kutryk MJB, Fitchett D, Freeman M, Camack N, Su Y, Della Siega A, Bilodeau L, Burton JR, Proulx G, Radhakrishnan S, NORTHERN Trial Investigators. 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: 1109-1115
131. Stewart DJ, Hilton JD, Arnold JMO, Gregoire J, Rivard A, Archer SL, Charbonneau F, Cohen E, Curtis M, Buller CE, Mendelsohn FO, Dib N, Page P, Ducas J, Plante S, Sullivan J, Macko J, Rasmussen C, Kessler PD, Rasmussen HS. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther 2006; 13: 1503-1511
132. Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrott P, Pratt C, Kleiman N, Angiogene GENe Therapy (AGENT-2) Study Group. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol 2003; 42: 1339-1347
133. Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R, Andrasfay T, Engler RL. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol 2007; 50: 1038-1046
134. Hedman M, Hartikainen J, Ylä-Herttuala S. Progress and prospects: hurdles to cardiovascular gene therapy clinical trials. Gene Ther 2011; 18: 743-749
135. 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
136. Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med 2012; 2: a011056
137. Iwasaki H, Kawamoto A, Tjwa M, Horii M, Hayashi S, Oyamada A, Matsumoto T, Suehiro S, Carmeliet P, Asahara T. PlGF repairs myocardial ischemia through mechanisms of angiogenesis, cardioprotection and recruitment of myo-Angiogenic competent marrow progenitors. PLoS ONE 2011; 6: e24872
138. Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, Holubarsch C, Posival H, Just H, Drexler H. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res 1994; 75: 434-442
139. Shareef MA, Anwer LA, Poizat C. Cardiac SERCA2A/B: therapeutic targets for heart failure. Eur J Pharmacol 2014; 724: 1-8
140. Gwathmey JK, Yerevanian A, Hajjar RJ. Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. Hum Gene Ther 2013; 24: 937-947
141. Kawase Y. 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: 1112-1119
142. Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan G-C, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW II, MacLennan DH, Kremastinos DT, Kranias EG. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest 2003; 111: 869-876
143. Kato K, Kimura S. S100ao (alpha alpha) protein is mainly located in the heart and striated muscles. Biochim Biophys Acta 1985; 842: 146-150
144. Most P, Seifert H, Gao E, Funakoshi H, Vö lkers M, Heierhorst J, Remppis A, Pleger ST, DeGeorge BR, Eckhart AD, Feldman AM, Koch WJ. Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 2006; 114: 1258-1268
145. Kettlewell S, Most P, Currie S, Koch WJ, Smith GL. S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. J Mol Cell Cardiol 2005; 39: 900-910
146. Boerries M, Most P, Gledhill JR, Walker JE, Katus HA, Koch WJ, Aebi U, Schoenenberger C-A. Ca2+-dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes. Mol Cell Biol 2007; 27: 4365-4373
147. Most P, Pleger ST, Vö lkers M, Heidt B, Boerries M, Weichenhan D, Lö ffler E, Janssen PML, Eckhart AD, Martini J, Williams ML, Katus HA, Remppis A, Koch WJ. Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. J Clin Invest 2004; 114: 1550-1563
148. Remppis A, Pleger ST, Most P, Lindenkamp J, Ehlermann P, Schweda C, Lö ffler E, Weichenhan D, Zimmermann W, Eschenhagen T, Koch WJ, Katus HA. S100A1 gene transfer: a strategy to strengthen engineered cardiac grafts. J Gene Med 2004; 6: 387-394
149. Brinks H, Rohde D, Voelkers M, Qiu G, Pleger ST, Herzog N, Rabinowitz J, Ruhparwar A, Silvestry S, Lerchenmüller C, Mather PJ, Eckhart AD, Katus HA, Carrel T, Koch WJ, Most P. S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes. J Am Coll Cardiol 2011; 58: 966-973
150. Marks AR. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest 2013; 123: 46-52
151. Roth DM, Bayat H, Drumm JD, Gao MH, Swaney JS, Ander A, Hammond HK. Adenylyl cyclase increases survival in cardiomyopathy. Circulation 2002; 105: 1989-1994
152. Brodde OE. Beta-Adrenoceptors in cardiac disease. Pharmacol Ther 1993; 60: 405-430
153. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 2009; 54: 1747-1762
154. Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the beta 2-Adrenergic receptor. Science 1994; 264: 582-586
155. Zhu W, Petrashevskaya N, Ren S, Zhao A, Chakir K, Gao E, Chuprun JK, Wang Y, Talan M, Dorn GW, Lakatta EG, Koch WJ, Feldman AM, Xiao R-P. Gi-biased b2AR signaling links GRK2 upregulation to heart failure. Circ Res 2012; 110: 265-274
156. Gong H, Adamson DL, Ranu HK, Koch WJ, Heubach JF, Ravens U, Zolk O, Harding SE. The effect of Gi-protein inactivation on basal, and beta(1)-And beta(2)AR-stimulated contraction of myocytes from transgenic mice overexpressing the beta(2)-Adrenoceptor. Br J Pharmacol 2000; 131: 594-600
157. Iaccarino G, Ciccarelli M, Sorriento D, Galasso G, Campanile A, Santulli G, Cipolletta E, Cerullo V, Cimini V, Altobelli GG, Piscione F, Priante O, Pastore L, Chiariello M, Salvatore F, Koch WJ, Trimarco B. Ischemic neoangiogenesis enhanced by beta2-Adrenergic receptor overexpression: a novel role for the endothelial adrenergic system. Circ Res 2005; 97: 1182-1189
158. Lohse MJ. G-protein-coupled receptor kinases and the heart. Trends Cardiovasc Med 1995; 5: 63-68
159. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the beta-Adrenergic receptor kinase or a beta ARK inhibitor. Science 1995; 268: 1350-1353
160. Ungerer M, Kessebohm K, Kronsbein K, Lohse MJ, Richardt G. Activation of beta-Adrenergic receptor kinase during myocardial ischemia. Circ Res 1996; 79: 455-460
161. Harding VB, Jones LR, Lefkowitz RJ, Koch WJ, Rockman HA. Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci USA 2001; 98: 5809-5814
162. Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, DeGeorge BR Jr, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn GW II, Koch WJ. G proteincoupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 2008; 103: 413-422
163. Williams ML, Hata JA, Schroder J, Rampersaud E, Petrofski J, Jakoi A, Milano CA, Koch WJ. Targeted beta-Adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts. Circulation 2004; 109: 1590-1593
164. Raake PWJ, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S, Pleger S, Mier W, Haberkorn U, Koch WJ, Katus HA, Most P, Müller OJ. AAV6.bARKct 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: 1437-1447
165. Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 2008; 14: 355-367
166. Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ, Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators. 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: 171-181
167. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ, Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. 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: 304-313
168. Mearns BM. Gene therapy: can CUPID rescue the broken hearted? Nat Rev Cardiol 2011; 8: 481
169. Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, Hajjar RJ. Longterm effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res 2014; 114: 101-108
170. Pleger ST, Raake P, Katus HA, Most P. Cardiac calcium handling on trial targeting the failing cardiomyocyte signalosome. Circ Res 2014; 114: 12-14
171. Greenberg B, Yaroshinsky A, Zsebo KM, Butler J, Felker GM, Voors AA, Rudy JJ, Wagner K, Hajjar RJ. Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b). JACC Heart Fail 2014; 2: 84-92
172. Weber C, Neacsu I, Krautz B, Schlegel P, Sauer S, Raake P, Ritterhoff J, Jungmann A, Remppis AB, Stangassinger M, Koch WJ, Katus HA, Mü ller OJ, Most P, Pleger ST. Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model. Gene Ther 2014; 21: 131-138