Arterial Gene Transfer

  • Laurent J. Feldman
  • Ph. Gabriel Steg
Part of the Basic Science for the Cardiologist book series (BASC, volume 1)


Atherosclerosis and its complications represent the first cause of mortality and morbidity in the western world. Major advances have been made in the treatment and prevention of symptomatic atherosclerosis. Improved understanding of the pathophysiology of atherosclerosis and its complications [1], as well as spectacular advances in the molecular biology of the vascular wall [2] may open new perspectives for treatment based upon local delivery of genetic material designed to modify the atherosclerotic plaque at the molecular level [3]. Transfer of a functional gene into arterial wall cells, termed arterial gene therapy, may be used to replace or palliate a defective gene, or to express a protein with a therapeutic effect [4].


Gene Transfer Adenoviral Vector Intimal Hyperplasia Local Delivery Cationic Liposome 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.PubMedCrossRefGoogle Scholar
  2. 2.
    Gibbons GH, Dzau VJ. Molecular therapies for vascular diseases. Science. 1996;272:689–693.PubMedCrossRefGoogle Scholar
  3. 3.
    Nabel EG. Gene therapy for cardiovascular disease. Circulation. 1995;91:541–548.PubMedGoogle Scholar
  4. 4.
    Isner JM, Feldman LJ. Gene therapy for arterial disease. Lancet. 1994;344:1653–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Riessen R, Rahimizadeh H, Takeshita S, Gal D, Barry JJ, Isner JM. Successful vascular gene transfer using a hydrogel coated balloon angioplasty catheter. Hum Gene Ther. 1993;4:749–758.PubMedGoogle Scholar
  6. 6.
    Mulligan RC. The basic science of gene therapy. Science. 1993;260:926–932.PubMedCrossRefGoogle Scholar
  7. 7.
    Nabel EG, Plautz G, Nabel GJ. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science. 1990;249:1285–1288.PubMedCrossRefGoogle Scholar
  8. 8.
    Berkner KL. Expression of heterologous sequences in adenoviral vectors. Curr. Top. Microbiol. Immunol. 1992;158:39–66.PubMedGoogle Scholar
  9. 9.
    Steg PG, Feldman LJ, Scoazec JY, Tahlil O, Barry JJ, Boulechfar S, Ragot T, Isner JM, Perricaudet M. Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector. Circulation. 1994;90:1648–56.PubMedGoogle Scholar
  10. 10.
    Tripathy SK, Black HB, Goldwasser E, Leiden JM. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nature Med. 1996;2:545–550.PubMedCrossRefGoogle Scholar
  11. 11.
    Yang Y, Nunes FA, Berencsi K, Furth EE, Gönczöl E, Wilson JM. Cellular immunity to viral antigens limits El-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA. 1994;91:4407–4411.PubMedCrossRefGoogle Scholar
  12. 12.
    Schulick AH, Newman KD, Virmani R, Dichek DA. In vivo gene transfer into injured carotid arteries. Optimization and evaluation of acute toxicity. Circulation. 1995;91:2407–2414.PubMedGoogle Scholar
  13. 13.
    Feldman LJ, Pastore CJ, Aubailly N, Kearney M, Chen D, Perricaudet M, Steg PG, Isner JM. Improved efficiency of arterial gene transfer by use of poloxamer 407 as a vehicle for adenoviral vectors. Gene Ther. 1997;4:189–98.PubMedCrossRefGoogle Scholar
  14. 14.
    Newman KD, Dunn PF, Owens JW, Schulick AH, Virmani R, Sukhova G, Libby P, Dichek DA. Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J Clin Invest. 1995;96:2955–2965.PubMedCrossRefGoogle Scholar
  15. 15.
    Van Ginkel F, Liu C, Simecka J, Dong J, Greenway T, Frizzel R, Kiyono H, McGhee J, Pascual D. Intratracheal gene delivery with adenoviral vector induces elevated systemic IgG and mucosal IgA antibodies to adenovirus and ß-galactosidase. Hum Gene Ther. 1995;6:895–903.PubMedGoogle Scholar
  16. 16.
    Stratford-Perricaudet LD, Makeh I, Perricaudet M, Briand P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest. 1992;90:626–630.PubMedGoogle Scholar
  17. 17.
    Vilquin J-T, Guérette B, Kinoshita I, Roy B, Goulet M, Gravel C, Roy R, Tremblay JP. FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. Hum Gene Ther. 1995;6:1391–1401.PubMedGoogle Scholar
  18. 18.
    Engelhardt JF, Ye X, Doranz B, Wilson JM. Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci USA. 1994;91:6196–6200.PubMedCrossRefGoogle Scholar
  19. 19.
    Yeh P, Dedieu J-F, Orsini C, Vigne E, Denefle P, Perricaudet P. Efficient dual transcomplementation of adenovirus El and E4 regions from a 293-derived cell line expressing a minimal E4 functional unit. J Virol. 1996;70:559–565.PubMedGoogle Scholar
  20. 20.
    Wang Q, Finer MH. Second-generation adenovirus vectors. Nature Med. 1996;2:714–716.PubMedCrossRefGoogle Scholar
  21. 21.
    Felgner PL, Ringold GM. Cationic liposome-mediated transfection. Nature. 1989;337:387–388.PubMedCrossRefGoogle Scholar
  22. 22.
    Leclerc G, Gal D, Takeshita S, Nikol S, Weir L, Isner JM. Percutaneous arterial gene transfer in a rabbit model. Efficiency in normal and balloon-dilated atherosclerotic arteries. J Clin Invest. 1992;90:936–944.PubMedGoogle Scholar
  23. 23.
    Michael SI, Curiel DT. Strategies to achieve targeted gene delivery via the receptor-mediated endocytosis pathway. Gene Therapy. 1994; 1:223–232.PubMedGoogle Scholar
  24. 24.
    Morishita R, Gibbons G, Kaneda Y, Ogihara T, Dzau V. Novel and effective gene transfer technique for study of vascular renin angiotensin system. J Clin Invest. 1993;91:2580–2585.PubMedGoogle Scholar
  25. 25.
    von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA. 1995;92:1137–1141.PubMedCrossRefGoogle Scholar
  26. 26.
    Morishita R, Gibbons GH, Ellison KE, Nakajima M, von der Leynen H, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. Intimai hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides. J Clinlnvest. 1994;93:1458–1464.Google Scholar
  27. 27.
    Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakajima M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci USA. 1995;92:5855–5859.PubMedCrossRefGoogle Scholar
  28. 28.
    Riessen R, Isner JM. Prospects for site-specific delivery of pharmacologic and molecular therapies. J Am Coll Cardiol 1994;23:1234–1244.PubMedGoogle Scholar
  29. 29.
    Tahlil O, Brami M, Feldman LJ, Branellec D, Steg PG. The Dispatch catheter as a delivery tool for arterial gene transfer. Cardiovasc Res. 1997;33:181–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Isner JM, Pieczek A, Schainfield R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes JF. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet. 1996;348:370–374.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolinsky H, Thung SN. Use of a perforated balloon catheter to deliver concentrated heparin into the wall of the normal canine artery. J Am CollCardiol 1990;15:475–481.CrossRefGoogle Scholar
  32. 32.
    Lambert CR, Leone JE, Rowlands SM. Local drug delivery catheters: functional comparisson of porous and microporous designs. Cor Art Dis. 1993;4:469–475.Google Scholar
  33. 33.
    Feldman LJ, Steg PG, Zheng LP, Chen D, Kearney M, McGarr SE, Barry JJ, Dedieu JF, Perricaudet M, Isner JM. Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit. J Clin Invest. 1995;95:2662–71.PubMedGoogle Scholar
  34. 34.
    Lincoff AM, Topol EJ, Ellis SG. Local drug delivery for the prevention of restenosis. Fact, fancy, and future. Circulation. 1994;90:2070–2084.PubMedGoogle Scholar
  35. 35.
    Dichek DA, Neville RF, Zwiebel JA, Freeman SM, Leon MB, Anderson WF. Seeding of intravascular stents with genetically engineered endothelial cells. Circulation. 1989;80:1347–1353.PubMedGoogle Scholar
  36. 36.
    Dev V, Zeng H, Forrester JS, Eigler N, Tian Y, Hickey AJ, Fishbein MC, Kupfer J, Litvak F. Microspheres for drug delivery to the arterial wall: a study of kinetics, toxicity, and effects of corticosteroid loaded microspheres. J Am Coll Cardiol. 1994, 23:19 A. Abstract.Google Scholar
  37. 37.
    Slepian MJ, Sawhney A, Pathak CP, Khosravi F, Roth L, Massia SP, Hubbell JA. In situ photo-polymerized thin hydrogel barriers applied following arterial injury reduce intimai thickening. J Am Coll Cardiol. 1994;23:473A. Abstract.Google Scholar
  38. 38.
    Indolfi C, Awedimento EV, Rapacciuolo A, Di Lorenzo E, Esposito G, Stabile E, Mele E, Giuliano P, Condorelli GL, Chiariello M. Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nature Med. 1995;1:541–545.PubMedCrossRefGoogle Scholar
  39. 39.
    Simons M, Edelman ER, DeKeyser J-L, Langer R, Rosenberg RD. Antisense c-myb oligonucleotides inhibit intimai arterial smooth muscle cell accumulation in vivo. Nature. 1992;359:67–70.PubMedCrossRefGoogle Scholar
  40. 40.
    Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Feigner PL. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465–1468.PubMedCrossRefGoogle Scholar
  41. 41.
    French BA, Mazur W, Geske RS, Bolli R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation. 1994;90:2414–2424.PubMedGoogle Scholar
  42. 42.
    Barr E, Carroll J, Kalynych AM, Tripathy SK, Kozarsky K, Wilson JM. Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. Gene Ther, 1994;1:51–58.PubMedGoogle Scholar
  43. 43.
    Giordano FJ, Ping P, McKirnan MD, Nozaki S, DeMaria AN, Dillman WH, Mathieu-Costello O, Hammond HK. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nature Med. 1996;2:534–539.PubMedCrossRefGoogle Scholar
  44. 44.
    Logeart D, Hatem SN, Inamo J, Haddada H, Perricaudet M, Mercadier JJ. Increased efficiency of gene transfer to cardiac myocytes with recombinant adenovirus by altering the endothelial barrier permeability. Circulation. 1996;94(suppl I):1–590. Abstract.Google Scholar
  45. 45.
    Nabel EJ, Plautz G, Boyce DM, Stanley JC, Nabel GJ. Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science. 1989;244:1342–1344.PubMedCrossRefGoogle Scholar
  46. 46.
    Flugelman MY, Jaklitsch MT, Newman KD, Casscells W, Brathauer GL, Dichek DA. Low level in vivo gene transfer into the arterial wall through a perforated balloon catheter. Circulation. 1992;85:1110–1117.PubMedGoogle Scholar
  47. 47.
    Lemarchand P, Jones M, Yamada I, Crystal RG. In vivo gene transfer and expression in normal uninjured blood vessels using replication-deficient recombinant adenovirus vectors. Circ Res. 1993;72:1132–1138.PubMedGoogle Scholar
  48. 48.
    Schulick AH, Dong G, Newman KD, Virmani R, Dichek DA. Endothelium-specific in vivo gene transfer. Circ Res. 1995;77:475–485.PubMedGoogle Scholar
  49. 49.
    Rome JJ, Shayani V, Flugelman MY, Newman KD, Farb A, Virmani R, Dichek DA. Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall. Modeling with microscopic tracer particles and verification with a recombinant adenoviral vector. Arterioscler Thromb. 1994;14:148–161.PubMedGoogle Scholar
  50. 50.
    Maillard L, Ziol M, Tahlil O, Le Feuvre C, Feldman LJ, Branellec D, Bruneval P, Steg PG. Pre-treatment with elastase improves the efficiency of percutaneous adenovirus-mediated gene ransfer to the arterial media. Gene Ther. 1998. In press.Google Scholar
  51. 51.
    Bohl D, Naffakh N, Heard J-M. Long-term control of erythropoietin secretion by doxyxycline in mice transplanted with engineered primary myoblasts. Nature Med. 1997;3:299–305.PubMedCrossRefGoogle Scholar
  52. 52.
    Nabel EJ, Yang Z, Liptay S, San H, Gordon D, Haudenschild CC, Nabel GJ. Recombinant platelet-derived growth factor B gene expression in porcine arteries induces intimai hyperplasia in vivo. J. Clin. Invest. 1993;91:1822–1829.PubMedGoogle Scholar
  53. 53.
    Isner JM, Walsh K, Symes J, Pieczek A, Takeshita S, Lowry J, Rossow S, Rosenfield K, Weir L, Brogi E, Schainfeld R. Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. Circulation. 1995;91:2687–2691.PubMedGoogle Scholar
  54. 54.
    Lee JS, Feldman AM. Gene therapy for therapeutic myocardial angiogenesis: a promising synthesis of two emerging technologies. Nature Med. 1998;4:739–742.PubMedCrossRefGoogle Scholar
  55. 55.
    Chen S-J, Wilson JM, Muller DWM. Adenovirus-mediated gene transfer of soluble vascular cell adhesion molecule to porcine interposition vein grafts. Circulation. 1994;89:1922–1928.PubMedGoogle Scholar
  56. 56.
    Feldman LJ, Isner JM. Gene therapy for the vulnerable plaque. J Am Coll Cardiol 1995;26:826–35.PubMedCrossRefGoogle Scholar
  57. 57.
    Lafont A, Guérot C, Lemarchand P. Prospects for gene therapy in cardiovascular disease. Eur Heart J. 1996;17:1312–1317.PubMedGoogle Scholar
  58. 58.
    Clowes AW, Reidy MA, Clowes MM. Mechanisms of stenosis after arterial injury. Lab Invest. 1983;49:208–215.PubMedGoogle Scholar
  59. 59.
    Feldman LJ, Tahlil O, Steg PG. Perspectives of arterial gene therapy for the prevention of restenosis. Cardiovasc Res. 1996;32:194–207.PubMedCrossRefGoogle Scholar
  60. 60.
    Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM. Restenosis after experimental angioplasty. Intimai, medial, and adventitial changes associated with constrictive remodeling. CircRes. 1995;76:996–1002.Google Scholar
  61. 61.
    Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong SC, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty. A serial intravascular ultrasound study. Circulation. 1996;94:35–43.PubMedGoogle Scholar
  62. 62.
    Shi Y, Pieniek M, Fard A, O’Brien J, Mannion JD, Zalewski A. Adventitial remodeling after coronary arterial injury. Circulation. 1996;93:340–348.PubMedGoogle Scholar
  63. 63.
    Hoffmann R, S MG, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation. 1996;94:1247–1254.PubMedGoogle Scholar
  64. 64.
    Lafont A, Guerot C, Lemarchand P. Which gene for which restenosis? Lancet. 1995;346:1442–1443.PubMedCrossRefGoogle Scholar
  65. 65.
    Van Belle E, Maillard L, Rivard A, Fabre JE, Couffinhal T, Kearney M, Branellec D, Feldman LF, Walsh K, Isner JM. Effects of poloxamer 407 on transfection time and percutaneous adenovirus-mediated gene transfer in native and stented vessels. Hum Gene Ther. 1998;9:1013–1024.PubMedCrossRefGoogle Scholar
  66. 66.
    Baumgartner I, Pieczek AM, Blair R, Manor O, Walsh K, Isner JM. Evidence of therapeutic angiogenesis in patients with critical limb ischemia after intramuscular phVEGF165 gene transfer. Circulation. 1997;96:1–32. Abstract.Google Scholar
  67. 67.
    Schaper W, Ito WD. Molecular mechanisms of coronary collateral vessel growth. Circ Res. 1996;79:911–919.PubMedGoogle Scholar
  68. 68.
    Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, Horowitz JR, Symes JF, Isner JM. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation. 1996;94:3281–3290.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Laurent J. Feldman
    • 1
  • Ph. Gabriel Steg
    • 1
  1. 1.Cardiology Department and U460 INSERMFaculté Xavier BichatParisFrance

Personalised recommendations