In Utero Muscle Gene Transfer



Efficient, widespread transgene expression in the muscle is one of the major challenges of gene transfer for the treatment of genetic muscle disorders. A good example of this disease is the Duchenne muscular dystrophy (DMD), a progressive, degenerative disease whose clinical symptoms manifest after birth, but whose genetic defect causing the disease is present at conception. The availability of prenatal testing for genetic muscle diseases provides the basis for treatments in utero. In utero gene transfer has the potential to achieve widespread transgene expression in the muscle by accomplishing gene delivery when the tissue mass is small and the immune system is still immature. In this chapter, we present preclinical experience with gene delivery strategies to treat muscle disorders in utero. Important issues include experience with different gene delivery vectors in preclinical models, gene expression in muscle tissue, and effects on immunity.


Gene Delivery Duchenne Muscular Dystrophy Adenoviral Vector Duchenne Muscular Dystrophy Pompe Disease 



PRC is supported by VA resources (Pittsburgh VA Healthcare System, Pittsburgh, PA).


  1. Acsadi, G., Lochmuller, H., Jani, A., Huard, J., Massie, B., Prescott, S., Simoneau, M., Petrof, B.J., and Karpati, G. (1996). Dystrophin expression in muscles of mdx mice after adenovirus-mediated in vivo gene transfer. Hum Gene Ther 7, 129–140.PubMedCrossRefGoogle Scholar
  2. Baldwin, H.S., Mickanin, C., and Buck, C. (1997). Adenovirus-mediated gene transfer during initial organogenesis in the mammalian embryo is promoter-dependent and tissue-specific. Gene Ther 4, 1142–1149.PubMedCrossRefGoogle Scholar
  3. Bergelson, J.M., Cunningham, J.A., Droguett, G., Kurt-Jones, E.A., Krithivas, A., Hong, J.S., Horwitz, M.S., Crowell, R.L., and Finberg, R.W. (1997). Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323.PubMedCrossRefGoogle Scholar
  4. Bergelson, J.M., Krithivas, A., Celi, L., Droguett, G., Horwitz, M.S., Wickham, T., Crowell, R.L., and Finberg, R.W. (1998). The murine CAR homolog is a receptor for coxsackie B viruses and adenoviruses. J Virol 72, 415–419.PubMedGoogle Scholar
  5. Bilbao, R., Reay, D.P., Hughes, T., Biermann, V., Volpers, C., Goldberg, L., Bergelson, J., Kochanek, S., and Clemens, P.R. (2003). Fetal muscle gene transfer is not enhanced by an RGD capsid modification to high-capacity adenoviral vectors. Gene Ther 10, 1821–1829.PubMedCrossRefGoogle Scholar
  6. Bilbao, R., Reay, D.P., Li, J., Xiao, X., and Clemens, P.R. (2005a). Patterns of gene expression from in utero delivery of adenoviral-associated vector serotype 1. Hum Gene Ther 16, 678–684.PubMedCrossRefGoogle Scholar
  7. Bilbao, R., Reay, D.P., Wu, E., Zheng, H., Biermann, V., Kochanek, S., and Clemens, P.R. (2005b). Comparison of high-capacity and first-generation adenoviral vector gene delivery to murine muscle in utero. Gene Ther 12, 39–47.PubMedCrossRefGoogle Scholar
  8. Biressi, S., Molinaro, M., and Cossu, G. (2007). Cellular heterogeneity during vertebrate skeletal muscle development. Dev Biol 308, 281-293.PubMedCrossRefGoogle Scholar
  9. Blake, D.J., Weir, A., Newey, S.E., and Davies, K.E. (2002). Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev 82, 291–329.PubMedGoogle Scholar
  10. Bouchard, S., MacKenzie, T.C., Radu, A.P., Hayashi, S., Peranteau, W.H., Chirmule, N., and Flake, A.W. (2003). Long-term transgene expression in cardiac and skeletal muscle following fetal administration of adenoviral or adeno-associated viral vectors in mice. J Gene Med 5, 941–950.PubMedCrossRefGoogle Scholar
  11. Boyle, M.P., Enke, R.A., Adams, R.J., Guggino, W.B., and Zeitlin, P.L. (2001). In utero AAV-mediated gene transfer to rabbit pulmonary epithelium. Mol Ther 4, 115–121.PubMedCrossRefGoogle Scholar
  12. Brockstedt, D.G., Podsakoff, G.M., Fong, L., Kurtzman, G., Mueller-Ruchholtz, W., and Engleman, E.G. (1999). Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration. Clin Immunol 92, 67–75.PubMedCrossRefGoogle Scholar
  13. Buckingham, M., Bajard, L., Chang, T., Daubas, P., Hadchouel, J., Meilhac, S., Montarras, D., Rocancourt, D., and Relaix, F. (2003). The formation of skeletal muscle: from somite to limb. J Anat 202, 59–68.PubMedCrossRefGoogle Scholar
  14. Casal, M.L., and Wolfe, J.H. (1997). Amphotropic and ecotropic retroviral vector viruses transduce midgestational murine fetal liver cells in a dual-chambered cocultivation system. Gene Ther 4, 39–44.PubMedCrossRefGoogle Scholar
  15. Chao, H., Mao, L., Bruce, A.T., and Walsh, C.E. (2000). Sustained expression of human factor VIII in mice using a parvovirus-based vector. Blood 95, 1594–1599.PubMedGoogle Scholar
  16. Christ, B., and Ordahl, C.P. (1995). Early stages of chick somite development. Anat Embryol (Berl) 191, 381–396.CrossRefGoogle Scholar
  17. Christensen, G., Minamisawa, S., Gruber, P.J., Wang, Y., and Chien, K.R. (2000). High-efficiency, long-term cardiac expression of foreign genes in living mouse embryos and neonates. Circulation 101, 178–184.PubMedGoogle Scholar
  18. Clemens, P.R., Kochanek, S., Sunada, Y., Chan, S., Chen, H.H., Campbell, K.P., and Caskey, C.T. (1996). In vivo muscle gene transfer of full-length dystrophin with an adenoviral vector that lacks all viral genes. Gene Ther 3, 965–972.PubMedGoogle Scholar
  19. Cohen, J.C., Morrow, S.L., Cork, R.J., Delcarpio, J.B., and Larson, J.E. (1998). Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model. Mol Genet Metab 64, 108–118.PubMedCrossRefGoogle Scholar
  20. David, A., Cook, T., Waddington, S., Peebles, D., Nivsarkar, M., Knapton, H., Miah, M., Dahse, T., Noakes, D., Schneider, H., et al. (2003). Ultrasound-guided percutaneous delivery of adenoviral vectors encoding the beta-galactosidase and human factor IX genes to early gestation fetal sheep in utero. Hum Gene Ther 14, 353–364.PubMedCrossRefGoogle Scholar
  21. Dejneka, N.S., Surace, E.M., Aleman, T.S., Cideciyan, A.V., Lyubarsky, A., Savchenko, A., Redmond, T.M., Tang, W., Wei, Z., Rex, T.S., et al. (2004). In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9, 182–188.PubMedCrossRefGoogle Scholar
  22. Duxson, M.J., and Usson, Y. (1989). Cellular insertion of primary and secondary myotubes in embryonic rat muscles. Development 107, 243–251.PubMedGoogle Scholar
  23. Emerson, C.P., and Hauschka, S.D. (2004). Embryonic Origins of Skeletal Muscles. In Myology, A.G. Engel, and C. Franzini-Armstrong, eds. (NewYork, USA: McGraw-Hill), pp. 3–44.Google Scholar
  24. Emery, A. (1993). Duchenne Muscular Dystrophy, 2nd edition edn (Oxford University Press).Google Scholar
  25. Fischer, A., Abina, S.H., Thrasher, A., von Kalle, C., and Cavazzana-Calvo, M. (2004). LMO2 and gene therapy for severe combined immunodeficiency. N Engl J Med 350, 2526–2527; author reply 2526–2527.Google Scholar
  26. Garrett, D.J., Larson, J.E., Dunn, D., Marrero, L., and Cohen, J.C. (2003). In utero recombinant adeno-associated virus gene transfer in mice, rats, and primates. BMC Biotechnol 3, 16.PubMedCrossRefGoogle Scholar
  27. Gharwan, H., Wightman, L., Kircheis, R., Wagner, E., and Zatloukal, K. (2003). Nonviral gene transfer into fetal mouse livers (a comparison between the cationic polymer PEI and naked DNA). Gene Ther 10, 810–817.PubMedCrossRefGoogle Scholar
  28. Gilgenkrantz, H., Duboc, D., Juillard, V., Couton, D., Pavirani, A., Guillet, J.G., Briand, P., and Kahn, A. (1995). Transient expression of genes transferred in vivo into heart using first-generation adenoviral vectors: role of the immune response. Hum Gene Ther 6, 1265–1274.PubMedCrossRefGoogle Scholar
  29. Gillman.J (1948). The development of the gonads in man, with a consideration of the role of the fetal endocrines and the histogenesis of ovarian tumours. Contrib Embryol 32, 81–132.Google Scholar
  30. Gregory, L.G., Waddington, S.N., Holder, M.V., Mitrophanous, K.A., Buckley, S.M., Mosley, K.L., Bigger, B.W., Ellard, F.M., Walmsley, L.E., Lawrence, L., et al. (2004). Highly efficient EIAV-mediated in utero gene transfer and expression in the major muscle groups affected by Duchenne muscular dystrophy. Gene Ther 11, 1117–1125.PubMedCrossRefGoogle Scholar
  31. Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M.P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C.S., Pawliuk, R., Morillon, E., et al. (2003). LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415–419.PubMedCrossRefGoogle Scholar
  32. Haecker, S.E., Stedman, H.H., Balice-Gordon, R.J., Smith, D.B., Greelish, J.P., Mitchell, M.A., Wells, A., Sweeney, H.L., and Wilson, J.M. (1996). In vivo expression of full-length human dystrophin from adenoviral vectors deleted of all viral genes. Hum Gene Ther 7, 1907–1914.PubMedCrossRefGoogle Scholar
  33. Halbert, C.L., Rutledge, E.A., Allen, J.M., Russell, D.W., and Miller, A.D. (2000). Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 74, 1524–1532.PubMedCrossRefGoogle Scholar
  34. Han, X.D., Lin, C., Chang, J., Sadelain, M., and Kan, Y.W. (2007). Fetal gene therapy of alpha-thalassemia in a mouse model. Proc Natl Acad Sci USA 104, 9007–9011.PubMedCrossRefGoogle Scholar
  35. Hatzoglou, M., Lamers, W., Bosch, F., Wynshaw-Boris, A., Clapp, D.W., and Hanson, R.W. (1990). Hepatic gene transfer in animals using retroviruses containing the promoter from the gene for phosphoenolpyruvate carboxykinase. J Biol Chem 265, 17285–17293.PubMedGoogle Scholar
  36. Heckel, S., Favre, R., Flori, J., Koenig, M., Mandel, J., Gasser, B., and Chaigne, D. (1999). In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy. Fetal Diagn Ther 14, 127–132.PubMedCrossRefGoogle Scholar
  37. Hogan, B., Beddington, R., Constantini, F. and Lacy, E. (1994). Summary of mouse development. In: Manipulating the Mouse Embryo a laboratory manual, 2nd (Cold Spring Harbor Laboratory Press, Cold Spring Harbor).Google Scholar
  38. Holzinger, A., Trapnell, B.C., Weaver, T.E., Whitsett, J.A., and Iwamoto, H.S. (1995). Intraamniotic administration of an adenoviral vector for gene transfer to fetal sheep and mouse tissues. Pediatr Res 38, 844–850.PubMedCrossRefGoogle Scholar
  39. Huard, J., Feero, W.G., Watkins, S.C., Hoffman, E.P., Rosenblatt, D.J., and Glorioso, J.C. (1996). The basal lamina is a physical barrier to herpes simplex virus-mediated gene delivery to mature muscle fibers. J Virol 70, 8117–8123.PubMedGoogle Scholar
  40. Iwamoto, H.S., Trapnell, B.C., McConnell, C.J., Daugherty, C., and Whitsett, J.A. (1999). Pulmonary inflammation associated with repeated, prenatal exposure to an E1, E3-deleted adenoviral vector in sheep. Gene Ther 6, 98–106.PubMedCrossRefGoogle Scholar
  41. Jerebtsova, M., Batshaw, M.L., and Ye, X. (2002). Humoral immune response to recombinant adenovirus and adeno-associated virus after in utero administration of viral vectors in mice. Pediatr Res 52, 95–104.PubMedCrossRefGoogle Scholar
  42. Johnston, J., and Power, C. (1999). Productive infection of human peripheral blood mononuclear cells by feline immunodeficiency virus: implications for vector development. J Virol 73, 2491–2498.PubMedGoogle Scholar
  43. Johnston, J.C., Gasmi, M., Lim, L.E., Elder, J.H., Yee, J.K., Jolly, D.J., Campbell, K.P., Davidson, B.L., and Sauter, S.L. (1999). Minimum requirements for efficient transduction of dividing and nondividing cells by feline immunodeficiency virus vectors. J Virol 73, 4991–5000.PubMedGoogle Scholar
  44. Kantoff, P.W., Flake, A.W., Eglitis, M.A., Scharf, S., Bond, S., Gilboa, E., Erlich, H., Harrison, M.R., Zanjani, E.D., and Anderson, W.F. (1989). In utero gene transfer and expression: a sheep transplantation model. Blood 73, 1066–1073.PubMedGoogle Scholar
  45. Kim, V.N., Mitrophanous, K., Kingsman, S.M., and Kingsman, A.J. (1998). Minimal requirement for a lentivirus vector based on human immunodeficiency virus type 1. J Virol 72, 811–816.PubMedGoogle Scholar
  46. Kochanek, S., Clemens, P.R., Mitani, K., Chen, H.H., Chan, S., and Caskey, C.T. (1996). A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. Proc Natl Acad Sci USA 93, 5731–5736.PubMedCrossRefGoogle Scholar
  47. Kuller, J.A., Hoffman, E.P., Fries, M.H., and Golbus, M.S. (1992). Prenatal diagnosis of Duchenne muscular dystrophy by fetal muscle biopsy. Hum Genet 90, 34–40.PubMedCrossRefGoogle Scholar
  48. Lai, C.M., Lai, Y.K., and Rakoczy, P.E. (2002). Adenovirus and adeno-associated virus vectors. DNA Cell Biol 21, 895–913.PubMedCrossRefGoogle Scholar
  49. Lansdorp, P.M., Dragowska, W., and Mayani, H. (1993). Ontogeny-related changes in proliferative potential of human hematopoietic cells. J Exp Med 178, 787–791.PubMedCrossRefGoogle Scholar
  50. Larson, J.E., Morrow, S.L., Delcarpio, J.B., Bohm, R.P., Ratterree, M.S., Blanchard, J.L., and Cohen, J.C. (2000). Gene transfer into the fetal primate: evidence for the secretion of transgene product. Mol Ther 2, 631–639.PubMedCrossRefGoogle Scholar
  51. Larson, J.E., Morrow, S.L., Happel, L., Sharp, J.F., and Cohen, J.C. (1997). Reversal of cystic fibrosis phenotype in mice by gene therapy in utero. Lancet 349, 619–620.PubMedCrossRefGoogle Scholar
  52. Lewis, P., Hensel, M., and Emerman, M. (1992). Human immunodeficiency virus infection of cells arrested in the cell cycle. Embo J 11, 3053–3058.PubMedGoogle Scholar
  53. Lipshutz, G.S., Flebbe-Rehwaldt, L., and Gaensler, K.M. (1999a). Adenovirus-mediated gene transfer in the midgestation fetal mouse. J Surg Res 84, 150–156.PubMedCrossRefGoogle Scholar
  54. Lipshutz, G.S., Flebbe-Rehwaldt, L., and Gaensler, K.M. (1999b). Adenovirus-mediated gene transfer to the peritoneum and hepatic parenchyma of fetal mice in utero. Surgery 126, 171–177.PubMedGoogle Scholar
  55. Lipshutz, G.S., Sarkar, R., Flebbe-Rehwaldt, L., Kazazian, H., and Gaensler, K.M. (1999c). Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. Proc Natl Acad Sci USA 96, 13324–13329.PubMedCrossRefGoogle Scholar
  56. Lipshutz, G.S., Gruber, C.A., Cao, Y., Hardy, J., Contag, C.H., and Gaensler, K.M. (2001). In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. Mol Ther 3, 284–292.PubMedCrossRefGoogle Scholar
  57. Ljubic, A., Cvetkovic, M., Sulovic, V., Radunovic, N., Antonovic, O., Vukolic, D., Popovic, B., and Petkovic, S. (1999). New technique for artificial lung maturation. Direct intramuscular fetal corticosteroid therapy. Clin Exp Obstet Gynecol 26, 16–19.Google Scholar
  58. Luton, D., Oudrhiri, N., de Lagausie, P., Aissaoui, A., Hauchecorne, M., Julia, S., Oury, J.F., Aigrain, Y., Peuchmaur, M., Vigneron, J.P., et al. (2004). Gene transfection into fetal sheep airways in utero using guanidinium-cholesterol cationic lipids. J Gene Med 6, 328–336.PubMedCrossRefGoogle Scholar
  59. Lutzko, C., Omori, F., Abrams-Ogg, A.C., Shull, R., Li, L., Lau, K., Ruedy, C., Nanji, S., Gartley, C., Dobson, H., et al. (1999). Gene therapy for canine alpha-L-iduronidase deficiency: in utero adoptive transfer of genetically corrected hematopoietic progenitors results in engraftment but not amelioration of disease. Hum Gene Ther 10, 1521–1532.PubMedCrossRefGoogle Scholar
  60. MacKenzie, T.C., Kobinger, G.P., Kootstra, N.A., Radu, A., Sena-Esteves, M., Bouchard, S., Wilson, J.M., Verma, I.M., and Flake, A.W. (2002). Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes. Mol Ther 6, 349–358.PubMedCrossRefGoogle Scholar
  61. MacKenzie, T.C., Kobinger, G.P., Louboutin, J.P., Radu, A., Javazon, E.H., Sena-Esteves, M., Wilson, J.M., and Flake, A.W. (2005). Transduction of satellite cells after prenatal intramuscular administration of lentiviral vectors. J Gene Med 7, 50–58.PubMedCrossRefGoogle Scholar
  62. Mason, C.A., Bigras, J.L., O’Blenes, S.B., Zhou, B., McIntyre, B., Nakamura, N., Kaneda, Y., and Rabinovitch, M. (1999). Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin-dependent neointimal formation. Nat Med 5, 176–182.PubMedCrossRefGoogle Scholar
  63. McCray, P.B., Jr., Armstrong, K., Zabner, J., Miller, D.W., Koretzky, G.A., Couture, L., Robillard, J.E., Smith, A.E., and Welsh, M.J. (1995). Adenoviral-mediated gene transfer to fetal pulmonary epithelia in vitro and in vivo. J Clin Invest 95, 2620–2632.PubMedCrossRefGoogle Scholar
  64. Meertens, L., Zhao, Y., Rosic-Kablar, S., Li, L., Chan, K., Dobson, H., Gartley, C., Lutzko, C., Hopwood, J., Kohn, D., et al. (2002). In utero injection of alpha-L-iduronidase-carrying retrovirus in canine mucopolysaccharidosis type I: infection of multiple tissues and neonatal gene expression. Hum Gene Ther 13, 1809–1820.PubMedCrossRefGoogle Scholar
  65. Miller, D.G., Adam, M.A., and Miller, A.D. (1990). Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 10, 4239–4242.PubMedGoogle Scholar
  66. Mitchell, M., Jerebtsova, M., Batshaw, M.L., Newman, K., and Ye, X. (2000). Long-term gene transfer to mouse fetuses with recombinant adenovirus and adeno-associated virus (AAV) vectors. Gene Ther 7, 1986–1992.PubMedCrossRefGoogle Scholar
  67. Naldini, L., Blomer, U., Gage, F.H., Trono, D., and Verma, I.M. (1996a). Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 93, 11382–11388.PubMedCrossRefGoogle Scholar
  68. Naldini, L., Blomer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F.H., Verma, I.M., and Trono, D. (1996b). In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267.PubMedCrossRefGoogle Scholar
  69. Nathwani, A.C., Gray, J.T., McIntosh, J., Ng, C.Y., Zhou, J., Spence, Y., Cochrane, M., Gray, E., Tuddenham, E.G., and Davidoff, A.M. (2007). Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 109, 1414–1421.PubMedCrossRefGoogle Scholar
  70. O’Donoghue, K., and Fisk, N.M. (2004). Fetal stem cells. Best Pract Res Clin Obstet Gynaecol 18, 853–875.PubMedCrossRefGoogle Scholar
  71. Ontell, M., Bourke, D., and Hughes, D. (1988). Cytoarchitecture of the fetal murine soleus muscle. Am J Anat 181, 267–278.PubMedCrossRefGoogle Scholar
  72. Ontell, M., and Kozeka, K. (1984a). The organogenesis of murine striated muscle: a cytoarchitectural study. Am J Anat 171, 133–148.PubMedCrossRefGoogle Scholar
  73. Ontell, M., and Kozeka, K. (1984b). Organogenesis of the mouse extensor digitorum logus muscle: a quantitative study. Am J Anat 171, 149–161.PubMedCrossRefGoogle Scholar
  74. Ontell, M., Ontell, M.P., Sopper, M.M., Mallonga, R., Lyons, G., and Buckingham, M. (1993). Contractile protein gene expression in primary myotubes of embryonic mouse hindlimb muscles. Development 117, 1435–1444.PubMedGoogle Scholar
  75. Poeschla, E.M., Wong-Staal, F., and Looney, D.J. (1998). Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat Med 4, 354–357.PubMedCrossRefGoogle Scholar
  76. Prior, T.W., and Bridgeman, S.J. (2005). Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn 7, 317–326.PubMedGoogle Scholar
  77. Reay, D.P., Bilbao, R., Koppanati, B.M., Cai, L., O’Day, T.L., Jiang, Z., Zheng, H., Watchko, J.F., and Clemens, P.R. (2008). Full-length dystrophin gene transfer to the mdx mouse in utero. Gene Ther 15, 531–536.PubMedCrossRefGoogle Scholar
  78. Rich, D.P., Couture, L.A., Cardoza, L.M., Guiggio, V.M., Armentano, D., Espino, P.C., Hehir, K., Welsh, M.J., Smith, A.E., and Gregory, R.J. (1993). Development and analysis of recombinant adenoviruses for gene therapy of cystic fibrosis. Hum Gene Ther 4, 461–476.PubMedCrossRefGoogle Scholar
  79. Romano, G., Pacilio, C., and Giordano, A. (1999). Gene transfer technology in therapy: current applications and future goals. Stem Cells 17, 191–202.PubMedCrossRefGoogle Scholar
  80. Rosenfeld, M.A., Siegfried, W., Yoshimura, K., Yoneyama, K., Fukayama, M., Stier, L.E., Paakko, P.K., Gilardi, P., Stratford-Perricaudet, L.D., Perricaudet, M., et al. (1991). Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science 252, 431–434.PubMedCrossRefGoogle Scholar
  81. Rudnicki, M.A., Schnegelsberg, P.N., Stead, R.H., Braun, T., Arnold, H.H., and Jaenisch, R. (1993). MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75, 1351–1359.PubMedCrossRefGoogle Scholar
  82. Sabatino, D.E., Mackenzie, T.C., Peranteau, W., Edmonson, S., Campagnoli, C., Liu, Y.L., Flake, A.W., and High, K.A. (2007). Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Mol Ther 15, 1677–1685.PubMedCrossRefGoogle Scholar
  83. Sato, M., Tanigawa, M., and Kikuchi, N. (2004). Nonviral gene transfer to surface skin of mid-gestational murine embryos by intraamniotic injection and subsequent electroporation. Mol Reprod Dev 69, 268–277.PubMedCrossRefGoogle Scholar
  84. Schachtner, S., Buck, C., Bergelson, J., and Baldwin, H. (1999). Temporally regulated expression patterns following in utero adenovirus-mediated gene transfer. Gene Ther 6, 1249–1257.PubMedCrossRefGoogle Scholar
  85. Schneider, H., Muhle, C., Douar, A.M., Waddington, S., Jiang, Q.J., von der Mark, K., Coutelle, C., and Rascher, W. (2002). Sustained delivery of therapeutic concentrations of human clotting factor IX--a comparison of adenoviral and AAV vectors administered in utero. J Gene Med 4, 46–53.PubMedCrossRefGoogle Scholar
  86. Sekhon, H.S., and Larson, J.E. (1995). In utero gene transfer into the pulmonary epithelium. Nat Med 1, 1201–1203.PubMedCrossRefGoogle Scholar
  87. Senoo, M., Matsubara, Y., Fujii, K., Nagasaki, Y., Hiratsuka, M., Kure, S., Uehara, S., Okamura, K., Yajima, A., and Narisawa, K. (2000). Adenovirus-mediated in utero gene transfer in mice and guinea pigs: tissue distribution of recombinant adenovirus determined by quantitative TaqMan-polymerase chain reaction assay. Mol Genet Metab 69, 269–276.PubMedCrossRefGoogle Scholar
  88. Seppen, J., van der Rijt, R., Looije, N., van Til, N.P., Lamers, W.H., and Oude Elferink, R.P. (2003). Long-term correction of bilirubin UDPglucuronyltransferase deficiency in rats by in utero lentiviral gene transfer. Mol Ther 8, 593–599.PubMedCrossRefGoogle Scholar
  89. Shinnick, T.M., Lerner, R.A., and Sutcliffe, J.G. (1981). Nucleotide sequence of Moloney murine leukaemia virus. Nature 293, 543–548.PubMedCrossRefGoogle Scholar
  90. Srinivasakumar, N., Chazal, N., Helga-Maria, C., Prasad, S., Hammarskjold, M.L., and Rekosh, D. (1997). The effect of viral regulatory protein expression on gene delivery by human immunodeficiency virus type 1 vectors produced in stable packaging cell lines. J Virol 71, 5841–5848.PubMedGoogle Scholar
  91. Srivastava, A., Lusby, E.W., and Berns, K.I. (1983). Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol 45, 555–564.PubMedGoogle Scholar
  92. Sun, B., Zhang, H., Franco, L.M., Young, S.P., Schneider, A., Bird, A., Amalfitano, A., Chen, Y.T., and Koeberl, D.D. (2005). Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II. Mol Ther 11, 57–65.PubMedCrossRefGoogle Scholar
  93. Sylvester, K.G., Yang, E.Y., Cass, D.L., Crombleholme, T.M., and Adzick, N.S. (1997). Fetoscopic gene therapy for congenital lung disease. J Pediatr Surg 32, 964–969.PubMedCrossRefGoogle Scholar
  94. Tajbakhsh, S., Rocancourt, D., and Buckingham, M. (1996). Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice. Nature 384, 266–270.PubMedCrossRefGoogle Scholar
  95. Tajbakhsh, S., Rocancourt, D., Cossu, G., and Buckingham, M. (1997). Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD. Cell 89, 127–138.PubMedCrossRefGoogle Scholar
  96. Tarantal, A.F., O’Rourke, J.P., Case, S.S., Newbound, G.C., Li, J., Lee, C.I., Baskin, C.R., Kohn, D.B., and Bunnell, B.A. (2001). Rhesus monkey model for fetal gene transfer: studies with retroviral- based vector systems. Mol Ther 3, 128–138.PubMedCrossRefGoogle Scholar
  97. Taylor, P.A., McElmurry, R.T., Lees, C.J., Harrison, D.E., and Blazar, B.R. (2002). Allogenic fetal liver cells have a distinct competitive engraftment advantage over adult bone marrow cells when infused into fetal as compared with adult severe combined immunodeficient recipients. Blood 99, 1870–1872.PubMedCrossRefGoogle Scholar
  98. Themis, M., Waddington, S.N., Schmidt, M., von Kalle, C., Wang, Y., Al-Allaf, F., Gregory, L.G., Nivsarkar, M., Themis, M., Holder, M.V., et al. (2005). Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol Ther 12, 763–771.PubMedCrossRefGoogle Scholar
  99. Tripathy, S.K., Black, H.B., Goldwasser, E., and Leiden, J.M. (1996). Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 2, 545–550.PubMedCrossRefGoogle Scholar
  100. Turkay, A., Saunders, T., and Kurachi, K. (1999). Intrauterine gene transfer: gestational stage-specific gene delivery in mice. Gene Ther 6, 1685–1694.PubMedCrossRefGoogle Scholar
  101. Vincent, M.C., Trapnell, B.C., Baughman, R.P., Wert, S.E., Whitsett, J.A., and Iwamoto, H.S. (1995). Adenovirus-mediated gene transfer to the respiratory tract of fetal sheep in utero. Hum Gene Ther 6, 1019–1028.PubMedCrossRefGoogle Scholar
  102. Waddington, S.N., Buckley, S.M., Bernloehr, C., Bossow, S., Ungerechts, G., Cook, T., Gregory, L., Rahim, A., Themis, M., Neubert, W.J., et al. (2004a). Reduced toxicity of F-deficient Sendai virus vector in the mouse fetus. Gene Ther 11, 599–608.PubMedCrossRefGoogle Scholar
  103. Waddington, S.N., Nivsarkar, M.S., Mistry, A.R., Buckley, S.M., Kemball-Cook, G., Mosley, K.L., Mitrophanous, K., Radcliffe, P., Holder, M.V., Brittan, M., et al. (2004b). Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy. Blood 104, 2714–2721.PubMedCrossRefGoogle Scholar
  104. Waddington, S.N., Buckley, S.M., Nivsarkar, M., Jezzard, S., Schneider, H., Dahse, T., Kemball-Cook, G., Miah, M., Tucker, N., Dallman, M.J., et al. (2003a). In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood 101, 1359–1366.PubMedCrossRefGoogle Scholar
  105. Waddington, S.N., Mitrophanous, K.A., Ellard, F.M., Buckley, S.M., Nivsarkar, M., Lawrence, L., Cook, H.T., Al-Allaf, F., Bigger, B., Kingsman, S.M., et al. (2003b). Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice. Gene Ther 10, 1234–1240.PubMedCrossRefGoogle Scholar
  106. Wang, B., Li, J., Fu, F.H., and Xiao, X. (2009). Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J Orthop Res 27, 421–426.Google Scholar
  107. Wang, G., Williamson, R., Mueller, G., Thomas, P., Davidson, B.L., and McCray, P.B., Jr. (1998). Ultrasound-guided gene transfer to hepatocytes in utero. Fetal Diagn Ther 13, 197–205.PubMedCrossRefGoogle Scholar
  108. Wang, Z., Zhu, T., Qiao, C., Zhou, L., Wang, B., Zhang, J., Chen, C., Li, J., and Xiao, X. (2005). Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat biotechnol 23, 321–328.PubMedCrossRefGoogle Scholar
  109. Weiss, R.A. (1998). Retroviral zoonoses. Nat Med 4, 391–392.PubMedCrossRefGoogle Scholar
  110. Weiss, R.A., and Wrangham, R.W. (1999). From Pan to pandemic. Nature 397, 385–386.PubMedCrossRefGoogle Scholar
  111. Weisz, B., David, A.L., Gregory, L.G., Perocheau, D., Ruthe, A., Waddington, S.N., Themis, M., Cook, T., Coutelle, C., Rodeck, C.H., et al. (2005). Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy. Am J Obstet Gynecol 193, 1105–1109.PubMedCrossRefGoogle Scholar
  112. Wickham, T.J., Filardo, E.J., Cheresh, D.A., and Nemerow, G.R. (1994). Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol 127, 257–264.PubMedCrossRefGoogle Scholar
  113. Wickham, T.J., Mathias, P., Cheresh, D.A., and Nemerow, G.R. (1993). Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 73, 309–319.PubMedCrossRefGoogle Scholar
  114. Yang, E.Y., Kim, H.B., Shaaban, A.F., Milner, R., Adzick, N.S., and Flake, A.W. (1999). Persistent postnatal transgene expression in both muscle and liver after fetal injection of recombinant adenovirus. J Pediatr Surg 34, 766–772; discussion 772–763.Google Scholar
  115. Yang, Y., Nunes, F.A., Berencsi, K., Furth, E.E., Gonczol, E., and Wilson, J.M. (1994). Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 91, 4407–4411.PubMedCrossRefGoogle Scholar
  116. Yoshizawa, J., Li, X.K., Fujino, M., Kimura, H., Mizuno, R., Hara, A., Ashizuka, S., Kanai, M., Kuwashima, N., Kurobe, M., et al. (2004). Successful in utero gene transfer using a gene gun in midgestational mouse fetuses. J Pediatr Surg 39, 81–84.PubMedCrossRefGoogle Scholar
  117. Zhao, Y., Dai, Z.P., Lv, P., and Gao, X.M. (2002). Phenotypic and functional analysis of human T lymphocytes in early second- and third-trimester fetuses. Clin Exp Immunol 129, 302–308.PubMedCrossRefGoogle Scholar
  118. Ziegler, R.J., Bercury, S.D., Fidler, J., Zhao, M.A., Foley, J., Taksir, T.V., Ryan, S., Hodges, B.L., Scheule, R.K., Shihabuddin, L.S., et al. (2008). Ability of Adeno-Associated Virus Serotype 8-Mediated Hepatic Expression of Acid alpha-Glucosidase to Correct the Biochemical and Motor Function Deficits of Presymptomatic and Symptomatic Pompe Mice. Hum Gene Ther. 19, 609–621.Google Scholar
  119. Zufferey, R., Nagy, D., Mandel, R.J., Naldini, L., and Trono, D. (1997). Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat biotechnol 15, 871–875.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of PittsburghPittsburghUSA

Personalised recommendations