Fetal gene therapy: Opportunities and risks

Advanced Drug Delivery Reviews

Volumn 61, Issue 10, 2009, Pages 813-821

  Wagner, Anna M ^a   Schoeberlein, Andreina ^a   Surbek, Daniel ^a  

^a Inselspital   (Switzerland)

Author keywords

Fetal gene therapy; Hemoglobinopathies; In utero transplantation; Somatic gene delivery; Stem cells; Vector system

Indexed keywords

FETAL GENE THERAPY; HEMOGLOBINOPATHIES; IN-UTERO TRANSPLANTATION; SOMATIC GENE DELIVERY; STEM CELLS; VECTOR SYSTEM;

BACTERIOPHAGES; CELL MEMBRANES; DRUG DELIVERY; GENE TRANSFER; HEALTH RISKS; MOLECULAR BIOLOGY;

PHYSIOLOGICAL MODELS;

ADENOSINE DEAMINASE; ADENOVIRUS VECTOR; LENTIVIRUS VECTOR; LIPOSOME; PARVOVIRUS VECTOR; RETROVIRUS VECTOR;

ADENOSINE DEAMINASE DEFICIENCY; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; ALLOGENEIC STEM CELL TRANSPLANTATION; AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION; CLINICAL TRIAL; CORD BLOOD STEM CELL TRANSPLANTATION; ENGRAFTMENT; FETUS DISEASE; GENE THERAPY; GENETIC DISORDER; GRAFT VERSUS HOST REACTION; HEMOGLOBINOPATHY; HUMAN; IMMUNE DEFICIENCY; IMMUNOREACTIVITY; IN UTERO STEM CELL TRANSPLANTATION; IN VITRO GENE TRANSFER; IN VIVO GENE TRANSFER; MESENCHYMAL STEM CELL TRANSPLANTATION; MICROCHROMOSOME; NONHUMAN; NONVIRAL GENE DELIVERY SYSTEM; POSTNATAL CARE; PREGNANCY; PRENATAL CARE; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; SEVERE COMBINED IMMUNODEFICIENCY; SOMATIC CELL THERAPY; TARGET CELL; TRANSGENE; TREATMENT OUTCOME; VIRAL GENE DELIVERY SYSTEM;

FEMALE; FETAL DISEASES; FETAL THERAPIES; GENE THERAPY; GENE TRANSFER TECHNIQUES; GENETIC DISEASES, INBORN; GENETIC VECTORS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; MESENCHYMAL STEM CELL TRANSPLANTATION; PREGNANCY; RISK;

EID: 67649372497     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.addr.2009.04.011     Document Type: Review

References (147)

1. Surbek D.V., and Holzgreve W. Why do we need non-invasive prenatal diagnosis?. In: Hahn S., and Holzgreve W. (Eds). Fetal Cells and Fetal DNA in Maternal Blood. New Developments for a New Millenium (2001) 21-27
2. Holzgreve W. Will ultrasound-screening and ultrasound-guided procedures be replaced by non-invasive techniques for the diagnosis of fetal chromosome anomalies?. Ultrasound Obstet. Gynecol. 9 (1997) 217-219
3. Cheung M.C., Goldberg J.D., and Kan Y.W. Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood. Nat. Genet. 14 (1996) 264-268
4. Li Y., Di Naro E., Vitucci A., Zimmermann B., Holzgreve W., and Hahn S. Detection of paternally inherited fetal point mutations for beta-thalassemia using size-fractionated cell-free DNA in maternal plasma. JAMA 293 (2005) 843-849
5. Buckley R.H., Schiff S.E., Schiff R.I., Markert L., Williams L.W., Roberts J.L., Myers L.A., and Ward F.E. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N. Engl. J. Med. 340 (1999) 508-516
6. Escolar M.L., Poe M.D., Provenzale J.M., Richards K.C., Allison J., Wood S., Wenger D.A., Pietryga D., Wall D., Champagne M., Morse R., Krivit W., and Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N. Engl. J. Med. 352 (2005) 2069-2081
7. Lucarelli G., Clift R.A., Galimberti M., Angelucci E., Giardini C., Baronciani D., Polchi P., Andreani M., Gaziev D., Erer B., Ciaroni A., D'Adamo F., Albertini F., and Muretto P. Bone marrow transplantation in adult thalassemic patients. Blood 93 (1999) 1164-1167
8. Shapiro E., Krivit W., Lockman L., Jambaque I., Peters C., Cowan M., Harris R., Blanche S., Bordigoni P., Loes D., Ziegler R., Crittenden M., Ris D., Berg B., Cox C., Moser H., Fischer A., and Aubourg P. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356 (2000) 713-718
9. Manno C.S., Chew A.J., Hutchison S., Larson P.J., Herzog R.W., Arruda V.R., Tai S.J., Ragni M.V., Thompson A., Ozelo M., Couto L.B., Leonard D.G., Johnson F.A., McClelland A., Scallan C., Skarsgard E., Flake A.W., Kay M.A., High K.A., and Glader B. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101 (2003) 2963-2972
10. Blaese R.M., Culver K.W., Miller A.D., Carter C.S., Fleisher T., Clerici M., Shearer G., Chang L., Chiang Y., Tolstoshev P., Greenblatt J.J., Rosenberg S.A., Klein H., Berger M., Mullen C.A., Ramsey W.J., Muul L., Morgan R.A., and Anderson W.F. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270 (1995) 475-480
11. Kohn D.B., Hershfield M.S., Carbonaro D., Shigeoka A., Brooks J., Smogorzewska E.M., Barsky L.W., Chan R., Burotto F., Annett G., Nolta J.A., Crooks G., Kapoor N., Elder M., Wara D., Bowen T., Madsen E., Snyder F.F., Bastian J., Muul L., Blaese R.M., Weinberg K., and Parkman R. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat. Med. 4 (1998) 775-780
12. Kohn D.B., Weinberg K.I., Nolta J.A., Heiss L.N., Lenarsky C., Crooks G.M., Hanley M.E., Annett G., Brooks J.S., el-Khoureiy A., et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat. Med. 1 (1995) 1017-1023
13. Buckley R.H. Gene therapy for human SCID: dreams become reality. Nat. Med. 6 (2000) 623-624
14. Cavazzana-Calvo M., Hacein-Bey S., de Saint Basile G., Gross F., Yvon E., Nusbaum P., Selz F., Hue C., Certain S., Casanova J.L., Bousso P., Deist F.L., and Fischer A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288 (2000) 669-672
15. Anderson W.F. Human gene therapy. Nature 392 (1998) 25-30
16. Blau H., and Khavari P. Gene therapy: progress, problems, prospects. Nat. Med. 3 (1997) 612-613
17. Hacein-Bey S. N. Engl. J. Med. 348 (2003) 255-256
18. Hacein-Bey S. Science 302 (2003) 415-419
19. Hacein-Bey-Abina S., von Kalle C., Schmidt M., Le Deist F., Wulffraat N., McIntyre E., Radford I., Villeval J.L., Fraser C.C., Cavazzana-Calvo M., and Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348 (2003) 255-256
20. 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., Sorensen R., Forster A., Fraser P., Cohen J.I., de Saint Basile G., Alexander I., Wintergerst U., Frebourg T., Aurias A., Stoppa-Lyonnet D., Romana S., Radford-Weiss I., Gross F., Valensi F., Delabesse E., Macintyre E., Sigaux F., Soulier J., Leiva L.E., Wissler M., Prinz C., Rabbitts T.H., Le Deist F., Fischer A., and Cavazzana-Calvo M. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302 (2003) 415-419
21. Hacein-Bey-Abina S., Garrigue A., Wang G.P., Soulier J., Lim A., Morillon E., Clappier E., Caccavelli L., Delabesse E., Beldjord K., Asnafi V., MacIntyre E., Dal Cortivo L., Radford I., Brousse N., Sigaux F., Moshous D., Hauer J., Borkhardt A., Belohradsky B.H., Wintergerst U., Velez M.C., Leiva L., Sorensen R., Wulffraat N., Blanche S., Bushman F.D., Fischer A., and Cavazzana-Calvo M. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118 (2008) 3132-3142
22. Verma I.M., and Somia N. Gene therapy - promises, problems and prospects. Nature 389 (1997) 239-242
23. Bestor T.H. Gene silencing as a threat to the success of gene therapy. J. Clin. Invest. 105 (2000) 409-411
24. Qin L., Ding Y., Pahud D.R., Chang E., Imperiale M.J., and Bromberg J.S. Promoter attenuation in gene therapy: interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum. Gene Ther. 8 (1997) 2019-2029
25. Bunting K.D., Sangster M.Y., Ihle J.N., and Sorrentino B.P. Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer. Nat. Med. 4 (1998) 58-64
26. Lutzko C., Kruth S., Abrams-Ogg A.C., Lau K., Li L., Clark B.R., Ruedy C., Nanji S., Foster R., Kohn D., Shull R., and Dube I.D. Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency. Blood 93 (1999) 1895-1905
27. Bhatia M., Bonnet D., Murdoch B., Gan O.I., and Dick J.E. A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat. Med. 4 (1998) 1038-1045
28. Goodell M.A., Rosenzweig M., Kim H., Marks D.F., DeMaria M., Paradis G., Grupp S.A., Sieff C.A., Mulligan R.C., and Johnson R.P. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat. Med. 3 (1997) 1337-1345
29. Ziegler B.L., Valtieri M., Porada G.A., De Maria R., Muller R., Masella B., Gabbianelli M., Casella I., Pelosi E., Bock T., Zanjani E.D., and Peschle C. KDR receptor: a key marker defining hematopoietic stem cells. Science 285 (1999) 1553-1558
30. Snyder R.O., Miao C., Meuse L., Tubb J., Donahue B.A., Lin H.F., Stafford D.W., Patel S., Thompson A.R., Nichols T., Read M.S., Bellinger D.A., Brinkhous K.M., and Kay M.A. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat. Med. 5 (1999) 64-70
31. Herzog R.W., Yang E.Y., Couto L.B., Hagstrom J.N., Elwell D., Fields P.A., Burton M., Bellinger D.A., Read M.S., Brinkhous K.M., Podsakoff G.M., Nichols T.C., Kurtzman G.J., and High K.A. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat. Med. 5 (1999) 56-63
32. Bainbridge J.W., Smith A.J., Barker S.S., Robbie S., Henderson R., Balaggan K., Viswanathan A., Holder G.E., Stockman A., Tyler N., Petersen-Jones S., Bhattacharya S.S., Thrasher A.J., Fitzke F.W., Carter B.J., Rubin G.S., Moore A.T., and Ali R.R. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358 (2008) 2231-2239
33. Brenner M.K. Gene transfer to hematopoietic cells. N. Engl. J. Med. 335 (1996) 337-339
34. Kalberer C.P., Pawliuk R., Imren S., Bachelot T., Takekoshi K.J., Fabry M., Eaves C.J., London I.M., Humphries R.K., and Leboulch P. Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta-globin in engrafted mice. Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 5411-5415
35. Abonour R., Williams D.A., Einhorn L., Hall K.M., Chen J., Coffman J., Traycoff C.M., Bank A., Kato I., Ward M., Williams S.D., Hromas R., Robertson M.J., Smith F.O., Woo D., Mills B., Srour E.F., and Cornetta K. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells. Nat. Med. 6 (2000) 652-658
36. Conneally E., Eaves C.J., and Humphries R.K. Efficient retroviral-mediated gene transfer to human cord blood stem cells with in vivo repopulating potential. Blood 91 (1998) 3487-3493
37. Harrington J.J., Van Bokkelen G., Mays R.W., Gustashaw K., and Willard H.F. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nat. Genet. 15 (1997) 345-355
38. Naldini L., Blomer U., Gallay P., Ory D., Mulligan R., Gage F.H., Verma I.M., and Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272 (1996) 263-267
39. Zufferey R., Nagy D., Mandel R.J., Naldini L., and Trono D. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15 (1997) 871-875
40. Kafri T., Blomer U., Peterson D.A., Gage F.H., and Verma I.M. Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors. Nat. Genet. 17 (1997) 314-317
41. Sutton R.E., Wu H.T., Rigg R., Bohnlein E., and Brown P.O. Human immunodeficiency virus type 1 vectors efficiently transduce human hematopoietic stem cells. J. Virol. 72 (1998) 5781-5788
42. Case S.S., Price M.A., Jordan C.T., Yu X.J., Wang L., Bauer G., Haas D.L., Xu D., Stripecke R., Naldini L., Kohn D.B., and Crooks G.M. Stable transduction of quiescent CD34(+)CD38(-) human hematopoietic cells by HIV-1-based lentiviral vectors. Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 2988-2993
43. Uchida N., Sutton R.E., Friera A.M., He D., Reitsma M.J., Chang W.C., Veres G., Scollay R., and Weissman I.L. HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells. Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 11939-11944
44. Miyoshi H., Smith K.A., Mosier D.E., Verma I.M., and Torbett B.E. Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283 (1999) 682-686
45. May C., Rivella S., Callegari J., Heller G., Gaensler K.M., Luzzatto L., and Sadelain M. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 406 (2000) 82-86
46. Jimenez D.F., Lee C.I., O'Shea C.E., Kohn D.B., and Tarantal A.F. HIV-1-derived lentiviral vectors and fetal route of administration on transgene biodistribution and expression in rhesus monkeys. Gene Ther. 12 (2005) 821-830
47. Lee C.C., Jimenez D.F., Kohn D.B., and Tarantal A.F. Fetal gene transfer using lentiviral vectors and the potential for germ cell transduction in rhesus monkeys (Macaca mulatta). Hum. Gene Ther. 16 (2005) 417-425
48. Seppen J., van der Rijt R., Looije N., van Til N.P., Lamers W.H., and Oude Elferink R.P. Long-term correction of bilirubin UDPglucuronyltransferase deficiency in rats by in utero lentiviral gene transfer. Mol. Ther. 8 (2003) 593-599
49. Larson J.E., Morrow S.L., Happel L., Sharp J.F., and Cohen J.C. Reversal of cystic fibrosis phenotype in mice by gene therapy in utero. Lancet 349 (1997) 619-620
50. Sekhon H.S., and Larson J.E. In utero gene transfer into the pulmonary epithelium. Nat. Med. 1 (1995) 1201-1203
51. Wang G., Williamson R., Mueller G., Thomas P., Davidson B.L., and McCray Jr. P.B. Ultrasound-guided gene transfer to hepatocytes in utero. Fetal Diagn. Ther. 13 (1998) 197-205
52. Hayashi S.I., Morishita R., Aoki M., Moriguchi A., Kida I., Nakajima M., Kaneda Y., Higaki J., and Ogihara T. In vivo transfer of gene and oligodeoxynucleotides into skin of fetal rats by incubation in amniotic fluid. Gene Ther. 3 (1996) 878-885
53. Wu Y., Liu J., Woo S., Finegold M.J., and Brandt M.L. Prenatal orogastric gene delivery results in transduction of the small bowel in the fetal rabbit. Fetal Diagn. Ther. 14 (1999) 323-327
54. Woo Y.J., Raju G.P., Swain J.L., Richmond M.E., Gardner T.J., and Balice-Gordon R.J. In utero cardiac gene transfer via intraplacental delivery of recombinant adenovirus. Circulation 96 (1997) 3561-3569
55. L.A. Davies, A. Varathalingam, H. Painter, A.E. Lawton, S.G. Sumner-Jones, G.A. Nunez-Alonso, M. Chan, F. Munkonge, E.W. Alton, S.C. Hyde, D.R. Gill, Adenovirus-mediated in utero expression of CFTR does not improve survival of CFTR knockout mice, Mol Ther. 16(5) (2008) 812-818. (Electronic publication ahead of print 2008 Mar 11).
56. Mason C.A., Bigras J.L., O'Blenes S.B., Zhou B., McIntyre B., Nakamura N., Kaneda Y., and Rabinovitch M. Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin-dependent neointimal formation. Nat. Med. 5 (1999) 176-182
57. David A.L., Peebles D.M., Gregory L., Themis M., Cook T., Coutelle C., and Rodeck C.H. Percutaneous ultrasound-guided injection of the trachea in fetal sheep: a novel technique to target the fetal airways. Fetal Diagn. Ther. 18 (2003) 385-390
58. Peebles D., Gregory L.G., David A., Themis M., Waddington S.N., Knapton H.J., Miah M., Cook T., Lawrence L., Nivsarkar M., Rodeck C., and Coutelle C. Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero. Gene Ther. 11 (2004) 70-78
59. Tsukamoto M., Ochiya T., Yoshida S., Sugimura T., and Terada M. Gene transfer and expression in progeny after intravenous DNA injection into pregnant mice. Nat. Genet. 9 (1995) 243-248
60. 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., Glover E., Maguire A.M., Pugh Jr. E.N., Jacobson S.G., and Bennett J. In utero gene therapy rescues vision in a murine model of congenital blindness. Mol. Ther. 9 (2004) 182-188
61. Rucker M., Fraites Jr. T.J., Porvasnik S.L., Lewis M.A., Zolotukhin I., Cloutier D.A., and Byrne B.J. Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease. Development 131 (2004) 3007-3019
62. Waddington S.N., Kennea N.L., Buckley S.M., Gregory L.G., Themis M., and Coutelle C. Fetal and neonatal gene therapy: benefits and pitfalls. Gene Ther. 11 Suppl 1 (2004) S92-97
63. Waddington S.N., Buckley S.M., Nivsarkar M., Jezzard S., Schneider H., Dahse T., Kemball-Cook G., Miah M., Tucker N., Dallman M.J., Themis M., and Coutelle C. In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood 101 (2003) 1359-1366
64. Senut M.C., Suhr S.T., and Gage F.H. Gene transfer to the rodent placenta in situ. A new strategy for delivering gene products to the fetus. J. Clin. Invest. 101 (1998) 1565-1571
65. Portmann-Lanz B., and Surbek D. Placental mesenchymal stem cells. Am. J. Obstet. Gynecol. 196 (2007) e18-e19
66. Coutelle C., Themis M., Waddington S.N., Buckley S.M., Gregory L.G., Nivsarkar M.S., David A.L., Peebles D., Weisz B., and Rodeck C. Gene therapy progress and prospects: fetal gene therapy-first proofs of concept-some adverse effects. Gene Ther. 12 (2005) 1601-1607
67. Schoeberlein A., Schatt S., Troeger C., Surbek D., Holzgreve W., and Hahn S. Engraftment kinetics of human cord blood and murine fetal liver stem cells following in utero transplantation into immunodeficient mice. Stem Cells Dev. 13 (2004) 677-684
68. Miyasaka M., and Morris B. The ontogeny of the lymphoid system and immune responsiveness in sheep. Prog. Vet. Microbiol. Immunol. 4 (1988) 21-55
69. Surbek D., Holzgreve W., and Nicolaides K.H. Hematopoietic stem cell transplantation and gene therapy in the fetus: ready for clinical use?. Hum. Reprod. Update 7 (2001) 85-91
70. Surbek D.V., Schoeberlein A., and Portmann-Lanz B. Perinatology 8 (2007) 249-262
71. E. Colleti, S. Lindstedt, P.J. Park, G. Almeida-Porada, C.D. Porada, Early fetal gene delivery utilizes both central and peripheral mechanisms of tolerance induction, Exp. Hematol. (2008) 816-822.
72. Zanjani E.D., and Anderson W.F. Prospects for in utero human gene therapy. Science 285 (1999) 2084-2088
73. Coutelle C., Douar A.M., Colledge W.H., and Froster U. The challenge of fetal gene therapy. Nat. Med. 1 (1995) 864-866
74. Douar A.M., Themis M., and Coutelle C. Fetal somatic gene therapy. Mol. Hum. Reprod. 2 (1996) 633-641
75. Luther-Wyrsch A., Costello E., Thali M., Buetti E., Nissen C., Surbek D., Holzgreve W., Gratwohl A., Tichelli A., and Wodnar-Filipowicz A. Stable transduction with lentiviral vectors and amplification of immature hematopoietic progenitors from cord blood of preterm human fetuses. Hum. Gene. Ther. 12 (2001) 377-389
76. Piacibello W., Sanavio F., Garetto L., Severino A., Bergandi D., Ferrario J., Fagioli F., Berger M., and Aglietta M. Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood 89 (1997) 2644-2653
77. Wyrsch A., dalle Carbonare V., Jansen W., Chklovskaia E., Nissen C., Surbek D., Holzgreve W., Tichelli A., and Wodnar-Filipowicz A. Umbilical cord blood from preterm human fetuses is rich in committed and primitive hematopoietic progenitors with high proliferative and self-renewal capacity. Exp. Hematol. 27 (1999) 1338-1345
78. Ekhterae D., Crumbleholme T., Karson E., Harrison M.R., Anderson W.F., and Zanjani E.D. Retroviral vector-mediated transfer of the bacterial neomycin resistance gene into fetal and adult sheep and human hematopoietic progenitors in vitro. Blood 75 (1990) 365-369
79. Geiger H., Sick S., Bonifer C., and Muller A.M. Globin gene expression is reprogrammed in chimeras generated by injecting adult hematopoietic stem cells into mouse blastocysts. Cell 93 (1998) 1055-1065
80. 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. In utero gene transfer and expression: a sheep transplantation model. Blood 73 (1989) 1066-1073
81. Lutzko C., Omori F., Abrams-Ogg A.C., Shull R., Li L., Lau K., Ruedy C., Nanji S., Gartley C., Dobson H., Foster R., Kruth S., and Dube I.D. 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 (1999) 1521-1532
82. Omori F., Lutzko C., Abrams-Ogg A., Lau K., Gartley C., Dobson H., Nanji S., Ruedy C., Singaraja R., Li L., Stewart A.K., Kruth S., and Dube I.D. Adoptive transfer of genetically modified human hematopoietic stem cells into preimmune canine fetuses. Exp. Hematol. 27 (1999) 242-249
83. Winkler A., Kiem H.P., Shields L.E., Sun Q.H., and Andrews R.G. Gene transfer into fetal baboon hematopoietic progenitor cells. Hum. Gene Ther. 10 (1999) 667-677
84. Surbek D.V., Tercanli S., and Holzgreve W. Transabdominal first trimester embryofetoscopy as a potential approach to early in utero stem cell transplantation and gene therapy. Ultrasound Obstet. Gynecol. 15 (2000) 302-307
85. Moon N., Yang S.J., Park B.B., Chung Y.S., Lee J.W., and Oh I.H. Efficient bone marrow transduction by gene transfer with allogeneic umbilical cord blood serum and plasma: an implication for clinical trials. Hum. Gene Ther. (2008)
86. Schoeberlein A., Holzgreve W., Dudler L., Hahn S., and Surbek D.V. In utero transplantation of autologous and allogeneic fetal liver stem cells in ovine fetuses. Am. J. Obstet. Gynecol. 191 (2004) 1030-1036
87. Surbek D.V., Young A., Danzer E., Schoeberlein A., Dudler L., and Holzgreve W. Ultrasound-guided stem cell sampling from the early ovine fetus for prenatal ex vivo gene therapy. Am. J. Obstet. Gynecol. 187 (2002) 960-963
88. Portmann-Lanz C.B., Schoeberlein A., Huber A., Sager R., Malek A., Holzgreve W., and Surbek D.V. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am. J. Obstet. Gynecol. 194 (2006) 664-673
89. Milner R., Shaaban A., Kim H.B., Fichter C., Scully M., Asakur T., and Flake A.W. Long term high level expression of donor hemoglobin after in utero HSC transplantation in thalassemic knockout mice - selective advantage for donor red cells. Blood 92 (1998) 696a
90. Allay J.A., Persons D.A., Galipeau J., Riberdy J.M., Ashmun R.A., Blakley R.L., and Sorrentino B.P. In vivo selection of retrovirally transduced hematopoietic stem cells. Nat. Med. 4 (1998) 1136-1143
91. Guenechea G., Segovia J.C., Albella B., Lamana M., Ramirez M., Regidor C., Fernandez M.N., and Bueren J.A. Delayed engraftment of nonobese diabetic/severe combined immunodeficient mice transplanted with ex vivo-expanded human CD34(+) cord blood cells. Blood 93 (1999) 1097-1105
92. Clapp D.W., Freie B., Lee W.H., and Zhang Y.Y. Molecular evidence that in situ-transduced fetal liver hematopoietic stem/progenitor cells give rise to medullary hematopoiesis in adult rats. Blood 86 (1995) 2113-2122
93. Porada C.D., Tran N., Eglitis M., Moen R.C., Troutman L., Flake A.W., Zhao Y., Anderson W.F., and Zanjani E.D. In utero gene therapy: transfer and long-term expression of the bacterial neo(r) gene in sheep after direct injection of retroviral vectors into preimmune fetuses. Hum. Gene Ther. 9 (1998) 1571-1585
94. Tran N.D., Porada C.D., Zhao Y., Almeida-Porada G., Anderson W.F., and Zanjani E.D. In utero transfer and expression of exogenous genes in sheep. Exp. Hematol. 28 (2000) 17-30
95. Baumgartner T.L., Baumgartner B.J., Hudon L., and Moise Jr. K.J. Ultrasonographically guided direct gene transfer in utero: successful induction of beta-galactosidase in a rabbit model. Am. J. Obstet. Gynecol. 181 (1999) 848-852
96. Lipshutz G.S., Sarkar R., Flebbe-Rehwaldt L., Kazazian H., and Gaensler K.M. 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. U. S. A. 96 (1999) 13324-13329
97. Schachtner S., Buck C., Bergelson J., and Baldwin H. Temporally regulated expression patterns following in utero adenovirus-mediated gene transfer. Gene Ther. 6 (1999) 1249-1257
98. Themis M., Schneider H., Kiserud T., Cook T., Adebakin S., Jezzard S., Forbes S., Hanson M., Pavirani A., Rodeck C., and Coutelle C. Successful expression of beta-galactosidase and factor IX transgenes in fetal and neonatal sheep after ultrasound-guided percutaneous adenovirus vector administration into the umbilical vein. Gene Ther. 6 (1999) 1239-1248
99. Persons D.A., Allay E.R., Sabatino D.E., Kelly P., Bodine D.M., and Nienhuis A.W. Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy. Blood 97 (2001) 3275-3282
100. Han X.D., Lin C., Chang J., Sadelain M., and Kan Y.W. Fetal gene therapy of alpha-thalassemia in a mouse model. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 9007-9011
101. Silver J.N., and Flotte T.R. Towards a rAAV-based gene therapy for ADA-SCID: from ADA deficiency to current and future treatment strategies. Pharmacogenomics 9 (2008) 947-968
102. Billings P.R. In utero gene therapy: the case against. Nat. Med. 5 (1999) 255-256
103. King D., Shakespeare T., Nicholson R., Clarke A., and McLean S. Risks inherent in fetal gene therapy. Nature 397 (1999) 383
104. Waddington S.N., Kramer M.G., Hernandez-Alcoceba R., Buckley S.M., Themis M., Coutelle C., and Prieto J. In utero gene therapy: current challenges and perspectives. Mol. Ther. 11 (2005) 661-676
105. Carter A.M., and Enders A.C. Comparative aspects of trophoblast development and placentation. Reprod. Biol. Endocrinol. 2 (2004) 46
106. 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., Buckley S.M., Dighe N., Ruthe A.T., Mistry A., Bigger B., Rahim A., Nguyen T.H., Trono D., Thrasher A.J., and Coutelle C. Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol. Ther. 12 (2005) 763-771
107. Ye X., Gao G.P., Pabin C., Raper S.E., and Wilson J.M. Evaluating the potential of germ line transmission after intravenous administration of recombinant adenovirus in the C3H mouse. Hum. Gene Ther. 9 (1998) 2135-2142
108. Tavian M., Coulombel L., Luton D., Clemente H.S., Dieterlen-Lievre F., and Peault B. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87 (1996) 67-72
109. Flake A.W., and Zanjani E.D. In utero hematopoietic stem cell transplantation. A status report. JAMA 278 (1997) 932-937
110. Blau C.A., and Stamatoyannopoulos G. Preemptive therapy for genetic disease. Nat. Med. 2 (1996) 161-162
111. Flake A.W., and Zanjani E.D. In utero hematopoietic stem cell transplantation: ontogenic opportunities and biologic barriers. Blood 94 (1999) 2179-2191
112. Flake A.W., Roncarolo M.G., Puck J.M., Almeida-Porada G., Evans M.I., Johnson M.P., Abella E.M., Harrison D.D., and Zanjani E.D. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N. Engl. J. Med. 335 (1996) 1806-1810
113. Pirovano S., Notarangelo L.D., Malacarne F., Mazzolari E., Porta F., Lanfranchi A., Giliani S., Zucca S., Pecorelli S., Albertini A., Ugazio A.G., and Imberti L. Reconstitution of T-cell compartment after in utero stem cell transplantation: analysis of T-cell repertoire and thymic output. Haematologica 89 (2004) 450-461
114. Sanna M., Monni G., and Ibba R. In utero stem cell transplantation for beta-thalassemia: a case report. Bone Marrow Transplant. 23 (1999) S109
115. Westgren M., Ringden O., Eik-Nes S., Ek S., Anvret M., Brubakk A.M., Bui T.H., Giambona A., Kiserud T., Kjaeldgaard A., Maggio A., Markling L., Seiger A., and Orlandi F. Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies. Transplantation 61 (1996) 1176-1179
116. Bambach B.J., Moser H.W., Blakemore K., Corson V.L., Griffin C.A., Noga S.J., Perlman E.J., Zuckerman R., Wenger D.A., and Jones R.J. Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy. Bone Marrow Transplant. 19 (1997) 399-402
117. Surbek D.V., Gratwohl A., and Holzgreve W. In utero hematopoietic stem cell transfer: current status and future strategies. Eur. J. Obstet. Gynecol. Reprod. Biol. 85 (1999) 109-115
118. Milner R., Shaaban A., Kim H., Fichter C., and Flake A. Natural killer cells do not mediate allograft rejection after in utero hematopoietic stem cell transplantation. Blood 92 (1998) 288b
119. Peranteau W.H., Endo M., Adibe O.O., and Flake A.W. Evidence for an immune barrier after in utero hematopoietic-cell transplantation. Blood 109 (2007) 1331-1333
120. Touraine J.L., Raudrant D., Golfier F., Rebaud A., Sembeil R., Roncarolo M.G., Bacchetta R., D'Oiron R., Lambert T., and Gebuhrer L. Reappraisal of in utero stem cell transplantation based on long-term results. Fetal Diagn. Ther. 19 (2004) 305-312
121. Troeger C., Surbek D., Schoberlein A., Schatt S., Dudler L., Hahn S., and Holzgreve W. In utero haematopoietic stem cell transplantation. Experiences in mice, sheep and humans. Swiss Med. Wkly. 137 Suppl 155 (2007) 14S-19S
122. Young A.J., Holzgreve W., Dudler L., Schoeberlein A., and Surbek D.V. Engraftment of human cord blood-derived stem cells in preimmune ovine fetuses after ultrasound-guided in utero transplantation. Am. J. Obstet. Gynecol. 189 (2003) 698-701
123. Zanjani E.D., Flake A.W., Rice H., Hedrick M., and Tavassoli M. Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep. J. Clin. Invest. 93 (1994) 1051-1055
124. Shields L.E., Bryant E.M., Easterling T.R., and Andrews R.G. Fetal liver cell transplantation for the creation of lymphohematopoietic chimerism in fetal baboons. Am. J. Obstet. Gynecol. 173 (1995) 1157-1160
125. Archer D.R., Turner C.W., Yeager A.M., and Fleming W.H. Sustained multilineage engraftment of allogeneic hematopoietic stem cells in NOD/SCID mice after in utero transplantation. Blood 90 (1997) 3222-3229
126. Turner C.W., Archer D.R., Wong J., Yeager A.M., and Fleming W.H. In utero transplantation of human fetal haemopoietic cells in NOD/SCID mice. Br. J. Haematol. 103 (1998) 326-334
127. Noia G., Pierelli L., Bonanno G., Monego G., Perillo A., Rutella S., Cavaliere A.F., Straface G., Fortunato G., Cesari E., Scambia G., Terzano M., Iannace E., Zelano G., Michetti F., Leone G., and Mancuso S. The intracoelomic route: a new approach for in utero human cord blood stem cell transplantation. Fetal Diagn. Ther. 19 (2004) 13-22
128. Santolaya-Forgas J., Galan I., Deleon-Luis J., and Wolf R. A study to determine if human umbilical cord hematopoietic stem cells can survive in baboon extra-embryonic celomic fluid: a prerequisite for determining the feasibility of in-utero stem cell xeno-transplantation via celocentesis. Fetal Diagn. Ther. 22 (2007) 131-135
129. Almeida-Porada G., Flake A.W., Glimp H.A., and Zanjani E.D. Cotransplantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero. Exp. Hematol. 27 (1999) 1569-1575
130. Almeida-Porada G., Porada C.D., Tran N., and Zanjani E.D. Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation. Blood 95 (2000) 3620-3627
131. Schoeberlein A., Holzgreve W., Dudler L., Hahn S., and Surbek D.V. Tissue-specific engraftment after in utero transplantation of allogeneic mesenchymal stem cells into sheep fetuses. Am. J. Obstet. Gynecol. 192 (2005) 1044-1052
132. Carrier E., Lee T.H., Busch M.P., and Cowan M.J. Induction of tolerance in nondefective mice after in utero transplantation of major histocompatibility complex-mismatched fetal hematopoietic stem cells. Blood 86 (1995) 4681-4690
133. Hayashi S., Peranteau W.H., Shaaban A.F., and Flake A.W. Complete allogeneic hematopoietic chimerism achieved by a combined strategy of in utero hematopoietic stem cell transplantation and postnatal donor lymphocyte infusion. Blood 100 (2002) 804-812
134. Hayward A., Ambruso D., Battaglia F., Donlon T., Eddelman K., Giller R., Hobbins J., Hsia Y.E., Quinones R., Shpall E., Trachtenberg E., and Giardina P. Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1. Fetal Diagn. Ther. 13 (1998) 8-14
135. Peranteau W.H., Hayashi S., Hsieh M., Shaaban A.F., and Flake A.W. High-level allogeneic chimerism achieved by prenatal tolerance induction and postnatal nonmyeloablative bone marrow transplantation. Blood 100 (2002) 2225-2234
136. Petersen S.M., Gendelman M., Murphy K.M., Torbenson M., Jones R.J., Althaus J.E., Stetten G., Bird C., and Blakemore K.J. Use of T-cell antibodies for donor dosaging in a canine model of in utero hematopoietic stem cell transplantation. Fetal Diagn. Ther. 22 (2007) 175-179
137. Bhattacharyya S., Chawla A., Smith K., Zhou Y., Talib S., Wardwell B., and Cowan M.J. Multilineage engraftment with minimal graft-versus-host disease following in utero transplantation of S-59 psoralen/ultraviolet a light-treated, sensitized T cells and adult T cell-depleted bone marrow in fetal mice. J. Immunol. 169 (2002) 6133-6140
138. Peranteau W.H., Endo M., Adibe O.O., Merchant A., Zoltick P.W., and Flake A.W. CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation. Blood 108 (2006) 4268-4274
139. Shaaban A.F., Kim H.B., Gaur L., Liechty K.W., and Flake A.W. Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment. Exp. Hematol. 34 (2006) 1278-1287
140. Shields L.E., Gaur L., Delio P., Potter J., Sieverkropp A., and Andrews R.G. Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates. Stem Cells 22 (2004) 759-769
141. Norbeck O., Tolfvenstam T., Shields L.E., Westgren M., and Broliden K. Parvovirus B19 capsid protein VP2 inhibits hematopoiesis in vitro and in vivo: implications for therapeutic use. Exp. Hematol. 32 (2004) 1082-1087
142. Liechty K.W., MacKenzie T.C., Shaaban A.F., Radu A., Moseley A.M., Deans R., Marshak D.R., and Flake A.W. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat. Med. 6 (2000) 1282-1286
143. Le Blanc K., Gotherstrom C., Ringden O., Hassan M., McMahon R., Horwitz E., Anneren G., Axelsson O., Nunn J., Ewald U., Norden-Lindeberg S., Jansson M., Dalton A., Astrom E., and Westgren M. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 79 (2005) 1607-1614
144. Horwitz E.M., Prockop D.J., Gordon P.L., Koo W.W., Fitzpatrick L.A., Neel M.D., McCarville M.E., Orchard P.J., Pyeritz R.E., and Brenner M.K. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97 (2001) 1227-1231
145. Fletcher J.C., and Richter G. Human fetal gene therapy: moral and ethical questions. Hum. Gene Ther. 7 (1996) 1605-1614
146. Caplan A.L., and Wilson J.M. The ethical challenges of in utero gene therapy. Nat. Genet. 24 (2000) 107
147. Schneider H., and Coutelle C. In utero gene therapy: the case for. Nat. Med. 5 (1999) 256-257