Advertisement

International Journal of Hematology

, Volume 73, Issue 2, pp 162–169 | Cite as

Clinical Gene Therapy in Hematology: Past and Future

  • Johan Richter
  • Stefan Karlsson
Review Article

Abstract

Gene transfer into hematopoietic cells using viral vectors has focused mostly on lymphocytes and hematopoietic stem cells (HSCs). HSCs have been considered particularly important as target cells because of their pluripotency and ability to reconstitute hematopoiesis after myeloablation and transplantation. HSCs are believed to have the ability to live a long time, perhaps a lifetime, in the recipient following bone marrow transplantation. Genetic correction of HSCs can therefore potentially last a lifetime and permanently cure hematologic disorders in which genetic deficiencies cause the pathology. Oncoretroviral vectors have been the main vectors used for HSCs because of their ability to integrate into the chromosomes of their target cells. Gene-transfer efficiency of murine HSCs is high using oncoretroviral vectors. In contrast, gene-transfer efficiency using the same viral vectors to transduce human HSCs or HSCs from large animals has been much lower. Although these difficulties may have several causes, the main reason for the low efficiency of human HSC transduction with oncoretroviral vectors is probably because of the nondividing nature of HSCs. Murine HSCs can be easily stimulated to divide in culture, whereas it is more problematic to stimulate human HSCs to divide rapidly in vitro. Because oncoretroviral vectors require dividing target cells for successful nuclear import of the preintegration complex and subsequent integration of the provirus, only the dividing fraction of the target cells can be transduced. This review focuses on gene transfer into human hematopoietic cells, particularly human HSCs. We review the clinical studies that have been reported, including the recent successful gene therapy for X-linked severe combined immunodeficiency. We discuss how the gene-transfer efficiency of human HSCs can be improved using oncoretroviral and lentiviral vectors.

Key words

Gene therapy Lentiviral vectors Retroviral vectors Hematopoietic stem cells Genetic diseases 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Richter J. Gene transfer to hematopoietic cell—the clinical experience.Eur J Haematol. 1997;59:67–75.CrossRefPubMedGoogle Scholar
  2. 2.
    Brenner M. Gene marking.Hum Gene Ther. 1996;7:1927–1936.CrossRefPubMedGoogle Scholar
  3. 3.
    Kohn D. Gene therapy for hematopoietic and lymphoid disorders.Clin Exp Immunol. 1997;107:54–57.PubMedGoogle Scholar
  4. 4.
    Mulligan R. The science of gene therapy.Science. 1993;260:926–932.CrossRefPubMedGoogle Scholar
  5. 5.
    Brenner MK, Rill DR, Holladay MS, et al. Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients.Lancet. 1993;342:1134–1137.CrossRefPubMedGoogle Scholar
  6. 6.
    Brenner MK, Rill DR, Moen RC, et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation.Lancet. 1993;341:85–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Deisseroth AB, Zu Z, Claxton D, et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML.Blood. 1994;83:3068–3076.PubMedGoogle Scholar
  8. 8.
    Rill DR, Santana VM, Roberts WM, et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells.Blood. 1994;84:380–383.PubMedGoogle Scholar
  9. 9.
    Dunbar CE, Cottler-Fox M, O’Shaughnessy JA, et al. Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation.Blood. 1995;85:3048–3057.PubMedGoogle Scholar
  10. 10.
    Emmons RV, Doren S, Zujewski J, et al. Retroviral gene transduction of adult peripheral blood or marrow-derived CD34+ cells for six hours without growth factors or on autologous stroma does not improve marking efficiency assessed in vivo.Blood. 1997;89:4040–4046.PubMedGoogle Scholar
  11. 11.
    Cowan KH, Moscow JA, Huang H, et al. Paclitaxel chemotherapy after autologous stem-cell transplantation and engraftment of hematopoietic cells transduced with a retrovirus containing the multidrug resistance complementary DNA (MDR1) in metastatic breast cancer patients.Clin Cancer Res. 1999;5:1619–1628.PubMedGoogle Scholar
  12. 12.
    Devereux S, Corney C, Macdonald C, et al. Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high- dose therapy and peripheral blood stem cell transplantation for lymphoma.Gene Ther. 1998;5:403–408.CrossRefPubMedGoogle Scholar
  13. 13.
    Hanania EG, Giles RE, Kavanagh J, et al. Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy [published erratum appears inProc Natl Acad Sci U S A. 1997;94:5495].Proc Natl Acad Sci U S A. 1996;93:15346–15351.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hesdorffer C, Ayello J, Ward M, et al. Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemo-protection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation.J Clin Oncol. 1998;16:165–172.CrossRefPubMedGoogle Scholar
  15. 15.
    Moscow JA, Huang H, Carter C, et al. Engraftment of MDR1 and NeoR gene-transduced hematopoietic cells after breast cancer chemotherapy.Blood. 1999;94:52–61.PubMedGoogle Scholar
  16. 16.
    Rahman Z, Kavanagh J, Champlin R, et al. Chemotherapy immediately following autologous stem-cell transplantation in patients with advanced breast cancer.Clin Cancer Res. 1998;4:2717–2721.PubMedGoogle Scholar
  17. 17.
    Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years.Science. 1995;270:475–480.CrossRefPubMedGoogle Scholar
  18. 18.
    Bordignon C, Notarangelo LD, Nobili N, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immuno-deficient patients.Science. 1995;270:470–475.CrossRefPubMedGoogle Scholar
  19. 19.
    Kohn DB, Weinberg KI, Nolta JA, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency.Nat Med. 1995;1:1017–1023.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kohn DB, Hershfield MS, Carbonaro D, et al. 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. 1998;4:775–780.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dunbar CE, Kohn DB, Schiffmann R, et al. Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: in vivo detection of transduced cells without myeloablation.Hum Gene Ther. 1998;9:2629–2640.CrossRefPubMedGoogle Scholar
  22. 22.
    Barranger JA, Rice EO, Swaney WP. Gene transfer approaches to the lysosomal storage disorders.Neurochem Res. 1999;24:601–615.CrossRefPubMedGoogle Scholar
  23. 23.
    Malech HL, Maples PB, Whiting-Theobald N, et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.Proc Natl Acad Sci U S A. 1997;94:12133–12138.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Malech HL. Progress in gene therapy for chronic granulomatous disease.J Infect Dis. 1999;179(suppl 2):S318-S325.CrossRefPubMedGoogle Scholar
  25. 25.
    Liu JM, Kim S, Read EJ, et al. Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC).Hum Gene Ther. 1999;10:2337–2346.CrossRefPubMedGoogle Scholar
  26. 26.
    Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.Science. 2000;288:669–672.CrossRefPubMedGoogle Scholar
  27. 27.
    Miller DG, Miller AD. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection.Mol Cell Biol. 1990;10:4239–4242.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Orlic D, Girard LJ, Jordan CT, Anderson SM, Cline AP, Bodine DM. The level of mRNA encoding the amphotropic retrovirus receptor in mouse and human hematopoietic stem cells is low and correlates with the efficiency of retrovirus transduction.Proc Natl Acad Sci U S A. 1996;93:11097–11102.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Medin JA, Karlsson S. Viral vectors for gene therapy of hematopoietic cells.Immunotechnology. 1997;3:3–19.CrossRefPubMedGoogle Scholar
  30. 30.
    Luens KM, Travis MA, Chen BP, Hill BL, Scollay R, Murray LJ. Thrombopoietin, kit ligand, and flk2/flt3 ligand together induce increased numbers of primitive hematopoietic progenitors from human CD34+Thy-1+Lin cells with preserved ability to engraft SCID-hu bone.Blood. 1998;91:1206–1215.PubMedGoogle Scholar
  31. 31.
    Ramsfjell V, Bryder D, Bjorgvinsdottir H, et al. Distinct requirements for optimal growth and in vitro expansion of human CD34(+)CD38() bone marrow long-term culture-initiating cells (LTC-IC), extended LTC-IC, and murine in vivo long-term reconstituting stem cells.Blood. 1999;94:4093–4102.PubMedGoogle Scholar
  32. 32.
    Petzer AL, Hogge DE, Landsdorp PM, Reid DS, Eaves CJ. Self-renewal of primitive human hematopoietic cells (long-term- culture-initiating cells) in vitro and their expansion in defined medium.Proc Natl Acad Sci U S A. 1996;93:1470–1474.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ueda T, Tsuji K, Yoshino H, et al. Expansion of human NOD/SCID- repopulating cells by stem cell factor, Flk2/Flt3 ligand, thrombopoietin, IL-6, and soluble IL-6 receptor.J Clin Invest. 2000;105: 1013–1021.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Conneally E, Eaves CJ, Humphries RK. Efficient retroviral-mediated gene transfer to human cord blood stem cells with in vivo repopulating potential.Blood. 1998;91:3487–3493.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Tisdale JF, Hanazono Y, Sellers SE, et al. Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability.Blood. 1998;92:1131–1141.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Kiem HP, Andrews RG, Morris J, et al. Improved gene transfer into baboon marrow repopulating cells using recombinant human fibronectin fragment CH-296 in combination with interleukin-6, stem cell factor, FLT-3 ligand, and megakaryocyte growth and development factor.Blood. 1998;92:1878–1886.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Goerner M, Bruno B, McSweeney PA, Buron G, Storb R, Kiem HP. The use of granulocyte colony-stimulating factor during retroviral transduction on fibronectin fragment CH-296 enhances gene transfer into hematopoietic repopulating cells in dogs.Blood. 1999;94:2287–2292.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Rosenzweig M, MacVittie TJ, Harper D, et al. Efficient and durable gene marking of hematopoietic progenitor cells in nonhuman primates after nonablative conditioning.Blood. 1999;94:2271–2286.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kiem HP, Heyward S, Winkler A, et al. Gene transfer into marrow repopulating cells: comparison between amphotropic and gibbon ape leukemia virus pseudotyped retroviral vectors in a competitive repopulation assay in baboons.Blood. 1997;90:4638–4645.PubMedPubMedCentralGoogle Scholar
  40. 40.
    van Hennik PB, Verstegen MM, Bierhuizen MF, et al. Highly efficient transduction of the green fluorescent protein gene in human umbilical cord blood stem cells capable of cobblestone formation in long-term cultures and multilineage engraftment of immunodeficient mice.Blood. 1998;92:4013–4022.PubMedGoogle Scholar
  41. 41.
    Hanenberg H, Xiao XL, Dilloo D, Hashino K, Kato I, Williams DA. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells.Nat Med. 1996;2:876–882.CrossRefPubMedGoogle Scholar
  42. 42.
    Allay JA, Persons DA, Galipeau J, et al. In vivo selection of retrovirally transduced hematopoietic stem cells.Nat Med. 1998;4: 1136–1143.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ito K, Ueda Y, Kokubun M, et al. Development of a novel selective amplifier gene for controllable expansion of transduced hematopoietic cells.Blood. 1997;90:3884–3892.PubMedGoogle Scholar
  44. 44.
    Matsuda KM, Kume A, Ueda Y, Urabe M, Hasegawa M, Ozawa K. Development of a modified selective amplifier gene for hematopoietic stem cell gene therapy.Gene Ther. 1999;6:1038–1044.CrossRefPubMedGoogle Scholar
  45. 45.
    Richard RE, Wood B, Zeng H, Jin L, Papayannopoulou T, Blau CA. Expansion of genetically modified primary human hemopoietic cells using chemical inducers of dimerization.Blood. 2000;95:430–436.PubMedGoogle Scholar
  46. 46.
    Cassel A, Cottler-Fox M, Doren S, Dunbar CE. Retroviral-mediated gene transfer into CD34-enriched human peripheral blood stem cells.Exp Hematol. 1993;21:585–591.PubMedGoogle Scholar
  47. 47.
    Hughes PF, Thacker JD, Hogge D, et al. Retroviral gene transfer to primitive normal and leukemic hematopoietic cells using clinically applicable procedures.J Clin Invest. 1992;89:1817–1824.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lewis PF, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus.J Virol. 1994;68:510–516.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Miyoshi H, Takahashi M, Gage FH, Verma IM. Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector.Proc Natl Acad Sci U S A. 1997;94:10319–10323.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Naldini L, Blomer U, Gallay P, et al. In vivo delivery and stable transduction of nondividing cells by a lentiviral vector.Science. 1996;272:263–267.CrossRefPubMedGoogle Scholar
  51. 51.
    Akkina RK, Walton RM, Chen ML, Li QX, Planelles V, Chen IS. High-efficiency gene transfer into CD34+ cells with a human immunodeficiency virus type 1-based retroviral vector pseudo-typed with vesicular stomatitis virus envelope glycoprotein G.J Virol. 1996;70:2581–2585.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Miyake K, Suzuki N, Matsuoka H, Tohyama T, Shimada T. Stable integration of human immunodeficiency virus-based retroviral vectors into the chromosomes of nondividing cells.Hum Gene Ther. 1998;9:467–475.CrossRefPubMedGoogle Scholar
  53. 53.
    Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo.Nat Biotechnol. 1997;15:871–875.CrossRefPubMedGoogle Scholar
  54. 54.
    Mastromarino P, Conti C, Goldoni P, Hauttecoeur B, Orsi N. Characterization of membrane components of the erythrocyte involved in vesicular stomatitis virus attachment and fusion at acidic pH.J Gen Virol. 1987;68:2359–2369.CrossRefPubMedGoogle Scholar
  55. 55.
    Burns JC, Friedman T, Driever W, Burrascano M, Yee JK. Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells.Proc Natl Acad Sci U S A. 1993;90:8033–8037.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Dull T, Zufferey R, Kelly M, et al. A third-generation lentivirus vector with a conditional packaging system.J Virol. 1998;72:8463–8471.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Kafri T, van Praag H, Ouyang L, Gage FH, Verma IM. A packaging cell line for lentivirus vectors.J Virol. 1999;73:576–584.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Reiser J, Harmisson G, Kluepfel-Stahl S, Brady RO, Karlsson S, Schubert M. Transduction of nondividing cells using pseudotyped defective high-titer HIV type 1 particles.Proc Natl Acad Sci U S A. 1996;93:15266–15271.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Sutton RE, Reitsma MJ, Uchida N, Brown PO. Transduction of human progenitor hematopoietic stem cells by human immunodeficiency virus type 1-based vectors is cell cycle dependent.J Virol. 1999;73:3649–3460.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Sutton R, Wu HT, Rigg R, Böhnlein E, Brown PO. Human immunodeficiency virus type 1 vectors efficiently transduce human hematopoietic stem cells.J Virol. 1998;72:5781–5788.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Uchida N, Sutton RE, Friera AM, et al. 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. 1998;95:11939–11944.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Miyoshi H, Smith KA, Mosier DE, Verma IM, Torbett BE. Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors.Science. 1999;283: 682–686.CrossRefPubMedGoogle Scholar
  63. 63.
    Case SS, Price MA, Jordan CT, et al. Stable transduction of quiescent CD34+CD38 human hematopoietic cells by HIV-1-based lentiviral vectors.Proc Natl Acad Sci U S A. 1999;96:2988–2993.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Douglas J, Kelly P, Evans JT, Garcia JV. Efficient transduction of human lymphocytes and CD34+ cells via human immunodeficiency virus-based gene transfer vectors.Hum Gene Ther. 1999;10:935–945.CrossRefPubMedGoogle Scholar
  65. 65.
    Fahlman C, Woods NB, Mikkola H, et al. Lentiviral gene transfer into secondary NODSCID repopulating cells and lentiviral vector design for expression in CD34+ cells.Blood. 1999;94(suppl 1):359a.Google Scholar
  66. 66.
    Cashman JH, Eaves CJ. Human growth factor-enhanced regeneration of transplantable human hematopoietic stem cells in nonobese diabetic/severe combined immunodeficient mice.Blood. 1999;93:481–487.PubMedGoogle Scholar
  67. 67.
    Larochelle A, Vormoor J, Hananberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy.Nat Med. 1996;2:1329–1337.CrossRefPubMedGoogle Scholar
  68. 68.
    Wang JC, Doedens M, Dick JE. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay.Blood. 1997;89:3919–3924.PubMedGoogle Scholar
  69. 69.
    Hamaguchi I, Panagopoulos I, Andersson E, et al. Lentiviral gene expression during ES cell derived hematopoietic development in vitro [abstract].Exp Hematol. 1999;27(suppl 1):62.Google Scholar
  70. 70.
    Kung SK, An DS, Chen IS. A murine leukemia virus (MuLV) long terminal repeat derived from rhesus macaques in the context of a lentivirus vector and MuLV gag sequence results in high-level gene expression in human T lymphocytes.J Virol. 2000;74:3668–3681.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Mikkola H, Helgadottir H, Woods NB, et al. Lentiviral gene transfer and expression in c-kit+sca1+ mouse hematopoietic stem cells.Blood. 1999;94(suppl 1):356a.Google Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.Molecular Medicine and Gene TherapyInstitute for Laboratory MedicineLundSweden
  2. 2.Department of MedicineLund University HospitalLundSweden

Personalised recommendations