Skip to main content

Advertisement

SpringerLink
Log in

Clinical Gene Therapy in Hematology: Past and Future

  • Review Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Richter J. Gene transfer to hematopoietic cell—the clinical experience.Eur J Haematol. 1997;59:67–75.

    Article  PubMed  CAS  Google Scholar 

  2. Brenner M. Gene marking.Hum Gene Ther. 1996;7:1927–1936.

    Article  PubMed  CAS  Google Scholar 

  3. Kohn D. Gene therapy for hematopoietic and lymphoid disorders.Clin Exp Immunol. 1997;107:54–57.

    PubMed  Google Scholar 

  4. Mulligan R. The science of gene therapy.Science. 1993;260:926–932.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  22. Barranger JA, Rice EO, Swaney WP. Gene transfer approaches to the lysosomal storage disorders.Neurochem Res. 1999;24:601–615.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Malech HL. Progress in gene therapy for chronic granulomatous disease.J Infect Dis. 1999;179(suppl 2):S318-S325.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Medin JA, Karlsson S. Viral vectors for gene therapy of hematopoietic cells.Immunotechnology. 1997;3:3–19.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  42. Allay JA, Persons DA, Galipeau J, et al. In vivo selection of retrovirally transduced hematopoietic stem cells.Nat Med. 1998;4: 1136–1143.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 

Download references

Author information

Authors and Affiliations

  1. Molecular Medicine and Gene Therapy, Institute for Laboratory Medicine, Lund, Sweden

    Johan Richter

  2. Department of Medicine, Lund University Hospital, Lund, Sweden

    Stefan Karlsson

Authors
  1. Johan Richter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Karlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Karlsson.

About this article

Cite this article

Richter, J., Karlsson, S. Clinical Gene Therapy in Hematology: Past and Future. Int J Hematol 73, 162–169 (2001). https://doi.org/10.1007/BF02981933

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02981933

Key words

Search

Navigation