Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Hematopoietic Stem Cell Gene Therapy

  • 132 Accesses

  • 19 Citations

Abstract

Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some of the seminal clinical trials in the field, and describe several recent advances directed toward overcoming these limitations.

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

References

  1. 1.

    Cline MJ, Stang H, Mercola K, et al. Gene transfer in intact animals.Nature. 1980;284:422–425.

  2. 2.

    Friedmann T. The origins, evolution and directions of human gene therapy. In: Friedmann T, ed.The Development of Human Gene Therapy. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1999:1–20.

  3. 3.

    Ferrari G, Rossini S, Giavazzi R, et al. An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency.Science. 1991;251:1363–1366.

  4. 4.

    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.

  5. 5.

    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.

  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.

  7. 7.

    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.

  8. 8.

    Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID defect without PEG-ADA therapy by stem/progenitor cell gene therapy combined with a non-myeloablative conditioning.Blood. 2001;98:780a-781a.

  9. 9.

    Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. Isolation of a candidate human hematopoietic stem-cell population.Proc Natl Acad Sci U S A. 1992;89:2804–2808.

  10. 10.

    Thomas ED. Landmarks in the development of hematopoietic cell transplantation.World J Surg. 2000;24:815–818.

  11. 11.

    Molineux G, Pojda Z, Hampson IN, Lord BI, Dexter TM. Transplantation potential of peripheral blood stem cells induced by granulocyte colony-stimulating factor.Blood. 1990;76:2153–2158.

  12. 12.

    Dreger P, Suttorp M, Haferlach T, Loffler H, Schmitz N, Schroyens W. Allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for treatment of engraftment failure after bone marrow transplantation.Blood. 1993;81:1404–1407.

  13. 13.

    Matsunaga T, Sakamaki S, Kohgo Y, Ohi S, Hirayama Y, Niitsu Y. Recombinant human granulocyte colony-stimulating factor can mobilize sufficient amounts of peripheral blood stem cells in healthy volunteers for allogeneic transplantation.Bone Marrow Transplant. 1993;11:103–108.

  14. 14.

    Shpall EJ, Cagnoni PJ, Bearman SI, Ross M, Jones RB. Peripheral blood stem cells for autografting.Annu Rev Med. 1997;48:241–251.

  15. 15.

    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.

  16. 16.

    Dunbar CE, Seidel NE, Doren S, et al. Improved retroviral gene transfer into murine and rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granu-locyte colony-stimulating factor.Proc Natl Acad Sci U S A. 1996;93:11871–11876.

  17. 17.

    Adler BK, Salzman DE, Carabasi MH, Vaughan WP, Reddy VV, Prchal JT. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration.Blood. 2001;97:3313–3314.

  18. 18.

    Lu L, Xiao M, Shen RN, Grigsby S, Broxmeyer HE. Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential.Blood. 1993;81:41–48.

  19. 19.

    Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation.Exp Hematol. 2000;28:1197–1205.

  20. 20.

    Parkman R, Weinberg K, Crooks G, Nolta J, Kapoor N, Kohn D. Gene therapy for adenosine deaminase deficiency.Annu Rev Med. 2000;51:33–47.

  21. 21.

    Repka T, Weisdorf DJ. Nonmyeloablative HPC transplantation.Transfusion. 2000;40:758–760.

  22. 22.

    Nilsson SK, Dooner MS, Tiarks CY, Weier HU, Quesenberry PJ. Potential and distribution of transplanted hematopoietic stem cells in a nonablated mouse model.Blood. 1997;89:4013–4020.

  23. 23.

    Maris M, Sandmaier BM, Maloney DG, et al. Non-myeloablative hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 1999;5:316–321.

  24. 24.

    Storb R, Yu C, Barnett T, et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosup-pression after marrow transplantation.Blood. 1999;94:1131–1136.

  25. 25.

    Miller AD, Eckner RJ, Jolly DJ, Friedmann T, Verma IM. Expression of retrovirus encoding human HPRT in mice.Science. 1983;225:630–632.

  26. 26.

    Miller AD, Rosman GJ. Improved retroviral vectors for gene transfer and expression.BioTechniques. 1989;7:980–890.

  27. 27.

    Yee JK. Retroviral vectors. In: Friedmann T, ed.The Development of Human Gene Therapy. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1999:21–45.

  28. 28.

    Miller AD, Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production.Mol Cell Biol. 1986;6:2895–2902.

  29. 29.

    Markowitz D, Goff S, Bank A. A safe packaging line for gene transfer: separating viral genes on two different plasmids.J Virol. 1988;62:1120–1124.

  30. 30.

    Miller AD, Miller DG, Garcia JV, Lynch CM. Use of retroviral vectors for gene transfer and expression.Methods Enzymol. 1993;217:581–599.

  31. 31.

    Miller AD, Whelan J. Progress in transcriptionally targeted and regulatable vectors for gene therapy.Hum Gene Ther. 1997;8:803–815.

  32. 32.

    Karlsson S, Papayannopoulou, T, Schweiger SG, Stamatoy-annopoulos G, Nienhuis AW. Retroviral-mediated transfer of genomic globin genes leads to regulated production of RNA and protein.Proc Natl Acad Sci U S A. 1987;84:2411–2415.

  33. 33.

    Emery DW, Morrish F, Li Q, Stamatoyannopoulos G. Analysis of γ-globin expression cassettes in retrovirus vectors.Hum Gene Ther. 1999;10:877–888.

  34. 34.

    Challita PM, Skelton D, El-Khoueiry A, Yu XJ, Weinberg K, Kohn DB. Multiple modifications in cis elements in the long terminal repeat of retroviral vectors lead to increased expression and decreased DNA methylation in embryonic carcinoma cells.J Virol. 1995;69:748–755.

  35. 35.

    Robbins PB, Yu XJ, Skelton DM, et al. Increased probability of expression from modified retroviral vectors in embryonal stem cells and embryonal carcinoma cells.J Virol. 1997;71:9466–9474.

  36. 36.

    Hawley RG, Lieu FH, Fong AZ, Hawley TS. Versatile retroviral vectors for potential use in gene therapy.Gene Ther. 1994;1:136–138.

  37. 37.

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

  38. 38.

    Kalberer CP, Pawliuk R, Imren S, et al. Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta-glo-bin in engrafted mice.Proc Natl Acad Sci U S A. 2000;97:5411–5415.

  39. 39.

    Cheng L, Du C, Lavau C, et al. Sustained gene expression in retrovirally transduced, engrafting human hematopoietic stem cells and their lympho-myeloid progeny.Blood. 1998;92:83–92.

  40. 40.

    Bodine DM, Karlsson S, Nienhuis AW. Combination of interleukin 3 and 6 preserves stem cell function in culture and enhances retro-virus-mediated gene transfer into hematopoietic stem cells.Proc Natl Acad Sci U S A. 1989;86:8897–8901.

  41. 41.

    Bodine DM, Barette S, Seidel N, Orlic D, Miller AD. Transduction of mouse hematopoietic stem cells is more efficient with 10A1 retrovirus vectors than with amphotropic vectors.Stem Cells. 2000;18:152–153.

  42. 42.

    Emery DW, Andrews RG, Papayannopoulou T. Differences among nonhuman primates in susceptibility to bone marrow progenitor transduction with retrovirus vectors.Gene Ther. 2000;7:359–367.

  43. 43.

    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.

  44. 44.

    Miller AD, Garcia VJ, von Shur N, Lynch CM, Wilson C, Eiden MV. Construction and properties of retrovirus packaging cells based on gibbon ape leukemia virus.J Virol. 1991;65:2220–2224.

  45. 45.

    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.

  46. 46.

    Kelly PF, Vandergriff J, Nathwani A, Nienhuis AW, Vanin EF. Highly efficient gene transfer into cord blood nonobese diabetic/ severe combined immunodeficiency repopulating cells by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein.Blood. 2000;96:1206–1214.

  47. 47.

    Goerner M, Horn PA, Peterson L, et al. Sustained multilineage gene persistence and expression in dogs transplanted with CD34(+) marrow cells transduced by RD114-pseudotype oncoretrovirus vectors.Gene Ther. 2001;98:2065–2070.

  48. 48.

    Barrette S, Douglas J, Orlic D, et al. Superior transduction of mouse hematopoietic stem cells with 10A1 and VSV-G pseudotyped retrovirus vectors.Mol Ther. 2000;1:330–338.

  49. 49.

    Nolta JA, Kohn DB. Comparison of the effects of growth factors on retroviral-mediated gene transfer and the proliferative status of human hematopoietic progenitor cells.Hum Gene Ther. 1990;1:257–268.

  50. 50.

    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.

  51. 51.

    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.

  52. 52.

    Donahue RE, Sorrentino BP, Hawley RG, An DS, Chen IS, Wersto RP. Fibronectin fragment CH-296 inhibits apoptosis and enhances ex vivo gene transfer by murine retrovirus and human lentivirus vectors independent of viral tropism in nonhuman primate CD34+ cells.Mol Ther. 2001;3:359–367.

  53. 53.

    Sanyal A, Schuening FG. Increased gene transfer into human cord blood cells by centrifugation-enhanced transduction in fibronectin fragment-coated tubes.Hum Gene Ther. 1999;10:2859–2868.

  54. 54.

    Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.Science. 1996;272:263–267.

  55. 55.

    Kafri T, van Praag H, Ouyang L, Gage FH, Verma IM. A packaging cell line for lentivirus vectors.J Virol. 1999;73:576–584.

  56. 56.

    Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P. HIV-1 genome nuclear import is mediated by a central DNA flap.Cell. 2000;101:173–185.

  57. 57.

    May C, Rivella S, Callegari J, et al. Therapeutic haemoglobin synthesis in β-thalassaemic mice expressing lentivirus-encoded human β-globin.Nature. 2000;406:82–86.

  58. 58.

    Pawliuk R, Westerman KA, Fabry ME, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy.Science. 2001;294:2368–2371.

  59. 59.

    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.

  60. 60.

    Hirata RK, Miller AD, Andrews RG, Russell DW. Transduction of hematopoietic cells by foamy virus vectors.Blood. 1996;88:3654–3661.

  61. 61.

    Russell DW, Miller AD. Foamy virus vectors.J Virol. 1996;70:217–222.

  62. 62.

    Trobridge GD, Russell DW. Helper-free foamy virus vectors.Hum Gene Ther. 1998;9:2517–2525.

  63. 63.

    Vassilopoulos G, Trobridge GD, Josephson NC, Russell DW. Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors.Blood. 2001;98:604–609.

  64. 64.

    Josephson NC, Vassilopoulos G, Trobridge GD, et al. Transduction of SCID repopulating cells by a human foamy virus vector.Mol Ther. 2001;5:S302.

  65. 65.

    Robbins PD, Tahara H, Ghivizzani SC. Viral vectors for gene therapy.Trends Biotechnol. 1998;16:35–40.

  66. 66.

    Muzyczka N. Use of adeno-associated virus as a general transduction vector for mammalian cells.Curr Top Microbiol Immunol. 1992;158:97–129.

  67. 67.

    Allen JM, Halbert CL, Miller AD. Improved adeno-associated virus vector production with transfection of a single helper adenovirus gene, E4orf6.Mol Ther. 2000;1:88–95.

  68. 68.

    Rutledge EA, Russell DW. Adeno-associated virus vector integration junctions.J Virol. 1997;71:8429–8436.

  69. 69.

    Fisher-Adams G, Wong KK, Podsakoff G, Forman SJ, Chatterjee S. Integration of adeno-associated virus vectors in CD34+ human hematopoietic progenitor cells after transduction.Blood. 1996;88:492–504.

  70. 70.

    Russell DW, Kay MA. Adeno-associated virus vectors and hematology.Blood. 1999;94:864–874.

  71. 71.

    Hirata RK, Russell D. Design and packaging of adeno-associated virus gene targeting vectors.J Virol. 2000;74:4612–4620.

  72. 72.

    Shayakhmetov DM, Papayannopoulou T, Stamatoyannopoulos G, Lieber A. Efficient gene transfer into human CD34(+) cells by a retargeted adenovirus vector.J Virol. 2000;74:2567–2583.

  73. 73.

    Lieber A, Steinwaerder DS, Carlson CA, Kay MA. Integrating ade-novirus-adeno-associated virus hybrid vectors devoid of all viral genes.J Virol. 1999;73:9314–9324.

  74. 74.

    Karpen GH. Position-effective variegation and the new biology of heterochromatin.Curr Opin Genet Dev. 1994;4:281–291.

  75. 75.

    Neff T, Shotkoski F, Stamatoyannopoulos G. Stem cell gene therapy, position effects and chromatin insulators.Stem Cells. 1997;15(suppl 1):265–271.

  76. 76.

    Rivella S, Sadelain M. Genetic treatment of severe hemoglobinopathies: the combat against transgene variegation and trans-gene silencing.Semin Hematol. 1998;35:112–125.

  77. 77.

    Raftopoulos H, Ward M, Leboulch P, Bank A. Long-term transfer and expression of the human β-globin gene in a mouse transplant model.Blood. 1997;90:3414–3422.

  78. 78.

    Lung Hy, Meeus IS, Weinberg RS, Atweh GF. In vivo silencing of the human γ-globin gene in murine erythroid cells following retroviral transduction.Blood Cells Mol Dis. 2000;26:613–619.

  79. 79.

    Emery DW, Yannaki E, Tubb J, Stamatoyannopoulos G. A chromatin insulator protects retrovirus vectors from position effects.Proc Natl Acad Sci U S A. 2000;97:9150–9155.

  80. 80.

    Rivella S, Callegari JA, May C, Tan CW, Sadelain M. The cHS4 insulator increases the probability of retroviral expression at random chromosomal integration sites.J Virol. 2000;74:4679–4687.

  81. 81.

    Emery DW, Stamatoyannopoulos G. Stem cell gene therapy for the β-chain hemoglobinopathies—problems and progress.Ann NY Acad Sci. 1999;872:94–107.

  82. 82.

    Bell AC, Felsenfeld G. Stopped at the border: boundaries and insulators.Curr Opin Genet Dev. 1999;9:191–198.

  83. 83.

    Udvardy A. Dividing the empire: boundary chromatin elements delimit the territory of enhancers.EMBO J. 1999;18:1–8.

  84. 84.

    Prioleau MN, Nony P, Simpson M, Felsenfeld G. An insulator element and condensed chromatin region separate the chicken β-globin locus from an independently regulated erythroid-specific folate receptor gene.EMBO J. 1999;18:4035–4048.

  85. 85.

    Chung JH, Bell AC, Felsenfeld G. Characterization of the chicken pj-globin insulator.Proc Natl Acad Sci U S A. 1997;94:575–580.

  86. 86.

    Chung JH, Whiteley M, Felsenfeld G. A 5′ element of the chicken pj-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila.Cell. 1993;74:505–514.

  87. 87.

    Wang Y, DeMayo FJ, Tsai SY, O’Malley BW. Ligand-inducible and liver-specific target gene expression in transgenic mice.Nat Biotechnol. 1997;15:239–243.

  88. 88.

    Taboit-Dameron F, Malassagne B, Viglietta C, et al. Association of the 5′ HS4 sequence of the chicken β-globin locus control region with human EF1 alpha gene promoter induces ubiquitous and high expression of human CD55 and CD59 cDNAs in transgenic rabbits.Transgenic Res. 1999;8:223–235.

  89. 89.

    Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.Cell. 1999;98:387–396.

  90. 90.

    Yannaki E, Emery DW, Tubb J, Stamatoyannopoulos G. Topological constraints governing the use of a chicken HS4 insulator in retrovirus vectors [abstract].Mol Ther. 2000;1(pt 2):S138.

  91. 91.

    Emery DW, Yannaki E, Nishino T, Tubb J, Li Q, Stamatoyannopoulos G. Flanking an oncoretrovirus vector for human gamma globin with a chromatin insulator greatly reduces gene silencing in vivo [abstract].Mol Ther. 2001;3:S150.

  92. 92.

    Chen CJ, Chin JE, Ueda K, et al. Internal duplication and homology with bacterial transport proteins in the MDR1 (P-glycopro-tein) gene from multidrug-resistant human cells.Cell. 1986;47:381–389.

  93. 93.

    Pastan I, Gottesman MM, Ueda K, Lovelace E, Rutherford AV, Willingham MC. A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells.Proc Natl Acad Sci U S A. 1988;85:4486–4490.

  94. 94.

    Galski H, Sullivan M, Willingham MC, et al. Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of trans-genic mice: resistance to daunomycin-induced leukopenia.Mol Cell Biol. 1989;9:4357–4363.

  95. 95.

    Mickisch GH, Licht T, Merlino GT, Gottesman MM, Pastan I. Chemotherapy and chemosensitization of transgenic mice which express the human multidrug resistance gene in bone marrow: efficacy, potency, and toxicity.Cancer Res. 1991;51:5417–5424.

  96. 96.

    Sorrentino BP, Brandt SJ, Bodine D, et al. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1.Science. 1992;257:99–103.

  97. 97.

    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.

  98. 98.

    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.Proc Natl Acad Sci U S A. 1996;93:15346–15351.

  99. 99.

    Blau CA, Neff T, Papayannopoulou T. Cytokine prestimulation as a gene therapy strategy: implications for using the MDR1 gene as a dominant selectable marker.Blood. 1997;89:146–154.

  100. 100.

    Bunting KD, Galipeau J, Topham D, Benaim E, Sorrentino B P. Transduction of murine bone marrow cells with an MDR1 vector enables ex vivo stem cell expansion, but these expanded grafts cause a myeloproliferative syndrome in transplanted mice.Blood. 1998;92:2269–2279.

  101. 101.

    Sellers SE, Tisdale JF, Agricola BA, et al. The effect of multidrug-resistance 1 gene versus neo transduction on ex vivo and in vivo expansion of rhesus macaque hematopoietic repopulating cells.Blood 2001;97:1888–1891.

  102. 102.

    Simonsen CC, Levinson AD. Isolation and expression of an altered mouse dihydrofolate reductase cDNA.Proc Natl Acad Sci U S A. 1983;80:2495–2499.

  103. 103.

    Antonchuk J, Sauvageau G, Humphries RK. HOXB4 overexpres-sion mediates very rapid stem cell regeneration and competitive hematopoietic repopulation.Exp Hematol. 2001;29:1125–1134.

  104. 104.

    Ito K, Ueda Y, Kokubun M, et al. Development of a novel selective amplifier gene for controllable expansion of transduced hemato-poietic cells.Blood. 1997;90:3884–3892.

  105. 105.

    Matsuda KM, Kume A, Ueda Y, Urabe M, Hasegawa M, Ozawa K. Development of a modified selective amplifier gene for hemato-poietic stem cell gene therapy.Gene Ther. 1999;6:1038–1044.

  106. 106.

    Xu R, Kume A, Matsuda KM, et al. A selective amplifier gene for tamoxifen-inducible expansion of hematopoietic cells.J Gene Med. 1999;1:236–244.

  107. 107.

    Zeng H, Masuko M, Jin L, Neff T, Otto KG, Blau CA. Receptor specificity in the self-renewal and differentiation of primary multi-potential hemopoietic cells.Blood. 2001;98:328–334.

  108. 108.

    Blau CA, Peterson KR, Drachman JG, Spencer DM. A proliferation switch for genetically modified cells.Proc Natl Acad Sci U S A. 1997;94:3076–3081.

  109. 109.

    Jin L, Asano H, Blau CA. Stimulating cell proliferation through the pharmacologic activation of c-kit.Blood. 1998;91:890–897.

  110. 110.

    Jin L, Siritanaratkul N, Emery DW, et al. Targeted expansion of genetically modified bone marrow cells.Proc Natl Acad Sci U S A. 1998;95:8093–8097.

  111. 111.

    Jin L, Zeng H, Chien S, et al. In vivo selection using a cell-growth switch.Nat Genet. 2000;26:64–66.

  112. 112.

    Richard RE, Wood B, Zeng H, Jin L, Papayannopoulou T, Blau CA. Expansion of genetically modified primary human hemopoi-etic cells using chemical inducers of dimerization.Blood. 2000;95:430–436.

Download references

Author information

Correspondence to David W. Emery or Tamon Nishino or Ken Murata or Michalis Fragkos or George Stamatoyannopoulos.

About this article

Cite this article

Emery, D.W., Nishino, T., Murata, K. et al. Hematopoietic Stem Cell Gene Therapy. Int J Hematol 75, 228–236 (2002). https://doi.org/10.1007/BF02982035

Download citation

Key words

  • Gene therapy
  • Hematopoiesis
  • Stem cells
  • Virus vectors