Gene therapy for β-thalassaemia: the continuing challenge

Evangelia Yannaki; David W. Emery; George Stamatoyannopoulos

doi:10.1017/S1462399410001626

Gene therapy for β-thalassaemia: the continuing challenge

Published online by Cambridge University Press: 01 October 2010

Evangelia Yannaki ,

David W. Emery and

George Stamatoyannopoulos

Show author details

Evangelia Yannaki*: Affiliation:
Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, Thessaloniki, Greece.
David W. Emery: Affiliation:
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
George Stamatoyannopoulos: Affiliation:
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA. Department of Genome Sciences, University of Washington, Seattle, WA, USA.
*: *Corresponding author: Evangelia Yannaki, G. Papanicolaou Hospital, Gene and Cell Therapy Center, Hematology-BMT Unit, Thessaloniki 57010, Greece. E-mail: [email protected]

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

The β-thalassaemias are inherited anaemias that form the most common class of monogenic disorders in the world. Treatment options are limited, with allogeneic haematopoietic stem cell transplantation offering the only hope for lifelong cure. However, this option is not available for many patients as a result of either the lack of compatible donors or the increased risk of transplant-related mortality in subjects with organ damage resulting from accumulated iron. The paucity of alternative treatments for patients that fall into either of these categories has led to the development of a revolutionary treatment strategy based on gene therapy. This approach involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patient-derived, autologous haematopoietic stem cells. This highly attractive strategy offers several advantages, including bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. This review discusses the many advances that have been made towards this endeavour as well as the hurdles that must still be overcome before gene therapy for β-thalassaemia, as well as many other gene therapy applications, can be widely applied in the clinic.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e31

DOI: https://doi.org/10.1017/S1462399410001626 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Stamatoyannopoulos, G. et al. (2001). The Molecular Basis of Blood Diseases. W.B. Saunders, Philadelphia, PA, USAGoogle Scholar

2Weatherall, D.J. and Clegg, J.B. (2001) Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization 79, 704-712Google Scholar PubMed

3Lucarelli, G., Andreani, M. and Angelucci, E. (2002) The cure of thalassemia by bone marrow transplantation. Blood Reviews 16, 81-85CrossRef Google Scholar PubMed

4Gaziev, D. et al. (1997) Graft-versus-host disease after bone marrow transplantation for thalassemia: an analysis of incidence and risk factors. Transplantation 63, 854-860CrossRef Google Scholar PubMed

5Lucarrelli, G. et al. (1999) Bone marrow transplantation in adult thalassemic patients. Blood 93, 1164-1167CrossRef Google Scholar

6La Nasa, G. et al. (2002) Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes. Blood 15, 4350-4356CrossRef Google Scholar

7La Nasa, G. et al. (2005) Unrelated donor stem cell transplantation in adult patients with thalassemia. Bone Marrow Transplantation 36, 971-975CrossRef Google Scholar PubMed

8Gaziev, D. et al. (2000) Bone marrow transplantation from alternative donors for thalassemia: HLA-phenotypically identical relative and HLA-nonidentical sibling or parent transplants. Bone Marrow Transplantation 25, 815-821CrossRef Google Scholar PubMed

9Lucarelli, G. and Gaziev, J. (2008) Advances in the allogeneic transplantation for thalassemia. Blood Reviews 22, 53-63CrossRef Google Scholar PubMed

10Lisowski, L. and Sadelain, M. (2008) Current status of globin gene therapy for the treatment of beta-thalassaemia. British Journal of Haematology 141, 335-345CrossRef Google Scholar PubMed

11Emery, D.W. et al. (2002) Hematopoietic stem cell gene therapy. International Journal of Hematology 75, 228-236CrossRef Google Scholar PubMed

12Kohn, D.B. et al. (2003) American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. Molecular Therapy 8, 180-187CrossRef Google Scholar

13Berry, C. et al. (2006) Selection of target sites for mobile DNA integration in the human genome. PLoS Computation Biology 2, e157CrossRef Google Scholar PubMed

14Emery, D.W., Aker, M. and Stamatoyannopoulos, G. (2003) Chromatin insulators and position effects. In Gene Transfer and Expression in Mammalian Cells (Makrides, S.C., ed.), pp. 381-395, EIC Laboratories, Inc., Norwood, MA, USACrossRef Google Scholar

15Li, Q. et al. (2002) Locus control regions. Blood 100, 3077-3086CrossRef Google Scholar PubMed

16Grosveld, F. et al. (1987) Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell 51, 975-985CrossRef Google Scholar PubMed

17Blom van Assendelft, G. et al. (1989) The beta-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner. Cell 56, 969-977CrossRef Google Scholar

18Karlsson, S. et al. (1987) Retroviral-mediated transfer of genomic globin genes leads to regulated production of RNA and protein. Proceedings of the National Academy of Sciences of the United States of America 84, 2411-2415CrossRef Google Scholar PubMed

19Dzierzak, E.A., Papayannopoulou, T. and Mulligan, R.C. (1988) Lineage-specific expression of a human beta-globin gene in murine bone marrow transplant recipients reconstituted with retrovirus-transduced stem cells. Nature 331, 35-41CrossRef Google Scholar PubMed

20Plavec, I. et al. (1993) A human beta-globin gene fused to the human beta-globin locus control region is expressed at high levels in erythroid cells of mice engrafted with retrovirus-transduced hematopoietic stem cells. Blood 81, 1384-1392CrossRef Google Scholar

21Novak, U. et al. (1990) High-level beta-globin expression after retroviral transfer of locus activation region-containing human beta-globin gene derivatives into murine erythroleukemia cells. Proceedings of the National Academy of Sciences of the United States of America 87, 3386-3390CrossRef Google Scholar PubMed

22Emery, D.W. et al. (1998) Development of a condensed locus control region cassette and testing in retrovirus vectors for A gamma-globin. Blood Cells, Molecules, and Diseases 24, 322-339CrossRef Google Scholar PubMed

23Sadelain, M. et al. (1995) Generation of a high-titer retroviral vector capable of expressing high levels of the human beta-globin gene. Proceedings of the National Academy of Sciences of the United States of America 92, 6728-6732CrossRef Google Scholar PubMed

24Miller, A.D. et al. (1988) Design of retrovirus vectors for transfer and expression of the human beta-globin gene. Journal of Virology 62, 4337-4345CrossRef Google Scholar PubMed

25Leboulch, P. et al. (1994) Mutagenesis of retroviral vectors transducing human beta-globin gene and beta-globin locus control region derivatives results in stable transmission of an active transcriptional structure. EMBO Journal 13, 3065-3076CrossRef Google Scholar PubMed

26Emery, D.W. et al. (2002) Development of virus vectors for gene therapy of beta chain hemoglobinopathies: flanking with a chromatin insulator reduces gamma-globin gene silencing in vivo. Blood 100, 2012-2019CrossRef Google Scholar PubMed

27Miyoshi, H. et al. (1999) Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283, 682-686CrossRef Google Scholar PubMed

28Kumar, M. et al. (2001) Systematic determination of the packaging limit of lentiviral vectors. Human Gene Therapy 12, 1893-1905CrossRef Google Scholar PubMed

29May, C. et al. (2000) Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 406, 82-86CrossRef Google Scholar PubMed

30Dull, T. et al. (1998) A third-generation lentivirus vector with a conditional packaging system. Journal of Virology 72, 8463-8471CrossRef Google Scholar PubMed

31Miyoshi, H. et al. (1998) Development of a self-inactivating lentivirus vector. Journal of Virology 72, 8150-8157CrossRef Google Scholar PubMed

32Zufferey, R. et al. (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. Journal of Virology 72, 9873-9880CrossRef Google Scholar PubMed

33Naldini, L. and Verma, I.M. (2000) Lentiviral vectors. Advances in Virus Research 55, 599-609CrossRef Google Scholar PubMed

34Kay, M.A., Glorioso, J.C. and Naldini, L. (2001) Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nature Medicine 7, 33-40CrossRef Google Scholar PubMed

35Montini, E. et al. (2006) Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nature Biotechnology 24, 687-696CrossRef Google Scholar

36Arumugam, P.I. et al. (2009) Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region. Molecular Therapy 17, 1929-1937CrossRef Google Scholar PubMed

37Pawliuk, R. et al. (2001) Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294, 2368-2371CrossRef Google Scholar PubMed

38Imren, S. et al. (2002) Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America 99, 14380-14385CrossRef Google Scholar PubMed

39Persons, D.A. et al. (2003) The degree of phenotypic correction of murine beta -thalassemia intermedia following lentiviral-mediated transfer of a human gamma-globin gene is influenced by chromosomal position effects and vector copy number. Blood 101, 2175-2183CrossRef Google Scholar PubMed

40Rivella, S. et al. (2003) A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood 101, 2932-2939CrossRef Google Scholar PubMed

41Miccio, A. et al. (2008) In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proceedings of the National Academy of Sciences of the United States of America 105, 10547-10552CrossRef Google Scholar PubMed

42Perumbeti, A. et al. (2009) A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood 114, 1174-1185CrossRef Google Scholar

43Puthenveetil, G. et al. (2004) Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector. Blood 104, 3445-3453CrossRef Google Scholar PubMed

44Aker, M. et al. (2007) Extended core sequences from the cHS4 insulator are necessary for protecting retroviral vectors from silencing position effects. Human Gene Therapy 18, 333-343CrossRef Google Scholar PubMed

45Arumugam, P.I. et al. (2007) Improved human beta-globin expression from self-inactivating lentiviral vectors carrying the chicken hypersensitive site-4 (cHS4) insulator element. Molecular Therapy 15, 1863-1871CrossRef Google Scholar PubMed

46May, C. et al. (2002) Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene. Blood 99, 1902-1908CrossRef Google Scholar PubMed

47Cavazzana-Calvo, M. et al. (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669-672CrossRef Google Scholar PubMed

48Hacein-Bey-Abina, S. et al. (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine 346, 1185-1193CrossRef Google Scholar PubMed

49Gaspar, H.B. et al. (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181-2187CrossRef Google Scholar PubMed

50Aiuti, A. et al. (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. New England Journal of Medicine 360, 447-458CrossRef Google Scholar PubMed

51Hacein-Bey-Abina, S. et al. (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. Journal of Clinical Investigation 118, 3132-3142CrossRef Google Scholar PubMed

52Howe, S.J. et al. (2008) Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. Journal of Clinical Investigation 118, 3143-3150CrossRef Google Scholar PubMed

53Hacein-Bey-Abina, S. et al. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419CrossRef Google Scholar PubMed

54Ott, M.G. et al. (2006) Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nature Medicine 12, 401-409CrossRef Google Scholar PubMed

55Stein, S. et al. (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nature Medicine 16, 198-204CrossRef Google Scholar PubMed

56Aiuti, A. et al. (2007) Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. Journal of Clinical Investigation 117, 2233-2240CrossRef Google Scholar PubMed

57Li, Z. et al. (2002) Murine leukemia induced by retroviral gene marking. Science 296, 497CrossRef Google Scholar PubMed

58Shou, Y. et al. (2006) Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proceedings of the National Academy of Sciences of the United States of America 103, 11730-11735CrossRef Google Scholar

59Kustikova, O. et al. (2005) Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 308, 1171-1174CrossRef Google Scholar PubMed

60Li, C.L. et al. (2009) Genomic and functional assays demonstrate reduced gammaretroviral vector genotoxicity associated with use of the cHS4 chromatin insulator. Molecular Therapy 17, 716-724CrossRef Google Scholar PubMed

61Seggewiss, R. et al. (2006) Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque. Blood 107, 3865-3867CrossRef Google Scholar

62Sadelain, M. (2004) Insertional oncogenesis in gene therapy: how much of a risk? Gene Therapy 11, 569-573CrossRef Google Scholar PubMed

63Baum, C. et al. (2002) Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 101, 2099-2114CrossRef Google Scholar

64Aker, M. et al. (2006) Integration bias of gammaretrovirus vectors following transduction and growth of primary mouse hematopoietic progenitor cells with and without selection. Molecular Therapy 14, 226-235CrossRef Google Scholar PubMed

65Poeschla, E.M. (2008) Integrase, LEDGF/p75 and HIV replication. Cellular and Molecular Life Sciences 65, 1403-1424CrossRef Google Scholar PubMed

66Montini, E. et al. (2009) The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. Journal of Clinical Investigation 119, 964-975CrossRef Google Scholar

67Schroder, A.R. et al. (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521-529CrossRef Google Scholar PubMed

68Wu, W. et al. (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300, 1749-1751CrossRef Google Scholar PubMed

69Zychlinski, D. et al. (2008) Physiological promoters reduce the genotoxic risk of integrating gene vectors. Molecular Therapy 16, 718-725CrossRef Google Scholar PubMed

70Chang, A.H. and Sadelain, M. (2007) The genetic engineering of hematopoietic stem cells: the rise of lentiviral vectors, the conundrum of the LTR, and the promise of lineage-restricted vectors. Molecular Therapy 15, 445-456CrossRef Google Scholar PubMed

71Hargrove, P.W. et al. (2008) Globin lentiviral vector insertions can perturb the expression of endogenous genes in beta-thalassemic hematopoietic cells. Molecular Therapy 16, 525-533CrossRef Google Scholar PubMed

72Gaszner, M. and Felsenfeld, G. (2006) Insulators: exploiting transcriptional and epigenetic mechanisms. Nature Reviews Genetics 7, 703-713CrossRef Google Scholar PubMed

73Wallace, J.A. and Felsenfeld, G. (2007) We gather together: insulators and genome organization. Current Opinion in Genetics and Development 17, 400-407CrossRef Google Scholar PubMed

74Chung, J.H., Bell, A.C. and Felsenfeld, G. (1997) Characterization of the chicken beta-globin insulator. Proceedings of the National Academy of Sciences of the United States of America 94, 575-580CrossRef Google Scholar PubMed

75Rivella, S. et al. (2000) The cHS4 insulator increases the probability of retroviral expression at random chromosomal integration sites. Journal of Virology 74, 4679-4687CrossRef Google Scholar PubMed

76Emery, D.W. et al. (2000) A chromatin insulator protects retrovirus vectors from chromosomal position effects. Proceedings of the National Academy of Sciences of the United States of America 97, 9150-9155CrossRef Google Scholar PubMed

77Yannaki, E. et al. (2002) Topological constraints governing the use of the chicken HS4 chromatin insulator in oncoretrovirus vectors. Molecular Therapy 5, 589-598CrossRef Google Scholar PubMed

78Evans-Galea, M.V. (2007) Suppression of clonal dominance in cultured human lymphoid cells by addition of the cHS4 insulator to a lentiviral vector. Molecular Therapy 15, 801-809CrossRef Google Scholar PubMed

79Ramezani, A., Hawley, T.S. and Hawley, R.G. (2008) Combinatorial incorporation of enhancer-blocking components of the chicken beta-globin 5′HS4 and human T-cell receptor alpha/delta BEAD-1 insulators in self-inactivating retroviral vectors reduces their genotoxic potential. Stem Cells 26, 3257-3266CrossRef Google Scholar

80Nishino, T. et al. (2006) Effects of human gamma-globin in murine beta-thalassaemia. British Journal of Haematology 134, 100-108CrossRef Google Scholar PubMed

81Neff, T. et al. (2003) Methylguanine methyltransferase-mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal model. Journal of Clinical Investigation 112, 1581-1588CrossRef Google Scholar

82Ragg, S. et al. (2000) Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells. Cancer Research 60, 5187-5195Google Scholar PubMed

83Jin, L. et al. (2000) In vivo selection using a cell-growth switch. Nature Genetics 26, 64-66CrossRef Google Scholar PubMed

84Emery, D.W. et al. (2005) Selection with a regulated cell growth switch increases the likelihood of expression for a linked gamma-globin gene. Blood Cells, Molecules, and Diseases 34, 235-247CrossRef Google Scholar PubMed

85Zhao, H. et al. (2009) Amelioration of murine beta-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both gamma-globin and the MGMT drug-resistance gene. Blood 113, 5747-5756CrossRef Google Scholar PubMed

86Burroughs, L. and Storb, R. (2005) Low-intensity allogeneic hematopoietic stem cell transplantation for myeloid malignancies: separating graft-versus-leukemia effects from graft-versus-host disease. Current Opinion in Hematology 12, 45-54CrossRef Google Scholar PubMed

87Aiuti, A. et al. (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410-2413CrossRef Google Scholar PubMed

88Mardiney, M. and Malech, H.L. (1996) Enhanced engraftment of hematopoietic progenitor cells in mice treated with granulocyte colony-stimulating factor before low-dose irradiation: implications for gene therapy. Blood 87, 4049-4056Google Scholar PubMed

89Rosenzwieg, M. et al. (1999) Efficient and durable gene marking of hematopoietic progenitor cells in nonhuman primates after nonablative conditioning. Blood 94, 2271-2286CrossRef Google Scholar

90Bordignon, C. et al. (1995) Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270, 470-475CrossRef Google Scholar PubMed

91Kohn, D.B. et al. (1995) Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nature Medicine 1, 1017-1023CrossRef Google Scholar PubMed

92Malech, H.L. et al. (1997) Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proceedings of the National Academy of Sciences of the United States of America 94, 12133-12138CrossRef Google Scholar PubMed

93Kohn, D.B. et al. (1998) T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nature Medicine 4, 775-780CrossRef Google Scholar PubMed

94Dunbar, C.E. et al. (1998) Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: in vivo detection of transduced cells without myeloablation. Human Gene Therapy 9, 2629-2640CrossRef Google Scholar PubMed

95Schuening, F. et al. (1997) Retrovirus-mediated transfer of the cDNA for human glucocerebrosidase into peripheral blood repopulating cells of patients with Gaucher's disease. Human Gene Therapy 8, 2143-2160CrossRef Google Scholar PubMed

96Kelly, P. et al. (2007) Stem cell collection and gene transfer in Fanconi anemia. Molecular Therapy 15, 211-219CrossRef Google Scholar PubMed

97Kang, E.M. et al. (2010) Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood 115, 783-791CrossRef Google Scholar PubMed

98Gaspar, H.B. et al. (2006) Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning. Molecular Therapy 14, 505-513CrossRef Google Scholar PubMed

99Cartier, N. et al. (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818-823CrossRef Google Scholar PubMed

100Bank, A., Dorazio, R. and Leboulch, P. (2005) A phase I/II clinical trial of beta-globin gene therapy for beta-thalassemia. Annals of the New York Academy of Sciences, 1054, 308-316CrossRef Google Scholar PubMed

101Kaiser, J. (2010) Gene therapy. Beta-thalassemia treatment succeeds, with a caveat. Science 326, 1468-1469CrossRef Google Scholar

102Andreani, M. et al. (1996) Persistence of mixed chimerism in patients transplanted for the treatment of thalassemia. Blood 87, 3494-3499CrossRef Google Scholar PubMed

103Iannone, R. et al. (2003) Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biology of Blood and Marrow Transplantation 9, 519-528CrossRef Google Scholar PubMed

104Persons, D.A. et al. (2001) Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy. Blood 97, 3275-3282CrossRef Google Scholar PubMed

105Gratwohl, A. et al. (2006) EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplantation 37, 1069-1085CrossRef Google Scholar PubMed

106To, L.B. et al. (1997) The biology and clinical uses of blood stem cells. Blood 89, 2233-2258CrossRef Google Scholar PubMed

107Dunbar, C.E. et al. (1996) Improved retroviral gene transfer into murine and Rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor. Proceedings of the National Academy of Sciences of the United States of America 93, 11871-11876CrossRef Google Scholar PubMed

108Horn, P.A. et al. (2004) Efficient lentiviral gene transfer to canine repopulating cells using an overnight transduction protocol. Blood 103, 3710-3716CrossRef Google Scholar PubMed

109Thomasson, B. et al. (2003) Direct comparison of steady-state marrow, primed marrow, and mobilized peripheral blood for transduction of hematopoietic stem cells in dogs. Human Gene Therapy 14, 1683-1686CrossRef Google Scholar PubMed

110Hematti, P. et al. (2003) Retroviral transduction efficiency of G-CSF + SCF-mobilized peripheral blood CD34+ cells is superior to G-CSF or G-CSF + Flt3-L-mobilized cells in nonhuman primates. Blood 101, 2199-2205CrossRef Google Scholar PubMed

111Hematti, P. et al. (2004) Comparison of retroviral transduction efficiency in CD34+ cells derived from bone marrow versus G-CSF-mobilized or G-CSF plus stem cell factor-mobilized peripheral blood in nonhuman primates. Stem Cells 22, 1062-1069CrossRef Google Scholar PubMed

112Bodine, D.M. et al. (1994) Efficient retrovirus transduction of mouse pluripotent hematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor. Blood 84, 1482-1491CrossRef Google Scholar PubMed

113O'Malley, D.P., Whalen, M. and Banks, P.M. (2003) Spontaneous splenic rupture with fatal outcome following G-CSF administration for myelodysplastic syndrome. American Journal of Hematology 73, 294-295CrossRef Google Scholar PubMed

114Brown, S.L. and Dale, D.C. (1997) Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells. Biology of Blood and Marrow Transplantation 3, 341-343Google Scholar

115Becker, P.S. et al. (1997) Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells. Biology of Blood and Marrow Transplantation 3, 45-49Google Scholar

116Abboud, M., Laver, J. and Blau, C.A. (1998) Granulocytosis causing sickle-cell crisis. Lancet 351, 959CrossRef Google Scholar PubMed

117Adler, B.K. et al. (2001) Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood 97, 3313-3314CrossRef Google Scholar PubMed

118Broxmeyer, H.E. et al. (2005) Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. Journal of Experimental Medicine 201, 1307-1318CrossRef Google Scholar PubMed

119Larochelle, A. et al. (2006) AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood 107, 3772-3778CrossRef Google Scholar PubMed

120Li, K. et al. (1999) Granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in beta-thalassemia patients: kinetics of mobilization and composition of apheresis product. Experimental Hematology 27, 526-532CrossRef Google Scholar PubMed

121Yannaki, E. et al. (2010) Mobilization of hematopoietic stem cells in a thalassemic mouse model: implications for human gene therapy of thalassemia. Human Gene Therapy 21, 299-310CrossRef Google Scholar

122Yannaki, E. and Stamatoyannopoulos, G. (2010) Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease. Annals of the New York Academy of Sciences 1202, 59-63CrossRef Google Scholar PubMed

123Sadelain, M. et al. (2007) Therapeutic options for patients with severe beta-thalassemia: the need for globin gene therapy. Human Gene Therapy 18, 1-9CrossRef Google Scholar PubMed

124Persons, D.A. (2009) Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders. Hematology/The Education Program of the American Society of Hematology 2009, 690-697CrossRef Google Scholar

125Pathak, V.K. and Temin, H.M. (1990) Broad spectrum of in vivo forward mutations, hypermutations, and mutational hotspots in a retroviral shuttle vector after a single replication cycle: deletions and deletions with insertions. Proceedings of the National Academy of Sciences of the United States of America 87, 6024-6028CrossRef Google Scholar

126Patel, M. and Yang, S. (2010) Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Reviews 6, 367-380CrossRef Google Scholar PubMed

127Rashid, S.T. and Vallier, L. (2010) Induced pluripotent stem cells – alchemist's tale or clinical reality? Expert Reviews in Molecular Medicine 12, e25CrossRef Google Scholar PubMed

128Takahashi, K. and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676CrossRef Google Scholar PubMed

129Yu, J. et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920CrossRef Google Scholar PubMed

130Yu, J. et al. (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797-801CrossRef Google Scholar PubMed

131Kim, D. et al. (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cells 4, 472-476CrossRef Google Scholar PubMed

132Ebert, A.D. et al. (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277-280CrossRef Google Scholar PubMed

133Lee, G. et al. (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402-406CrossRef Google Scholar PubMed

134Kiskinis, E. and Eggan, K. (2010) Progress toward the clinical application of patient-specific pluripotent stem cells. Journal of Clinical Investigation 120, 51-59CrossRef Google Scholar PubMed

135Park, I. et al. (2008) Disease-specific induced pluripotent stem cells. Cell 134, 877-886CrossRef Google Scholar PubMed

136Hanna, J. et al. (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920-1923CrossRef Google Scholar PubMed

137Rega, A. et al. (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53-49Google Scholar

138Ye, L. et al. (2009) Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proceedings of the National Academy of Sciences of the United States of America 106, 9826-9830CrossRef Google Scholar PubMed

139Okita, K. and Yamanaka, S. (2010) Induction of pluripotency by defined factors. Experimental Cell Research 316, 2565-2570CrossRef Google Scholar PubMed

140Yamanaka, S. and Blau, H.M. (2010) Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704-712CrossRef Google Scholar PubMed

141Aiuti, A. and Roncarolo, M.G. (2010) Ten years of gene therapy for primary immune deficiencies. Hematology/The Education Program of the American Society of Hematology 2009, 682-689CrossRef Google Scholar

142Gaspar, H.B. et al. (2009) How I treat ADA deficiency. Blood 114, 3524-3532CrossRef Google Scholar

Article contents

Gene therapy for β-thalassaemia: the continuing challenge

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

Gene therapy for β-thalassaemia: the continuing challenge

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests