Molecular Diagnosis & Therapy

, Volume 23, Issue 2, pp 173–186 | Cite as

Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges

  • Valentina Ghiaccio
  • Maxwell Chappell
  • Stefano Rivella
  • Laura BredaEmail author
Review Article


Inherited monogenic disorders such as beta-hemoglobinopathies (BH) are fitting candidates for treatment via gene therapy by gene transfer or gene editing. The reported safety and efficacy of lentiviral vectors in preclinical studies have led to the development of several clinical trials for the addition of a functional beta-globin gene. Across trials, dozens of transfusion-dependent patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have been treated via gene therapy and have achieved reduced transfusion requirements. While overall results are encouraging, the outcomes appear to be strongly influenced by the level of lentiviral integration in transduced cells after engraftment, as well as the underlying genotype resulting in thalassemia. In addition, the method of procurement of hematopoietic stem cells can affect their quality and thus the outcome of gene therapy both in SCD and TDT. This suggests that new studies aimed at maximizing the number of corrected cells with long-term self-renewal potential are crucial to ensure successful treatment for every patient. Recent advancements in gene transfer and bone marrow transplantation have improved the success of this approach, and the results obtained by using these strategies demonstrated significant improvement of gene transfer outcome in patients. The advent of new gene-editing technologies has suggested additional therapeutic options. These are primarily focused on correcting the defective beta-globin gene or editing the expression of genes or genomic segments that regulate fetal hemoglobin synthesis. In this review, we aim to establish the potential benefits of gene therapy for BH, to summarize the status of the ongoing trials, and to discuss the possible improvement or direction for future treatments.


Compliance with Ethical Standards

Conflict of interest

LB, VG and MC declare no conflict of interest. SR is a consultant for Ionis Pharmaceuticals.


This review was made possible through the collaboration of LB and SR in the THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia (THALAMOSS), European Community: FP7-HEALTH-2012-INNOVATION. This work is supported by grants from the National Institutes of Health (NIDDK-R01DK090554 and NIDDK-R01DK095112 to S.R.). The authors gratefully acknowledge the generous support by the Jean, Schejola and Di Gaetano families and the Children’s Hospital of Philadelphia Foundation.


  1. 1.
    Piel FB, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142–51.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008;86(6):480–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Strocchio L, Locatelli F. Hematopoietic stem cell transplantation in thalassemia. Hematol Oncol Clin N Am. 2018;32(2):317–28.CrossRefGoogle Scholar
  4. 4.
    Locatelli F, Merli P, Strocchio L. Transplantation for thalassemia major: alternative donors. Curr Opin Hematol. 2016;23(6):515–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Angelucci E, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014;99(5):811–20.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Breda L, et al. Therapeutic hemoglobin levels after gene transfer in beta-thalassemia mice and in hematopoietic cells of beta-thalassemia and sickle cells disease patients. PLoS One. 2012;7(3):e32345.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Miccio A, et al. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105(30):10547–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Roselli EA, et al. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010;2(8):315–28.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Romero Z, Urbinati F, Geiger S, Cooper AR, Wherley J, Kaufman ML, Hollis RP, et al. β-globin gene transfer to human bone marrow for sickle cell disease. J Clin Investig. 2013;123(8):3317–30.CrossRefGoogle Scholar
  10. 10.
    Negre O, et al. Gene therapy of the beta-hemoglobinopathies by lentiviral transfer of the beta(A(T87Q))-globin gene. Hum Gene Ther. 2016;27(2):148–65.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Puthenveetil G, et al. Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector. Blood. 2004;104(12):3445–53.CrossRefPubMedGoogle Scholar
  12. 12.
    May C, et al. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature. 2000;406(6791):82–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Pawliuk R, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001;294(5550):2368–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Ferrari G, Cavazzana M, Mavilio F. Gene therapy approaches to hemoglobinopathies. Hematol Oncol Clin N Am. 2017;31(5):835–52.CrossRefGoogle Scholar
  15. 15.
    Mansilla-Soto J, et al. Cell and gene therapy for the beta-thalassemias: advances and prospects. Hum Gene Ther. 2016;27(4):295–304.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Marktel S, et al. Gene therapy for beta thalassemia: preliminary results from the phase I/II Tiget-Bthal Trial of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector. Atlanta: ASH 59th Annual Meeting and Exposition; 2017.Google Scholar
  17. 17.
    Kwiatkowski JL, et al. Clinical outcomes up to 3 years following lentiglobin gene therapy for transfusion-dependent β-thalassemia in the Northstar Hgb-204 study. Atlanta: ASH 59th Annual Meeting and Exposition; 2017.Google Scholar
  18. 18.
    Walters M, et al. Results from the Hgb-207 (Northstar-2) trial: a phase 3 study to evaluate safety and efficacy of lentiglobin gene therapy for transfusion-dependent β-thalassemia (TDT) in patients with non-β/β genotypes. Atlanta: ASH 59th Annual Meeting and Exposition; 2017.Google Scholar
  19. 19.
    Kanter J, Walters MC, Hsieh MM, Krishnamurti L, Kwiatkowski J, Kamble RT, von Kalle C, Kuypers FA, Cavazzana M, Leboulch P, Joseney-Antoine M, Asmal M, Thompson AA, Tisdale JF. Interim results from a phase 1/2 clinical study of lentiglobin gene therapy for severe sickle cell disease. San Diego: American Society of Hematology; 2016. p. 1176.Google Scholar
  20. 20.
    Ribeil JA, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848–55.CrossRefPubMedGoogle Scholar
  21. 21.
    Thompson AA, et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2018;378(16):1479–93.CrossRefPubMedGoogle Scholar
  22. 22.
    Sii-Felice K, et al. Hemoglobin disorders: lentiviral gene therapy in the starting blocks to enter clinical practice. Exp Hematol. 2018;64:12–32.CrossRefPubMedGoogle Scholar
  23. 23.
    Dever DP, Porteus MH. The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation. Curr Opin Hematol. 2017;24(6):481–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bak RO, et al. Multiplexed genetic engineering of human hematopoietic stem and progenitor cells using CRISPR/Cas9 and AAV6. Elife. 2017;6:e27873.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yu VWC, et al. CRISPR/Cas9 gene-edited hematopoietic stem cell therapy for sickle cell disease. Atlanta: 59th ASH Annual Meeting & Exposition; 2017.Google Scholar
  26. 26.
    Psatha N, et al. Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with beta-thalassemia major. Mol Ther Methods Clin Dev. 2018;10:313–26.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lidonnici MR, et al. Multiple integrated non-clinical studies predict the safety of lentivirus-mediated gene therapy for beta-thalassemia. Mol Ther Methods Clin Dev. 2018;11:9–28.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Duong HK, et al. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2014;20(9):1262–73.CrossRefPubMedGoogle Scholar
  29. 29.
    Fruehauf S, et al. The CXCR4 antagonist AMD3100 releases a subset of G-CSF-primed peripheral blood progenitor cells with specific gene expression characteristics. Exp Hematol. 2006;34(8):1052–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Karponi G, et al. Plerixafor + G-CSF-mobilized CD34+ cells represent an optimal graft source for thalassemia gene therapy. Blood. 2015;126(5):616–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Adler BK, et al. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood. 2001;97(10):3313–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Grigg AP. Granulocyte colony-stimulating factor-induced sickle cell crisis and multiorgan dysfunction in a patient with compound heterozygous sickle cell/beta + thalassemia. Blood. 2001;97(12):3998–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Abboud M, Laver J, Blau CA. Granulocytosis causing sickle-cell crisis. Lancet. 1998;351(9107):959.CrossRefPubMedGoogle Scholar
  34. 34.
    Yannaki E, et al. Hematopoietic stem cell mobilization for gene therapy of adult patients with severe beta-thalassemia: results of clinical trials using G-CSF or plerixafor in splenectomized and nonsplenectomized subjects. Mol Ther. 2012;20(1):230–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Choi E, et al. No evidence for cell activation or brain vaso-occlusion with plerixafor mobilization in sickle cell mice. Blood Cells Mol Dis. 2016;57:67–70.CrossRefPubMedGoogle Scholar
  36. 36.
    Tisdale JF, et al. Successful plerixafor-mediated mobilization, apheresis, and lentiviral vector transduction of hematopoietic stem cells in patients with severe sickle cell disease. GA: ASH 59th Annual Meeting and Exposition; 2017.Google Scholar
  37. 37.
    Boulad F, et al. Safety and efficacy trial of escalation of plerixafor for mobilization of CD34+ hematopoietic progenitor cells (HPCs) for globin gene transfer in patients with sickle cell disease. Atlanta: ASH 59th Annual Meeting and Exposition; 2017.Google Scholar
  38. 38.
    Esrick EB, et al. Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Blood Adv. 2018;2(19):2505–12.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Palchaudhuri R, et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol. 2016;34(7):738–45.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Levasseur DN, et al. Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood. 2003;102(13):4312–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Imren S, et al. Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci USA. 2002;99(22):14380–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Wilber A, et al. Therapeutic levels of fetal hemoglobin in erythroid progeny of beta-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer. Blood. 2011;117(10):2817–26.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Urbinati F, et al. Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34+ cells. Exp Hematol. 2015;43(5):346–51.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Poletti V, et al. Pre-clinical development of a lentiviral vector expressing the anti-sickling betaAS3 globin for gene therapy for sickle cell disease. Mol Ther Methods Clin Dev. 2018;11:167–79.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Negre O, et al. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of beta-thalassemia and sickle cell disease. Curr Gene Ther. 2015;15(1):64–81.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cavazzana-Calvo M, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318–22.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Naldini L, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263–7.CrossRefGoogle Scholar
  48. 48.
    Dull T, et al. A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998;72(11):8463–71.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Finkelshtein D, et al. LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus. Proc Natl Acad Sci USA. 2013;110(18):7306–11.CrossRefPubMedGoogle Scholar
  50. 50.
    Girard-Gagnepain A, et al. Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs. Blood. 2014;124(8):1221–31.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhang XY, La Russa VF, Reiser J. Transduction of bone-marrow-derived mesenchymal stem cells by using lentivirus vectors pseudotyped with modified RD114 envelope glycoproteins. J Virol. 2004;78(3):1219–29.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Trobridge GD, et al. Cocal-pseudotyped lentiviral vectors resist inactivation by human serum and efficiently transduce primate hematopoietic repopulating cells. Mol Ther. 2010;18(4):725–33.CrossRefPubMedGoogle Scholar
  53. 53.
    Malicorne S, et al. Genome-wide screening of retroviral envelope genes in the nine-banded armadillo (Dasypus novemcinctus, Xenarthra) reveals an unfixed chimeric endogenous betaretrovirus using the ASCT2 receptor. J Virol. 2016;90(18):8132–49.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Levy C, et al. Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent. Blood Adv. 2017;1(23):2088–104.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Coelen RJ, Jose DG, May JT. The effect of hexadimethrine bromide (Polybrene) on the infection of the primate retroviruses SSV 1/SSAV 1 and BaEV. Arch Virol. 1983;75(4):307–11.CrossRefPubMedGoogle Scholar
  56. 56.
    Davis HE, Morgan JR, Yarmush ML. Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem. 2002;97(2–3):159–72.CrossRefPubMedGoogle Scholar
  57. 57.
    Davis HE, et al. Charged polymers modulate retrovirus transduction via membrane charge neutralization and virus aggregation. Biophys J. 2004;86(2):1234–42.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fenard D, et al. Infectivity enhancement of different HIV-1-based lentiviral pseudotypes in presence of the cationic amphipathic peptide LAH4-L1. J Virol Methods. 2013;189(2):375–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Ingrao D, et al. Concurrent measures of fusion and transduction efficiency of primary CD34+ cells with human immunodeficiency virus 1-based lentiviral vectors reveal different effects of transduction enhancers. Hum Gene Ther Methods. 2014;25(1):48–56.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Majdoul S, et al. Molecular determinants of Vectofusin-1 and its derivatives for the enhancement of lentivirally mediated gene transfer into hematopoietic stem/progenitor cells. J Biol Chem. 2016;291(5):2161–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Vermeer LS, et al. Vectofusin-1, a potent peptidic enhancer of viral gene transfer forms pH-dependent alpha-helical nanofibrils, concentrating viral particles. Acta Biomater. 2017;64:259–68.CrossRefPubMedGoogle Scholar
  62. 62.
    Majdoul S, et al. Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells. J Biol Chem. 2017;292(45):18672–81.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Psatha N, Karponi G, Yannaki E. Optimizing autologous cell grafts to improve stem cell gene therapy. Exp Hematol. 2016;44(7):528–39.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    North TE, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447(7147):1007–11.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Zonari E, et al. Efficient ex vivo engineering and expansion of highly purified human hematopoietic stem and progenitor cell populations for gene therapy. Stem Cell Rep. 2017;8(4):977–90.CrossRefGoogle Scholar
  66. 66.
    Heffner GC, et al. Prostaglandin E2 increases lentiviral vector transduction efficiency of adult human hematopoietic stem and progenitor cells. Mol Ther. 2017.Google Scholar
  67. 67.
    Tisdale JF, Hanazono Y, Sellers SE, Agricola BA, Metzger ME, Donahue RE, Dunbar CE. Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability. Blood. 1998;92(4):1131–41.PubMedGoogle Scholar
  68. 68.
    Bhukhai K, et al. Ex vivo selection of transduced hematopoietic stem cells for gene therapy of beta-hemoglobinopathies. Mol Ther. 2017.Google Scholar
  69. 69.
    Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature. 1985;317(6034):230–4.CrossRefPubMedGoogle Scholar
  70. 70.
    Tebas P, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901–10.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Cradick TJ, et al. CRISPR/Cas9 systems targeting beta-globin and CCR5 genes have substantial off-target activity. Nucl Acids Res. 2013;41(20):9584–92.CrossRefPubMedGoogle Scholar
  72. 72.
    Hoban MD, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597–604.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Voit RA, et al. Nuclease-mediated gene editing by homologous recombination of the human globin locus. Nucl Acids Res. 2014;42(2):1365–78.CrossRefPubMedGoogle Scholar
  74. 74.
    Kuscu C, et al. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nat Biotechnol. 2014;32(7):677–83.CrossRefPubMedGoogle Scholar
  75. 75.
    Lin Y, et al. CRISPR/Cas9 systems have off-target activity with insertions or deletions between target DNA and guide RNA sequences. Nucl Acids Res. 2014;42(11):7473–85.CrossRefPubMedGoogle Scholar
  76. 76.
    Ihry RJ, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018;24(7):939–46.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Crudele JM, Chamberlain JS. Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun. 2018;9(1):3497.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Simhadri VL, et al. Prevalence of pre-existing antibodies to CRISPR-associated nuclease Cas9 in the USA population. Mol Ther Methods Clin Dev. 2018;10:105–12.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Charesworth CT, et al. Identification of pre-existing adaptive immunity to Cas9 proteins in humans. BioRXiv [Preprint] 2018.Google Scholar
  80. 80.
    Mettananda S, Fisher CA, Hay D, Badat M, Quek L, Clark K, Hublitz P, et al. Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia. Nat Commun. 2017;8(1):424.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hoban MD, et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol Ther. 2016;24(9):1561–9.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    DeWitt MA, et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci Transl Med. 2016;8(360):360ra134.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Dever DP, et al. CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature. 2016;539(7629):384–9.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Dever DP, et al. Preclinical development of HBB gene correction in autologous hematopoietic stem and progenitor cells to treat severe sickle cell disease. Atlanta: 59th ASH Annual Meeting and Exposition; 2017.Google Scholar
  85. 85.
    Lin S, et al. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. Elife. 2014;3:e04766.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Gu A, et al. Engraftment and lineage potential of adult hematopoietic stem and progenitor cells is compromised following short-term culture in the presence of an aryl hydrocarbon receptor antagonist. Hum Gene Ther Methods. 2014;25(4):221–31.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Wang J, et al. Homology-driven genome editing in hematopoietic stem and progenitor cells using ZFN mRNA and AAV6 donors. Nat Biotechnol. 2015;33(12):1256–63.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Andreani M, et al. Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica. 2011;96(1):128–33.CrossRefPubMedGoogle Scholar
  89. 89.
    Zou J, et al. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood. 2011;118(17):4599–608.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Cai L, et al. A universal approach to correct various HBB gene mutations in human stem cells for gene therapy of beta-thalassemia and sickle cell disease. Stem Cells Transl Med. 2018;7(1):87–97.CrossRefPubMedGoogle Scholar
  91. 91.
    Gaudelli NM, et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464–71.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Cox DBT, et al. RNA editing with CRISPR-Cas13. Science. 2017;358(6366):1019–27.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Uda M, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105(5):1620–5.CrossRefPubMedGoogle Scholar
  94. 94.
    Ley TJ, et al. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta + thalassemia. N Engl J Med. 1982;307(24):1469–75.CrossRefPubMedGoogle Scholar
  95. 95.
    Powars DR, et al. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood. 1984;63(4):921–6.PubMedGoogle Scholar
  96. 96.
    Nuinoon M, et al. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010;127(3):303–14.CrossRefPubMedGoogle Scholar
  97. 97.
    Quek L, Thein SL. Molecular therapies in beta-thalassaemia. Br J Haematol. 2007;136(3):353–65.CrossRefPubMedGoogle Scholar
  98. 98.
    Charache S, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79(10):2555–65.PubMedGoogle Scholar
  99. 99.
    Traxler EA, et al. A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat Med. 2016;22(9):987–90.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Sankaran VG, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839–42.CrossRefPubMedGoogle Scholar
  101. 101.
    Brendel C, et al. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J Clin Invest. 2016;126(10):3868–78.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Psatha N, et al. Introduction of two simultaneous mutations by genome editing greatly enhances the accumulation of the endogenous fetal hemoglobin in human normal erythroid cells. Atlanta: 59th ASH Annual Meeting and Exposition; 2017.Google Scholar
  103. 103.
    Lin MI, et al. RISPR/Cas9 genome editing to treat sickle cell disease and B-thalassemia: re-creating genetic variants to upregulate fetal hemoglobin appear well-tolerated, effective and durable. GA: 59th ASH Annual Meeting and Exposition; 2017.Google Scholar
  104. 104.
    Bjurstrom CF, et al. Reactivating fetal hemoglobin expression in human adult erythroblasts through BCL11A knockdown using targeted endonucleases. Mol Ther Nucl Acids. 2016;5:e351.CrossRefGoogle Scholar
  105. 105.
    Chang KH, et al. Long-term engraftment and fetal globin induction upon BCL11A gene editing in bone-marrow-derived CD34(+) hematopoietic stem and progenitor cells. Mol Ther Methods Clin Dev. 2017;4:137–48.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Luc S, et al. Bcl11a deficiency leads to hematopoietic stem cell defects with an aging-like phenotype. Cell Rep. 2016;16(12):3181–94.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Tsang JC, et al. Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells. Genome Biol. 2015;16:178.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Deng W, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158(4):849–60.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Breda L, et al. Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood. 2016;128(8):1139–43.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Borg J, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42(9):801–5.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Norton LJ, et al. KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells. Blood Adv. 2017;1(11):685–92.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Breda L, et al. Combining gene therapy and fetal hemoglobin induction for treatment of beta-thalassemia. Exp Rev Hematol. 2013;6(3):255–64.CrossRefGoogle Scholar
  113. 113.
    Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117(15):3945–53.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Valentina Ghiaccio
    • 1
  • Maxwell Chappell
    • 1
  • Stefano Rivella
    • 1
  • Laura Breda
    • 1
    Email author
  1. 1.Hematology DivisionChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations