1932

Abstract

Sickle cell disease (SCD) results from a single base pair change in the sixth codon of the β-globin chain of hemoglobin, which promotes aggregation of deoxyhemoglobin, increasing rigidity of red blood cells and causing vaso-occlusive and hemolytic complications. Allogeneic transplant of hematopoietic stem cells (HSCs) can eliminate SCD manifestations but is limited by absence of well-matched donors and immune complications. Gene therapy with transplantation of autologous HSCs that are gene-modified may provide similar benefits without the immune complications. Much progress has been made, and patients are realizing significant clinical improvements in multiple trials using different approaches with lentiviral vector–mediated gene addition to inhibit hemoglobin aggregation. Gene editing approaches are under development to provide additional therapeutic opportunities. Gene therapy for SCD has advanced from an attractive concept to clinical reality.

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/content/journals/10.1146/annurev-med-042921-021707
2023-01-27
2024-06-16
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Literature Cited

  1. 1.
    Piel FB, Patil AP, Howes RE et al. 2013. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381:142–51
    [Google Scholar]
  2. 2.
    CDC. Sickle Cell Disease. https://www.cdc.gov/ncbddd/sicklecell/data.html. Updated May 2, 2022
    [Google Scholar]
  3. 3.
    Sundd P, Gladwin MT, Novelli EM. 2019. Pathophysiology of sickle cell disease. Annu. Rev. Pathol. Mech. Dis. 14:263–92
    [Google Scholar]
  4. 4.
    Kato GJ, Piel FB, Reid CD et al. 2018. Sickle cell disease. Nat. Rev. Dis. Primers 4:18010
    [Google Scholar]
  5. 5.
    Lanzkron S, Carroll CP, Haywood C Jr. 2010. The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. Am. J. Hematol. 85:797–99
    [Google Scholar]
  6. 6.
    Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. 2010. Improved survival of children and adolescents with sickle cell disease. Blood 115:3447–52
    [Google Scholar]
  7. 7.
    Piel FB, Steinberg MH, Rees DC. 2017. Sickle cell disease. N. Engl. J. Med. 376:1561–73
    [Google Scholar]
  8. 8.
    Platt OS, Brambilla DJ, Rosse WF et al. 1994. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med. 330:1639–44
    [Google Scholar]
  9. 9.
    Akinsheye I, Alsultan A, Solovieff N et al. 2011. Fetal hemoglobin in sickle cell anemia. Blood 118:19–27
    [Google Scholar]
  10. 10.
    Nevitt SJ, Jones AP, Howard J. 2017. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst. Rev. 4:CD002202
    [Google Scholar]
  11. 11.
    Howard J. 2016. Sickle cell disease: when and how to transfuse. Hematol. Am. Soc. Hematol. Educ. Progr. 2016:625–31
    [Google Scholar]
  12. 12.
    Meier ER. 2018. Treatment options for sickle cell disease. Pediatr. Clinics North Am. 65:427–43
    [Google Scholar]
  13. 13.
    Niihara Y, Miller ST, Kanter J et al. 2018. A phase 3 trial of l-glutamine in sickle cell disease. N. Engl. J. Med. 379:226–35
    [Google Scholar]
  14. 14.
    Kapoor S, Little JA, Pecker LH. 2018. Advances in the treatment of sickle cell disease. Mayo Clin. Proc. 93:1810–24
    [Google Scholar]
  15. 15.
    Vichinsky E, Hoppe CC, Ataga KI et al. 2019. A phase 3 randomized trial of voxelotor in sickle cell disease. N. Engl. J. Med. 381:509–19
    [Google Scholar]
  16. 16.
    Quinn CT, Ware RE. 2021. Increased oxygen affinity: to have and to hold. Blood 138:1094–95
    [Google Scholar]
  17. 17.
    Kutlar A, Kanter J, Liles DK et al. 2019. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am. J. Hematol. 94:55–61
    [Google Scholar]
  18. 18.
    Hsieh MM, Kang EM, Fitzhugh CD et al. 2009. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N. Engl. J. Med. 361:2309–17
    [Google Scholar]
  19. 19.
    Shenoy S. 2013. Hematopoietic stem-cell transplantation for sickle cell disease: current evidence and opinions. Ther. Adv. Hematol. 4:335–44
    [Google Scholar]
  20. 20.
    Eapen M, Brazauskas R, Walters MC et al. 2019. Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study. Lancet Haematol. 6:e585–96
    [Google Scholar]
  21. 21.
    Kamani NR, Walters MC, Carter S et al. 2012. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol. Blood Marrow Transplant. 18:1265–72
    [Google Scholar]
  22. 22.
    Kanter J, Liem RI, Bernaudin F et al. 2021. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 5:3668–89
    [Google Scholar]
  23. 23.
    Hoban MD, Orkin SH, Bauer DE. 2016. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127:839–48
    [Google Scholar]
  24. 24.
    Bank A, Markowitz D, Lerner N. 1989. Gene transfer. A potential approach to gene therapy for sickle cell disease. Ann. N. Y. Acad. Sci. 565:37–43
    [Google Scholar]
  25. 25.
    Maetzig T, Galla M, Baum C, Schambach A. 2011. Gammaretroviral vectors: biology, technology and application. Viruses 3:677–713
    [Google Scholar]
  26. 26.
    Karlsson S, Bodine DM, Perry L et al. 1988. Expression of the human beta-globin gene following retroviral-mediated transfer into multipotential hematopoietic progenitors of mice. PNAS 85:6062–66
    [Google Scholar]
  27. 27.
    Plavec I, Papayannopoulou T, Maury C, Meyer F 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 81:1384–92
    [Google Scholar]
  28. 28.
    Pawliuk R, Bachelot T, Raftopoulos H et al. 1998. Retroviral vectors aimed at the gene therapy of human beta-globin gene disorders. Ann. N. Y. Acad Sci. 850:151–62
    [Google Scholar]
  29. 29.
    Cattoglio C, Facchini G, Sartori D et al. 2007. Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 110:1770–78
    [Google Scholar]
  30. 30.
    Naldini L, Trono D, Verma IM. 2016. Lentiviral vectors, two decades later. Science 353:1101–2
    [Google Scholar]
  31. 31.
    Miyoshi H, Blömer U, Takahashi M et al. 1998. Development of a self-inactivating lentivirus vector. J. Virol. 72:8150–57
    [Google Scholar]
  32. 32.
    Zufferey R, Dull T, Mandel RJ et al. 1998. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72:9873–80
    [Google Scholar]
  33. 33.
    May C, Rivella S, Callegari J et al. 2000. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 406:82–86
    [Google Scholar]
  34. 34.
    Murray N, Serjeant BE, Serjeant GR. 1988. Sickle cell-hereditary persistence of fetal haemoglobin and its differentiation from other sickle cell syndromes. Br. J. Haematol. 69:89–92
    [Google Scholar]
  35. 35.
    Uda M, Galanello R, Sanna S et al. 2008. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. PNAS 105:1620–25
    [Google Scholar]
  36. 36.
    Xu J, Peng C, Sankaran VG et al. 2011. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 334:993–96
    [Google Scholar]
  37. 37.
    Perumbeti A, Higashimoto T, Urbinati F 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 114:1174–85
    [Google Scholar]
  38. 38.
    Pestina TI, Hargrove PW, Jay D et al. 2009. Correction of murine sickle cell disease using γ-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin. Mol. Therapy 17:245–52
    [Google Scholar]
  39. 39.
    Nagel RL, Bookchin RM, Johnson J et al. 1979. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. PNAS 76:670–72
    [Google Scholar]
  40. 40.
    Pawliuk R, Westerman KA, Fabry ME et al. 2001. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294:2368–71
    [Google Scholar]
  41. 41.
    Kanter J, Walters MC, Krishnamurti L et al. 2022. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N. Engl. J. Med. 386:617–28
    [Google Scholar]
  42. 42.
    McCune SL, Reilly MP, Chomo MJ et al. 1994. Recombinant human hemoglobins designed for gene therapy of sickle cell disease. PNAS 91:9852–56
    [Google Scholar]
  43. 43.
    Levasseur DN, Ryan TM, Pawlik KM, Townes TM. 2003. Correction of a mouse model of sickle cell disease: lentiviral/anti-sickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102:4312–19
    [Google Scholar]
  44. 44.
    Romero Z, Urbinati F, Geiger S et al. 2013. β-globin gene transfer to human bone marrow for sickle cell disease. J. Clin. Investig. 123:3317–30
    [Google Scholar]
  45. 45.
    Morgan RA, Unti MJ, Aleshe B et al. 2020. Improved titer and gene transfer by lentiviral vectors using novel, small β-globin locus control region elements. Mol. Therapy 28:328–40
    [Google Scholar]
  46. 46.
    Han J, Tam K, Ma F et al. 2021. β-Globin lentiviral vectors have reduced titers due to incomplete vector RNA genomes and lowered virion production. Stem Cell Rep. 16:198–211
    [Google Scholar]
  47. 47.
    Urbinati F, Campo Fernandez B, Masiuk KE et al. 2018. Gene therapy for sickle cell disease: a lentiviral vector comparison study. Hum. Gene Ther. 29:1153–66
    [Google Scholar]
  48. 48.
    Guda S, Brendel C, Renella R et al. 2015. miRNA-embedded shRNAs for lineage-specific BCL11A knockdown and hemoglobin F induction. Mol. Ther. 23:1465–74
    [Google Scholar]
  49. 49.
    Brendel C, Negre O, Rothe M et al. 2020. Preclinical evaluation of a novel lentiviral vector driving lineage-specific BCL11A knockdown for sickle cell gene therapy. Mol. Ther. Methods Clin. Dev. 17:589–600
    [Google Scholar]
  50. 50.
    Esrick EB, Lehmann LE, Biffi A et al. 2021. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N. Engl. J. Med. 384:205–15
    [Google Scholar]
  51. 51.
    Bibikova M, Carroll D, Segal DJ et al. 2001. Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Mol. Cell. Biol. 21:289–97
    [Google Scholar]
  52. 52.
    Christian M, Cermak T, Doyle EL et al. 2010. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186:757–61
    [Google Scholar]
  53. 53.
    Jinek M, East A, Cheng A et al. 2013. RNA-programmed genome editing in human cells. eLife 2:e00471
    [Google Scholar]
  54. 54.
    Cong L, Ran FA, Cox D et al. 2013. Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–23
    [Google Scholar]
  55. 55.
    Doudna JA, Charpentier E. 2014. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346:1258096
    [Google Scholar]
  56. 56.
    Porteus MH, Baltimore D. 2003. Chimeric nucleases stimulate gene targeting in human cells. Science 300:763
    [Google Scholar]
  57. 57.
    Komor AC, Kim YB, Packer MS et al. 2016. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533:420–24
    [Google Scholar]
  58. 58.
    Richter MF, Zhao KT, Eton E et al. 2020. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 38:883–91
    [Google Scholar]
  59. 59.
    Bauer DE, Kamran SC, Lessard S et al. 2013. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342:253–57
    [Google Scholar]
  60. 60.
    Bjurström CF, Mojadidi M, Phillips J et al. 2016. Reactivating fetal hemoglobin expression in human adult erythroblasts through BCL11A knockdown using targeted endonucleases. Mol. Ther. Nucleic Acids 5:e351
    [Google Scholar]
  61. 61.
    Psatha N, Reik A, Phelps S et al. 2018. Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with β-thalassemia major. Mol. Ther. Methods Clin. Dev. 10:313–26
    [Google Scholar]
  62. 62.
    Demirci S, Leonard A, Essawi K, Tisdale JF. 2021. CRISPR-Cas9 to induce fetal hemoglobin for the treatment of sickle cell disease. Mol. Ther. Methods Clin. Dev. 23:276–85
    [Google Scholar]
  63. 63.
    Wu Y, Zeng J, Roscoe BP et al. 2019. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25:776–83
    [Google Scholar]
  64. 64.
    Frangoul H, Altshuler D, Cappellini MD et al. 2021. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 384:3252–60
    [Google Scholar]
  65. 65.
    Zeng J, Wu Y, Ren C et al. 2020. Therapeutic base editing of human hematopoietic stem cells. Nat. Med. 26:4535–41
    [Google Scholar]
  66. 66.
    Traxler EA, Yao Y, Wang YD et al. 2016. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22:987–90
    [Google Scholar]
  67. 67.
    Métais JY, Doerfler PA, Mayuranathan T et al. 2019. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv. 3:3379–92
    [Google Scholar]
  68. 68.
    Hoban MD, Lumaquin D, Kuo CY et al. 2016. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol. Ther. 24:1561–69
    [Google Scholar]
  69. 69.
    DeWitt MA, Magis W, Bray NL et al. 2016. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl. Med. 8:360ra134
    [Google Scholar]
  70. 70.
    Dever DP, Bak RO, Reinisch A et al. 2016. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539:384–89
    [Google Scholar]
  71. 71.
    Romero Z, Lomova A, Said S et al. 2019. Editing the sickle cell disease mutation in human hematopoietic stem cells: comparison of endonucleases and homologous donor templates. Mol. Ther. 27:1389–406
    [Google Scholar]
  72. 72.
    Newby GA, Yen JS, Woodard KJ et al. 2021. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595:295–302
    [Google Scholar]
  73. 73.
    Blackwell RQ, Oemijati S, Pribadi W et al. 1970. Hemoglobin G Makassar: beta-6 Glu leads to Ala. Biochim. Biophys. Acta 214:396–401
    [Google Scholar]
  74. 74.
    Li C, Georgakopoulou A, Mishra A et al. 2021. In vivo HSPC gene therapy with base editors allows for efficient reactivation of fetal γ-globin in β-YAC mice. Blood Adv 5:1122–35
    [Google Scholar]
  75. 75.
    Cannon P, Asokan A, Czechowicz A et al. 2021. Safe and effective in vivo targeting and gene editing in hematopoietic stem cells: strategies for accelerating development. Hum. Gene Ther. 32:31–42
    [Google Scholar]
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