Skip to main content
SpringerLink
Log in

Gene Therapy: The Path Toward Becoming a Realistic Cure for Sickle Cell Disease

  • Chapter
  • First Online:
Sickle Cell Disease and Hematopoietic Stem Cell Transplantation

Abstract

Unlike hydroxyurea or chronic blood transfusions to alleviate severity of sickle cell disease (SCD), hematopoietic stem cell transplantation (HSCT) is the only currently available curative option for patients with SCD. Data suggests an overall survival of >95% with a myeloablative regimen using HLA-matched sibling donors and >90% disease-free survival using a non-myeloablative regimen, yet less than 15% of patients with SCD have an appropriately matched donor. Allogeneic transplantation is further limited by morbidity and mortality from transplant conditioning, graft-versus-host disease (GVHD), and graft rejection; therefore other curative options are needed. The premise of gene therapy either by editing, modification, or gene insertion into autologous hematopoietic stem cells (HSCs) for the purpose of curative therapy for genetically based diseases raises the promise of a safer cure for SCD that is available to all patients. After decades of ongoing research, gene therapy for the cure of SCD is now a reality and is being investigated in multiple clinical trials.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ACS:

Acute chest syndrome

ADA:

Adenosine deaminase

BM:

Bone marrow

Cas9:

Bacterial CRISPR-associated protein 9

CGD:

Chronic granulomatous disease

cPPT:

Polypurine tract

CRISPR:

Clustered, regularly interspaced palindromic repeats

crRNA:

CRISPR-targeting RNA

DSB:

Double-stranded break

gRNA:

Guide RNA

GVHD:

Graft-versus-host disease

HbF:

Fetal hemoglobin

HDR:

Homology-directed repair

HEK293T:

Human embryonic kidney cells 293

HPFH:

Hereditary persistence of fetal hemoglobin

HS:

Hypersensitivity site

HSCs:

Hematopoietic stem cells

HSCT:

Hematopoietic stem cell transplantation

IDLV:

Integrase defective lentiviral vector

LCR:

Locus control region

LTR:

Long terminal repeat

NHEJ:

Nonhomologous end joining

PAM:

Protospacer adjacent motif

PB:

Peripheral blood

PBS:

Primer binding site

PBSCs:

Peripheral blood stem cells

PID:

Primary immunodeficiencies

RRE:

Rev response element

SCD:

Sickle cell disease

SCID:

Severe combined immune deficiency

SCID-X1:

X-linked SCID

SIN:

Self-inactivating

ssRNA:

Single-stranded RNA

TALENs:

Transcription activator-like effector nucleases

tat:

Trans-activator of transcription

VCN:

Vector copy number

VOC:

Vaso-occlusive crisis

WAS:

Wiskott-Aldrich syndrome

WPRE:

Woodchuck hepatitis virus posttranscriptional regulatory element

ZFNs:

Zinc-finger nucleases

Ψ:

Packaging element

References

  1. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175(4025):949–55.

    Article  CAS  PubMed  Google Scholar 

  2. Motulsky AG. Impact of genetic manipulation on society and medicine. Science. 1983;219(4581):135–40.

    Article  CAS  PubMed  Google Scholar 

  3. Grobstein C, Flower M. Gene therapy: proceed with caution. Hast Cent Rep. 1984;14(2):13–7.

    Article  CAS  Google Scholar 

  4. Orkin SH. Globin gene regulation and switching: circa 1990. Cell. 1990;63(4):665–72.

    Article  CAS  PubMed  Google Scholar 

  5. Rogers S, Pfuderer P. Use of viruses as carriers of added genetic information. Nature. 1968;219(5155):749–51.

    Article  CAS  PubMed  Google Scholar 

  6. Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, et al. Gene transfer into humans—immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990;323(9):570–8.

    Article  CAS  PubMed  Google Scholar 

  7. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80.

    Article  CAS  PubMed  Google Scholar 

  8. Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002;346(16):1185–93.

    Article  CAS  PubMed  Google Scholar 

  9. Cavazzana-Calvo M, Hacein-Bey S, de Saint BG, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288(5466):669–72.

    Article  CAS  PubMed  Google Scholar 

  10. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118(9):3132–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010;363(20):1918–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, et al. Gene therapy for Wiskott-Aldrich syndrome—long-term efficacy and genotoxicity. Sci Transl Med. 2014;6(227):227ra33.

    Article  PubMed  Google Scholar 

  13. Goebel WS, Dinauer MC. Gene therapy for chronic granulomatous disease. Acta Haematol. 2003;110(2–3):86–92.

    Article  CAS  PubMed  Google Scholar 

  14. Malech HL. Progress in gene therapy for chronic granulomatous disease. J Infect Dis. 1999;179(Suppl 2):S318–25.

    Article  CAS  PubMed  Google Scholar 

  15. Malech HL, Maples PB, Whiting-Theobald N, Linton GF, Sekhsaria S, Vowells SJ, et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci U S A. 1997;94(22):12133–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grez M, Reichenbach J, Schwäble J, Seger R, Dinauer MC, Thrasher AJ. Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther. 2011;19(1):28–35. doi:10.1038/mt.2010.232.

    Article  CAS  PubMed  Google Scholar 

  17. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12(4):401–9.

    Article  CAS  PubMed  Google Scholar 

  18. Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010;16(2):198–204.

    Article  CAS  PubMed  Google Scholar 

  19. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009;360(5):447–58.

    Article  CAS  PubMed  Google Scholar 

  20. Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296(5577):2410–3.

    Article  CAS  PubMed  Google Scholar 

  21. Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012;120(18):3635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001;164(11):1612.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Science magazine newstaff, “Breakthrough of the year: the runners up” Science. 2009;326(5960):1600–7.

    Google Scholar 

  24. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassemiaassaemia. Nature. 2010;467(7313):318–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848–55.

    Article  CAS  PubMed  Google Scholar 

  26. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  27. World Health Organization. Sickle-cell disease and other haemoglobin disorders. WHO fact sheet 308. Geneva: World Health Organization; 2011.

    Google Scholar 

  28. Grosse SD, Schechter MS, Kulkarni R, Lloyd-Puryear MA, Strickland B, Trevathan E. Models of comprehensive multidisciplinary care for individuals in the United States with genetic disorders. Pediatrics. 2009;123(1):407–12.

    Article  PubMed  Google Scholar 

  29. Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, et al. Defining sickle cell disease mortality using a population-based surveillance system, 2004 through 2008. Public Health Rep. 2016;131(2):367–75.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151(9):839–45.

    Article  CAS  PubMed  Google Scholar 

  31. Walters MC, Patience M, Leisenring W, Rogers ZR, Aquino VM, Buchanan GR, et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 2001;7(12):665–73.

    Article  CAS  PubMed  Google Scholar 

  32. Coffin JM, Hughes SH, Varmus HE, editors. The place of retroviruses in biology—Retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1997. Available from: https://www.ncbi.nlm.nih.gov/books/NBK19382/

    Google Scholar 

  33. Pollard VW, Malim MH. The HIV-1 Rev protein. Annu Rev Microbiol. 1998;52:491–532.

    Article  CAS  PubMed  Google Scholar 

  34. Cullen BR. Nuclear messenger RNA export: insights from virology. Trends Biochem Sci. 2003;28(8):419–24.

    Article  CAS  PubMed  Google Scholar 

  35. Klaver B, Berkhout B. Comparison of 5′ and 3′ long terminal repeat promoter function in human immunodeficiency virus. J Virol. 1994;68(6):3830–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zufferey R, Donello JE, Trono D, Hope TJ. Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by Retroviral Vectors. J Virol. 1999;73(4):2886–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Modlich U, Bohne J, Schmidt M, von Kalle C, Knoss S, Schambach A, et al. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity. Blood. 2006;108(8):2545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Challita PM, Kohn DB. Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo. Proc Natl Acad Sci U S A. 1994;91(7):2567–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol. 1998;72(12):9873–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Miyoshi H, Blömer U, Takahashi M, Gage FH, Verma IM. Development of a self-inactivating lentivirus vector. J Virol. 1998;72(10):8150–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Vigna E, Naldini L. Lentiviral vectors: excellent tools for experimental gene transfer and promising candidates for gene therapy. J Gene Med. 2000;2:308–16.

    Article  CAS  PubMed  Google Scholar 

  42. Geronimi F, Richard E, Redonnet-Vernhet I, Lamrissi-Garcia I, Lalanne M, Ged C, et al. Highly efficient lentiviral gene transfer in CD34+ and CD34+/38−/lin− cells from mobilized peripheral blood after cytokine prestimulation. Stem Cells. 2003;21:472–80.

    Article  CAS  PubMed  Google Scholar 

  43. Millington M, Arndt A, Boyd M, Applegate T, Shen S. Towards a clinically relevant lentiviral transduction protocol for primary human CD34 hematopoietic stem/progenitor cells. PLoS One. 2009;4:e6461.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Uchida N, Hsieh MM, Hayakawa J, Madison C, Washington KN, Tisdale JF. Optimal conditions for lentiviral transduction of engrafting human CD34+ cells. Gene Ther. 2011;18(11):1078–86.

    Article  CAS  PubMed  Google Scholar 

  45. Chandrakasan S, Malik P. Gene therapy for hemoglobinopathies: the state of the field and the future. Hematol Oncol Clin North Am. 2014;28(2):199–216.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996;335(6):369–76.

    Article  CAS  PubMed  Google Scholar 

  47. Hsieh MM, Fitzhugh CD, Weitzel R, Link ME, Coles WA, Zhao X, et al. Nonmyeloablative hla-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014;312(1):48–56.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Persons DA, Allay ER, Sabatino DE, Kelly P, Bodine DM, Nienhuis AW. Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy. Blood. 2001;97(10):3275–82.

    Article  CAS  PubMed  Google Scholar 

  49. Dzierzak EA, Papayannopoulou T, Mulligan RC. Lineage-specific expression of a human beta-globin gene in murine bone marrow transplant recipients reconstituted with retrovirus-transduced stem cells. Nature. 1988;331(6151):35–41.

    Article  CAS  PubMed  Google Scholar 

  50. May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, et al. Therapeutic haemoglobin synthesis in beta-thalassemiaassaemic mice expressing lentivirus-encoded human beta-globin. Nature. 2000;406(6791):82–6.

    Article  CAS  PubMed  Google Scholar 

  51. May C, Rivella S, Chadburn A, Sadelain M. Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene. Blood. 2002;99(6):1902–8.

    Article  CAS  PubMed  Google Scholar 

  52. Imren S, Payen E, Westerman KA, Pawliuk R, Fabry ME, Eaves CJ, et al. Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci U S A. 2002;99(22):14380–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pawliuk R, Westerman KA, Fabry ME, Payen E, Tighe R, Bouhassira EE, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001;294(5550):2368–71.

    Article  CAS  PubMed  Google Scholar 

  54. Levasseur DN, Ryan TM, Pawlik KM, Townes TM. 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. Epub 2003 Aug 21

    Article  CAS  PubMed  Google Scholar 

  55. Pestina TI, Hargrove PW, Jay D, Gray JT, Boyd KM, Persons DA. Correction of murine sickle cell disease using gamma-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin. Mol Ther. 2009;17(2):245–52.

    Article  CAS  PubMed  Google Scholar 

  56. Emery DW. The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors. Hum Gene Ther. 2011;22(6):761–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Arumugam PI, Scholes J, Perelman N, Xia P, Yee JK, Malik P. Improved human beta-globin expression from self-inactivating lentiviral vectors carrying the chicken hypersensitive site-4 (cHS4) insulator element. Mol Ther. 2007;15(10):1863–71.

    Article  CAS  PubMed  Google Scholar 

  58. Breda L, Casu C, Gardenghi S, Bianchi N, Cartegni L, Narla M, et al. Therapeutic hemoglobin levels after gene transfer in β-thalassemia mice and in hematopoietic cells of β-thalassemia and sickle cells disease patients. PLoS One. 2012;7(3):e32345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Romero Z, Urbinati F, Geiger S, Cooper AR, Wherley J, Kaufman ML, et al. β-Globin gene transfer to human bone marrow for sickle cell disease. J Clin Invest. 2013 Jul 1. pii: 67930.

    Google Scholar 

  60. Huang X, Wang Y, Yan W, Smith C, Ye Z, Wang J, et al. Production of gene-corrected adult beta globin protein in human erythrocytes differentiated from patient iPSCs after genome editing of the sickle point mutation. Stem Cells. 2015;33(5):1470–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hoban MD, Cost GJ, Mendel MC, Romero Z, Kaufman ML, Joglekar AV, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Voit RA, Hendel A, Pruett-Miller SM, Porteus MH. Nuclease-mediated gene editing by homologous recombination of the human globin locus. Nucleic Acids Res. 2014;42(2):1365–78.

    Article  CAS  PubMed  Google Scholar 

  63. Guda S, Brendel C, Renella R, Du P, Bauer DE, Canver MC, et al. miRNA-embedded shRNAs for lineage-specific BCL11A knockdown and hemoglobin F induction. Mol Ther. 2015;23(9):1465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature. 2015;527(7577):192–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Deng W, Rupon JW, Krivega I, Breda L, Motta I, Jahn KS, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158(4):849–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Manchinu MF, Marongiu MF, Poddie D, Casu C, Latini V, Simbula M, et al. In vivo activation of the human δ-globin gene: the therapeutic potential in β-thalassemiaassemic mice. Haematologica. 2014;99(1):76–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Samakoglu S, Lisowski L, Budak-Alpdogan T, Usachenko Y, Acuto S, Di Marzo R, et al. A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference. Nat Biotechnol. 2006;24(1):89–94.

    Article  CAS  PubMed  Google Scholar 

  68. Leboulch P. Gene therapy: primed for take-off. Nature. 2013;500(7462):280–2.

    Article  CAS  PubMed  Google Scholar 

  69. Thompson A, Rasko J, Hongeng S, Kwiatkowski J, Schiller G, von Kalle C, et al. Initial results from the Northstar study (HGB-204): a phase 1/2 study of gene therapy for β-thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex vivo with a lentiviral βΑ-T87Q -globin vector (LentiGlobin BB305 drug product). Blood. 2014;124(21):549.

    Google Scholar 

  70. Walters M, Rasko J, Hongeng S, Kwiatkowski J, Schiller G, Kletzel M, et al. Update of results from the Northstar study (HGB-204): a phase 1/2 study of gene therapy for beta-thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex-vivo with a lentiviral beta AT87Q-globin vector (LentiGlobin BB305 drug product). Blood. 2015;126(23):201.

    Google Scholar 

  71. Thompson A, Kwiatkowski J, Rasko J, Hongeng S, Schiller G, Anurathapan U, et al. Lentiglobin gene therapy for transfusion-dependent β-thalassemia: update from the Northstar Hgb-204 phase 1/2 clinical study. Blood. 2016;128(22):1175.

    Google Scholar 

  72. Ribeil J, Hacein-Bey-Abina S, Payen E, Semeraro M, Elisa M, Caccavelli L, et al. Update from the Hgb-205 phase 1/2 clinical study of lentiglobin gene therapy: sustained clinical benefit in severe hemoglobinopathies. Blood. 2016;128(22):2311.

    Google Scholar 

  73. Kanter J, Walters M, Hsieh MM, Lakshmanan K, Kwiatkowski J, Rammurti TK, et al. Initial results from study Hgb-206: interim results from a phase 1/2 clinical study of lentiglobin gene therapy for severe sickle cell disease. Blood. 2016;128:1176.

    Google Scholar 

  74. Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy. 2009;11(4):464–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Demuynck H, Pettengell R, de Campos E, Dexter TM, Testa NG. The capacity of peripheral blood stem cells mobilised with chemotherapy plus G-CSF to repopulate irradiated marrow stroma in vitro is similar to that of bone marrow. Eur J Cancer. 1992;28(2–3):381–6.

    CAS  PubMed  Google Scholar 

  76. Chao NJ, Schriber JR, Grimes K, Long GD, Negrin RS, Raimondi CM, et al. Granulocyte colony-stimulating factor “mobilized” peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. Blood. 1993;81(8):2031–5.

    CAS  PubMed  Google Scholar 

  77. Uchida N, Bonifacino A, Krouse AE, Metzger ME, Csako G, Lee-Stroka A, et al. Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34+ cells mobilized by G-CSF and plerixafor. Exp Hematol. 2011;39(7):795–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Choi E, Branch C, Cui MH, Yazdanbakhsh K, Mohandas N, Billett HH, 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.

    Article  CAS  PubMed  Google Scholar 

  79. Uchida N, Fujita A, Hsieh MM, Bonifacino AC, Krouse AE, Metzger ME, et al. Bone marrow as a hematopoietic stem cell source for gene therapy in sickle cell disease: evidence from rhesus and SCD patients.Hum Gene Ther Clin Dev. 2017 Apr 17. doi:10.1089/humc.2017.029. [Epub ahead of print].

  80. Hoban MD, Lumaquin D, Kuo CY, Romero Z, Long J, Ho M, et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol Ther. 2016;24(9):1561–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Cancer and Blood Disorders, Children’s National Medical Center, 111 Michigan Ave., NW, Washington, DC, 20010, USA

    Alexis Leonard

  2. Division of Blood and Marrow Transplantation, Children’s National Medical Center, Washington, DC, USA

    Allistair Abraham

Authors
  1. Alexis Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allistair Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexis Leonard .

Editor information

Editors and Affiliations

  1. Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USA

    Emily Riehm Meier

  2. Division of Blood and Marrow Transplantation, Children’s National Medical Center, Washington, DC, USA

    Allistair Abraham

  3. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA

    Ross M. Fasano

Additional information

This chapter is dedicated to Derek Persons, M.D., Ph.D. (1962–2015). A pioneer in the field of gene therapy for sickle cell disease, he made key contributions to the field, most important of which was to inspire the next generation to persevere in the goal of developing a widely available cure for this devastating disease.

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Cite this chapter

Leonard, A., Abraham, A. (2018). Gene Therapy: The Path Toward Becoming a Realistic Cure for Sickle Cell Disease. In: Meier, E., Abraham, A., Fasano, R. (eds) Sickle Cell Disease and Hematopoietic Stem Cell Transplantation . Springer, Cham. https://doi.org/10.1007/978-3-319-62328-3_15

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-62328-3_15

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-62327-6

  • Online ISBN: 978-3-319-62328-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation