Advertisement

pp 1-16 | Cite as

CRISPR/Cas9 for Sickle Cell Disease: Applications, Future Possibilities, and Challenges

  • Selami DemirciEmail author
  • Alexis Leonard
  • Juan J. Haro-Mora
  • Naoya Uchida
  • John F. TisdaleEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series

Abstract

Sickle cell disease (SCD) is an inherited monogenic disorder resulting in serious mortality and morbidity worldwide. Although the disease was characterized more than a century ago, there are only two FDA approved medications to lessen disease severity, and a definitive cure available to all patients with SCD is lacking. Rapid and substantial progress in genome editing approaches have proven valuable as a curative option given plausibility to either correct the underlying mutation in patient-derived hematopoietic stem/progenitor cells (HSPCs), induce fetal hemoglobin expression to circumvent sickling of red blood cells (RBCs), or create corrected induced pluripotent stem cells (iPSCs) among other approaches. Recent discovery of CRISPR/Cas9 has not only revolutionized genome engineering but has also brought the possibility of translating these concepts into a clinically meaningful reality. Here we summarize genome engineering applications using CRISPR/Cas9, addressing challenges and future perspectives of CRISPR/Cas9 as a curative option for SCD.

Keywords

Gene editing Gene therapy Hematopoietic stem cell transplantation Hemoglobinopathies Programmable endonucleases 

Abbreviations

AAV

Adeno-associated virus

BM

Bone marrow

Cas9

CRISPR associated protein 9

CRISPR

Clustered regularly interspaced short palindromic repeats

DSB

Double strand breaks

dCas9

Dead Cas9

ddPCR

Droplet digital PCR

eSpCas9

Enhanced specificity Streptococcus pyogenes Cas9

GVHD

Graft-vs-host disease

HbA

Adult hemoglobin

HbF

Fetal hemoglobin

HbS

Hemoglobin S

HDR

Homology directed repair

HLA

Human leukocyte antigen

HPFH

Hereditary persistence of fetal globin

HPLC

High performance liquid chromatography

HRI

Heme-regulated inhibitor

HSCT

Hematopoietic stem cell transplantation

HSPCs

Hematopoietic stem/progenitor cells

HU

Hydroxyurea

INDELs

Insertions/deletions

iPSCs

Induced pluripotent stem cells

LCR

Locus control region

MUD

Matched unrelated donor

NHEJ

Non-homologous end-joining

OTEs

Off-target effects

PACE

Phage-assisted continuous evolution

PAM

Protospacer-adjacent motif

QTL

Quantitative trait loci

RBCs

red blood cells

ScCas9

Streptococcus canis Cas9

SCD

Sickle cell disease

shRNAmiR

MicroRNA-adapted small hairpin (sh) RNAs

SpCas9-HF1

high fidelity Streptococcus pyogenes Cas9

TALENs

TAL-effector nucleases

UCBT

Umbilical cord blood transplantation

ZFNs

Zinc finger nucleases

Notes

Conflicts of Interest

The authors have no commercial, proprietary, or financial interest in the products described in this article.

References

  1. Adikusuma F, Piltz S, Corbett MA, Turvey M, McColl SR, Helbig KJ, Beard MR, Hughes J, Pomerantz RT, Thomas PQ (2018) Large deletions induced by Cas9 cleavage. Nature 560(7717):E8–E9Google Scholar
  2. Anders C, Bargsten K, Jinek M (2016) Structural plasticity of PAM recognition by engineered variants of the RNA-guided endonuclease Cas9. Mol Cell 61(6):895–902Google Scholar
  3. Antoniani C, Meneghini V, Lattanzi A, Felix T, Romano O, Magrin E, Weber L, Pavani G, El Hoss S, Kurita R (2018) Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human β-globin locus. Blood 131(17):1960–1973.  https://doi.org/10.1182/blood-2017-10-811505CrossRefGoogle Scholar
  4. Arnold SD, Brazauskas R, He N, Li Y, Aplenc R, Jin Z, Hall M, Atsuta Y, Dalal J, Hahn T (2017) Clinical risks and healthcare utilization of haematopoietic cell transplantation for sickle cell disease in the US using merged databases. Haematologica 102(11):1823–1832.  https://doi.org/10.3324/haematol.2017.169581CrossRefGoogle Scholar
  5. Bak RO, Gomez-Ospina N, Porteus MH (2018) Gene editing on center stage. Trends Genet 34(8):600–611Google Scholar
  6. Ballas SK (2009) The cost of health care for patients with sickle cell disease. Am J Hematol 84(6):320–322Google Scholar
  7. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L (2013) An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342(6155):253–257Google Scholar
  8. Bhatia M, Kolva E, Cimini L, Jin Z, Satwani P, Savone M, George D, Garvin J, Paz ML, Briamonte C (2015) Health-related quality of life after allogeneic hematopoietic stem cell transplantation for sickle cell disease. Biol Blood Marrow Transplant 21(4):666–672Google Scholar
  9. Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, Chen DD, Schupp PG, Vinjamur DS, Garcia SP (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527(7577):192–197Google Scholar
  10. Chakrabarti S, Bareford D (2007) A survey on patient perception of reduced-intensity transplantation in adults with sickle cell disease. Bone Marrow Transplant 39(8):447–451Google Scholar
  11. Charlesworth CT, Deshpande PS, Dever DP, Dejene B, Gomez-Ospina N, Mantri S, Pavel-Dinu M, Camarena J, Weinberg KI, Porteus MH (2018) Identification of pre-existing adaptive immunity to Cas9 proteins in humans. BioRxiv:243345.  https://doi.org/10.1101/243345
  12. Chatterjee P, Jakimo N, Jacobson JM (2018) Minimal PAM specificity of a highly similarSpCas9 ortholog. Sci Adv 4:eaau0766Google Scholar
  13. Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, Sternberg SH, Joung JK, Yildiz A, Doudna JA (2017) Enhanced proofreading governs CRISPR–Cas9 targeting accuracy. Nature 550(7676):407–410Google Scholar
  14. Chung JE, Magis W, Vu J, Heo S-J, Wartiovaara K, Walters MC, Kurita R, Nakamura Y, Boffelli D, Martin DI (2018) CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells. BioRxiv:335729.  https://doi.org/10.1101/335729
  15. Cromwell CR, Sung K, Park J, Krysler AR, Jovel J, Kim SK, Hubbard BP (2018) Incorporation of bridged nucleic acids into CRISPR RNAs improves Cas9 endonuclease specificity. Nat Commun 9(1):1448Google Scholar
  16. Demirci S, Uchida N, Tisdale JF (2018) Gene therapy for sickle cell disease: an update. Cytotherapy 20(7):899–910Google Scholar
  17. Dever DP, Bak RO, Reinisch A, Camarena J, Washington G, Nicolas CE, Pavel-Dinu M, Saxena N, Wilkens AB, Mantri S (2016) CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539(7629):384–389Google Scholar
  18. DeWitt MA, Magis W, Bray NL, Wang T, Berman JR, Urbinati F, Heo S-J, Mitros T, Muñoz DP, Boffelli D (2016) Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Science Transl Med 8(360):360ra134–360ra134Google Scholar
  19. Esrick EB, Bauer DE (2018) Genetic therapies for sickle cell disease. Semin Hematol 55(8):76–86Google Scholar
  20. Esrick EB, Brendel C, Manis JP, Armant MA, Negre H, Dansereau C, Ciuculescu MF, Patriarca S, Mackinnon B, Daley H (2018) Flipping the switch: initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. Blood 132:1023Google Scholar
  21. Ferreira AF, Calin GA, Picanço-Castro V, Kashima S, Covas DT, de Castro FA (2018) Hematopoietic stem cells from induced pluripotent stem cells–considering the role of microRNA as a cell differentiation regulator. J Cell Sci 131(4):jcs203018Google Scholar
  22. Fonfara I, Le Rhun A, Chylinski K, Makarova KS, Lecrivain A-L, Bzdrenga J, Koonin EV, Charpentier E (2013) Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems. Nucleic Acids Res 42(4):2577–2590Google Scholar
  23. Forget BG (1998) Molecular basis of hereditary persistence of fetal hemoglobin. Ann N Y Acad Sci 850(1):38–44Google Scholar
  24. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, Sander JD (2013) High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31(9):822–826Google Scholar
  25. Fu Y, Sander JD, Reyon D, Cascio VM, Joung JK (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32(3):279–284Google Scholar
  26. Fujita A, Uchida N, Haro-Mora JJ, Winkler T, Tisdale J (2016) β-globin-expressing definitive erythroid progenitor cells generated from embryonic and induced pluripotent stem cell-derived sacs. Stem Cells 34(6):1541–1552Google Scholar
  27. Glass Z, Lee M, Li Y, Xu Q (2018) Engineering the delivery system for CRISPR-based genome editing. Trends Biotechnol 36(2):173–185Google Scholar
  28. Gluckman E, Cappelli B, Bernaudin F, Labopin M, Volt F, Carreras J, Simões BP, Ferster A, Dupont S, De La Fuente J (2017) Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 129(11):1548–1556Google Scholar
  29. Grevet JD, Lan X, Hamagami N, Edwards CR, Sankaranarayanan L, Ji X, Bhardwaj SK, Face CJ, Posocco DF, Abdulmalik O (2018) Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science 361(6399):285–290Google Scholar
  30. Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB (2015) Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol 33(9):985–989.  https://doi.org/10.1038/nbt.3290CrossRefGoogle Scholar
  31. Hirano S, Nishimasu H, Ishitani R, Nureki O (2016) Structural basis for the altered PAM specificities of engineered CRISPR-Cas9. Mol Cell 61(6):886–894Google Scholar
  32. Hoban MD, Lumaquin D, Kuo CY, Romero Z, Long J, Ho M, Young CS, Mojadidi M, Fitz-Gibbon S, Cooper AR (2016a) CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol Ther 24(9):1561–1569Google Scholar
  33. Hoban MD, Orkin SH, Bauer DE (2016b) Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127(7):839–848Google Scholar
  34. Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF (2014) Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312(1):48–56Google Scholar
  35. Hu JH, Miller SM, Geurts MH, Tang W, Chen L, Sun N, Zeina CM, Gao X, Rees HA, Lin Z (2018) Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. Nature 556(7699):57–63Google Scholar
  36. Huang X, Wang Y, Yan W, Smith C, Ye Z, Wang J, Gao Y, Mendelsohn L, Cheng L (2015) 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 33(5):1470–1479Google Scholar
  37. Humbert O, Peterson CW, Norgaard ZK, Radtke S, Kiem H-P (2018) A nonhuman primate transplantation model to evaluate hematopoietic stem cell gene editing strategies for β-hemoglobinopathies. Mol Ther Methods Clin Dev 8:75–86Google Scholar
  38. Jiang C, Mei M, Li B, Zhu X, Zu W, Tian Y, Wang Q, Guo Y, Dong Y, Tan X (2017) A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res 27(3):440–443Google Scholar
  39. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821.  https://doi.org/10.1126/science.1225829CrossRefGoogle Scholar
  40. Kim YB, Komor AC, Levy JM, Packer MS, Zhao KT, Liu DR (2017) Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nat Biotechnol 35(4):371–376Google Scholar
  41. Kim S, Koo T, Jee H-G, Cho H-Y, Lee G, Lim D-G, Shin HS, Kim J-S (2018) CRISPR RNAs trigger innate immune responses in human cells. Genome Res 28:367–373.  https://doi.org/10.1101/gr.231936.117CrossRefGoogle Scholar
  42. Kleinstiver BP, Prew MS, Tsai SQ, Topkar VV, Nguyen NT, Zheng Z, Gonzales AP, Li Z, Peterson RT, Yeh J-RJ (2015a) Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523(7561):481–485Google Scholar
  43. Kleinstiver BP, Prew MS, Tsai SQ, Nguyen NT, Topkar VV, Zheng Z, Joung JK (2015b) Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition. Nat Biotechnol 33(12):1293–1298Google Scholar
  44. Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, Joung JK (2016) High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529(7587):490–495Google Scholar
  45. Kosicki M, Tomberg K, Bradley A (2018) Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol 36(8):765–771Google Scholar
  46. Lan X, Khandros E, Grevet JD, Peslak SA, Bhardwaj S, Keller CA, Giardine B, Garcia BA, Hardison RC, Shi J (2018) Domain-focused CRISPR-Cas9 screen identifies the E3 ubiquitin ligase substrate adaptor protein SPOP as a novel repressor of fetal hemoglobin. Blood 132:414Google Scholar
  47. Lanzkron S, Carroll CP, Haywood C Jr (2013) Mortality rates and age at death from sickle cell disease: US, 1979–2005. Public Health Rep 128(2):110–116Google Scholar
  48. Lee JK, Jeong E, Lee J, Jung M, Shin E, Kim Y-h, Lee K, Jung I, Kim D, Kim S (2018) Directed evolution of CRISPR-Cas9 to increase its specificity. Nat Commun 9(1):3048Google Scholar
  49. Leenay RT, Beisel CL (2017) Deciphering, communicating, and engineering the CRISPR PAM. J Mol Biol 429(2):177–191Google Scholar
  50. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G (2002) Locus control regions. Blood 100(9):3077–3086Google Scholar
  51. Li C, Ding L, Sun C-W, Wu L-C, Zhou D, Pawlik KM, Khodadadi-Jamayran A, Westin E, Goldman FD, Townes TM (2016) Novel HDAd/EBV reprogramming vector and highly efficient Ad/CRISPR-Cas sickle cell disease gene correction. Sci Rep 6:30422Google Scholar
  52. Li C, Psatha N, Sova P, Gil S, Wang H, Kim J, Kulkarni C, Valensisi C, Hawkins RD, Stamatoyannopoulos G (2018) Reactivation of γ-globin in adult β-YAC mice after ex vivo and in vivo hematopoietic stem cell genome editing. Blood 131:2915–2928.  https://doi.org/10.1182/blood-2018-03-838540CrossRefGoogle Scholar
  53. Liu P, Keller JR, Ortiz M, Tessarollo L, Rachel RA, Nakamura T, Jenkins NA, Copeland NG (2003) Bcl11a is essential for normal lymphoid development. Nat Immunol 4(6):525–532Google Scholar
  54. Liu N, Hargreaves VV, Zhu Q, Kurland JV, Hong J, Kim W, Sher F, Macias-Trevino C, Rogers JM, Kurita R (2018) Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell 173(2):430–442. e417Google Scholar
  55. Lobner K, Lanzkron S, Haywood C (2013) NIH and National Foundation Expenditures for sickle cell disease and cystic fibrosis are associated with Pubmed publications and FDA approvals. Blood 122:1739Google Scholar
  56. Lomova A, Clark DN, Campo-Fernandez B, Flores-Bjurström C, Kaufman ML, Fitz-Gibbon S, Wang X, Miyahira EY, Brown D, DeWitt MA (2018) Improving gene editing outcomes in human hematopoietic stem and progenitor cells by temporal control of DNA repair. Stem Cells:1–11.  https://doi.org/10.1002/stem.2935
  57. M Scharenberg A, Duchateau P, Smith J (2013) Genome engineering with TAL-effector nucleases and alternative modular nuclease technologies. Curr Gene Ther 13(4):291–303Google Scholar
  58. Magis W, DeWitt MA, Wyman SK, Vu JT, Heo S-J, Shao SJ, Hennig F, Romero ZG, Campo-Fernandez B, McNeill M (2018) In vivo selection for corrected β-globin alleles after CRISPR/Cas9 editing in human sickle hematopoietic stem cells enhances therapeutic potential. BioRxiv:432716.  https://doi.org/10.1101/432716
  59. Martin R, Ikeda K, Uchida N, Cromer MK, Nishimura T, Dever DP, Camarena J, Bak R, Lausten A, Jakobsen MR (2018) Selection-free, high frequency genome editing by homologous recombination of human pluripotent stem cells using Cas9 RNP and AAV6. BioRxiv:252163.  https://doi.org/10.1101/252163
  60. Martyn GE, Wienert B, Yang L, Shah M, Norton LJ, Burdach J, Kurita R, Nakamura Y, Pearson RC, Funnell AP (2018) Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat Genet 50(4):498–503Google Scholar
  61. Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell AP, Fisher C, Suciu M, Martyn GE, Norton LJ (2016) Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 351(6270):285–289Google Scholar
  62. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, Foglio M, Zelenika D, Boland A, Rooks H (2007) A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet 39(10):1197–1199Google Scholar
  63. Nihongaki Y, Kawano F, Nakajima T, Sato M (2015) Photoactivatable CRISPR-Cas9 for optogenetic genome editing. Nat Biotechnol 33(7):755–760Google Scholar
  64. Nishimasu H, Shi X, Ishiguro S, Gao L, Hirano S, Okazaki S, Noda T, Abudayyeh OO, Gootenberg JS, Mori H (2018) Engineered CRISPR-Cas9 nuclease with expanded targeting space. Science 361(6408):1259–1262Google Scholar
  65. Paikari A, Sheehan VA (2018) Fetal haemoglobin induction in sickle cell disease. Br J Haematol 180(2):189–200Google Scholar
  66. Park S, Gianotti-Sommer A, Molina-Estevez FJ, Vanuytsel K, Skvir N, Leung A, Rozelle SS, Shaikho EM, Weir I, Jiang Z (2017) A comprehensive, ethnically diverse library of sickle cell disease-specific induced Pluripotent stem cells. Stem Cell Rep 8(4):1076–1085Google Scholar
  67. Pattanayak V, Lin S, Guilinger JP, Ma E, Doudna JA, Liu DR (2013) High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nat Biotechnol 31(9):839–843Google Scholar
  68. Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, Grant AM, Hulihan MM (2016) Defining sickle cell disease mortality using a population-based surveillance system, 2004 through 2008. Public Health Rep 131(2):367–375Google Scholar
  69. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN (2013) Global burden of sickle cell anaemia in children under five, 2010–2050: modelling based on demographics, excess mortality, and interventions. PLoS Med 10(7):e1001484Google Scholar
  70. Psatha N, Reik A, Phelps S, Zhou Y, Dalas D, Yannaki E, Levasseur DN, Urnov FD, Holmes MC, Papayannopoulou T (2018) Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with β-thalassemia major. Mol Ther Methods Clin Dev 10:313–326Google Scholar
  71. Rahdar M, McMahon MA, Prakash TP, Swayze EE, Bennett CF, Cleveland DW (2015) Synthetic CRISPR RNA-Cas9–guided genome editing in human cells. Proc Natl Acad Sci 112(51):E7110–E7117Google Scholar
  72. Ran FA, Hsu PD, Lin C-Y, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154(6):1380–1389Google Scholar
  73. Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520(7546):186–191Google Scholar
  74. Roy B, Zhao J, Yang C, Luo W, Xiong T, Li Y, Fang X, Gao G, Singh CO, Madsen L (2018) CRISPR/cascade 9-mediated genome editing-challenges and opportunities. Front Genet 9:240–252Google Scholar
  75. Saenz C, Tisdale JF (2015) Assessing costs, benefits, and risks in chronic disease: taking the long view. Biol Blood Marrow Transplant 21(7):1149–1150Google Scholar
  76. Sankaran VG, Orkin SH (2013) The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 3(1):a011643Google Scholar
  77. Shim G, Kim D, Park GT, Jin H, Suh S-K, Oh Y-K (2017) Therapeutic gene editing: delivery and regulatory perspectives. Acta Pharmacol Sin 38(6):738–753Google Scholar
  78. Shin HY, Wang C, Lee HK, Yoo KH, Zeng X, Kuhns T, Yang CM, Mohr T, Liu C, Hennighausen L (2017) CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nat Commun 8:15464Google Scholar
  79. Simhadri VL, McGill J, McMahon S, Wang J, Jiang H, Sauna ZE (2018) Prevalence of pre-existing antibodies to CRISPR-associated nuclease Cas9 in the US population. Mol Ther Methods Clin Dev 10:105–112Google Scholar
  80. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351(6268):84–88Google Scholar
  81. Smith LA, Oyeku SO, Homer C, Zuckerman B (2006) Sickle cell disease: a question of equity and quality. Pediatrics 117(5):1763–1770Google Scholar
  82. Smith EC, Luc S, Croney DM, Woodworth MB, Greig LC, Fujiwara Y, Nguyen M, Sher F, Macklis JD, Bauer DE (2016) Strict in vivo specificity of the Bcl11a erythroid enhancer. Blood 128(19):2338–2342.  https://doi.org/10.1182/blood-2016-08-736249CrossRefGoogle Scholar
  83. Stamatoyannopoulos G, Wood W, Papayannopoulou T, Nute P (1975) A new form of hereditary persistence of fetal hemoglobin in blacks and its association with sickle cell trait. Blood 46(5):683–692Google Scholar
  84. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J (2003) Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 289(13):1645–1651Google Scholar
  85. Stoddard BL (2011) Homing endonucleases: from microbial genetic invaders to reagents for targeted DNA modification. Structure 19(1):7–15Google Scholar
  86. Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu Y-F, Goettel JA, Serrao E, Rowe RG, Malleshaiah M (2017) Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545(7655):432–438Google Scholar
  87. Tasan I, Jain S, Zhao H (2016) Use of genome-editing tools to treat sickle cell disease. Hum Genet 135(9):1011–1028Google Scholar
  88. Tsai SQ, Wyvekens N, Khayter C, Foden JA, Thapar V, Reyon D, Goodwin MJ, Aryee MJ, Joung JK (2014) Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat Biotechnol 32(6):569–576Google Scholar
  89. Tsai SQ, Zheng Z, Nguyen NT, Liebers M, Topkar VV, Thapar V, Wyvekens N, Khayter C, Iafrate AJ, Le LP (2015) GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol 33(2):187–197Google Scholar
  90. Tsang JC, Yu Y, Burke S, Buettner F, Wang C, Kolodziejczyk AA, Teichmann SA, Lu L, Liu P (2015) Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells. Genome Biol 16(1):178Google Scholar
  91. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G (2008) Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc Natl Acad Sci 105(5):1620–1625Google Scholar
  92. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11(9):636–646Google Scholar
  93. Vakulskas CA, Dever DP, Rettig GR, Turk R, Jacobi AM, Collingwood MA, Bode NM, McNeill MS, Yan S, Camarena J (2018) A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat Med 24(8):1216–1224Google Scholar
  94. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC (1996) Bone marrow transplantation for sickle cell disease. N Engl J Med 335(6):369–376Google Scholar
  95. Walters M, Patience M, Leisenring W, Rogers Z, Aquino V, Buchanan G, Roberts I, Yeager A, Hsu L, Adamkiewicz T (2001) Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 7(12):665–673Google Scholar
  96. Wang X, Thein SL (2018) Switching from fetal to adult hemoglobin. Nat Genet 50(4):478–480Google Scholar
  97. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, Thornburg CD, Rogers ZR, Kalpatthi RV (2011) Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377(9778):1663–1672Google Scholar
  98. Ware RE (2010) How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 115(26):5300–5311.  https://doi.org/10.1182/blood-2009-BloodCrossRefGoogle Scholar
  99. Watson J, Stahman AW, Bilello FP (1948) The significance of the paucity of sickle cells in newborn Negro infants. Obstet Gynecol Surv 3(6):819–820Google Scholar
  100. Wen J, Tao W, Hao S, Zu Y (2017) Cellular function reinstitution of offspring red blood cells cloned from the sickle cell disease patient blood post CRISPR genome editing. J Hematol Oncol 10(1):119Google Scholar
  101. Wiedenheft B, Sternberg SH, Doudna JA (2012) RNA-guided genetic silencing systems in bacteria and archaea. Nature 482(7385):331–338Google Scholar
  102. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG (2014) Non-viral vectors for gene-based therapy. Nat Rev Genet 15(8):541–555Google Scholar
  103. Zetsche B, Volz SE, Zhang F (2015) A split-Cas9 architecture for inducible genome editing and transcription modulation. Nat Biotechnol 33(2):139–142Google Scholar
  104. Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE (2007) Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood 110(3):1043–1047Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cellular and Molecular Therapeutics BranchNHLBI/NIDDK, National Institutes of HealthBethesdaUSA
  2. 2.Cellular and Molecular Therapeutics BranchNational Heart, Lung and Blood InstituteBethesdaUSA

Personalised recommendations