Use of genome-editing tools to treat sickle cell disease

Human Genetics

Volumn 135, Issue 9, 2016, Pages 1011-1028

  Tasan, Ipek ^a   Jain, Surbhi ^a   Zhao, Huimin ^a,b,c  

^a UNIVERSITY OF ILLINOIS AT URBANA CHAMPAIGN   (United States)

^b UNIVERSITY OF ILLINOIS AT URBANA CHAMPAIGN   (United States)

^c University of Illinois at Urbana Champaign   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL DNA; CRISPR ASSOCIATED PROTEIN; DNA BINDING PROTEIN; DOUBLE STRANDED DNA; GENOMIC DNA; GLOBIN; GUIDE RNA; HEMOGLOBIN BETA CHAIN; HEMOGLOBIN F; HEMOGLOBIN S; TRANSCRIPTION ACTIVATOR LIKE EFFECTOR NUCLEASE; TRANSCRIPTION FACTOR; ZINC FINGER NUCLEASE;

ALLOGENEIC STEM CELL TRANSPLANTATION; CD4+ T LYMPHOCYTE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; DNA CLEAVAGE; DNA END JOINING REPAIR; DNA REPAIR; DNA SEQUENCE; GENE LOCUS; GENE MUTATION; GENE TARGETING; GENETIC PROCEDURES; GENOME; GENOME EDITING TECHNIQUE; GLOBIN GENE; HOMOLOGOUS RECOMBINATION; HUMAN; INDUCED PLURIPOTENT STEM CELL; NONHUMAN; POINT MUTATION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN ENGINEERING; PROTEIN EXPRESSION; REVIEW; SICKLE CELL; SICKLE CELL ANEMIA; ANEMIA, SICKLE CELL; GENE EDITING; GENETICS;

ANEMIA, SICKLE CELL; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS; FETAL HEMOGLOBIN; GENE EDITING; HUMANS;

EID: 84973144109     PISSN: 03406717     EISSN: 14321203     Source Type: Journal    
DOI: 10.1007/s00439-016-1688-0     Document Type: Review

References (167)

1. Abil Z, Xiong X, Zhao H (2015) Synthetic biology for therapeutic applications. Mol Pharm 12:322–331
2. Ackermann M, Liebhaber S, Klusmann JH, Lachmann N (2015) Lost in translation: pluripotent stem cell-derived hematopoiesis. EMBO Mol Med 7:1388–1402
3. Aliyu ZY, Tumblin AR, Kato GJ (2006) Current therapy of sickle cell disease. Haematologica 91:7–10
4. Arora N, Daley GQ (2012) Pluripotent stem cells in research and treatment of hemoglobinopathies. Cold Spring Harb Perspect Med 2(4):a011841
5. Ashley-Koch A, Yang Q, Olney RS (2000) Sickle hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. Am J Epidemiol 151:839–845
6. Ballas SK (2015) Pathophysiology and principles of management of the many faces of the acute vaso-occlusive crisis in patients with sickle cell disease. Eur J Haematol 95:113–123
7. Barrangou R, Fremaux C, Deveau H et al (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315:1709–1712
8. Bauer DE, Kamran SC, Orkin SH (2012) Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders. Blood 120:2945–2953
9. Baum C, Düllmann J, Li Z et al (2003) Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 101:2099–2113
10. Berry M, Grosveld F, Dillon N (1992) A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin. Nature 358:499–502
11. Bianchi E, Zini R, Salati S et al (2010) c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression. Blood 116:e99–110
12. Bibikova M, Carroll D, Segal DJ et al (2001) Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Mol Cell Biol 21:289–297
13. Bibikova M, Golic M, Golic KG, Carroll D (2002) Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161:1169–1175
14. Boch J, Bonas U (2010) Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol 48:419–436
15. Boch J, Scholze H, Schornack S et al (2009) Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326:1509–1512
16. Bollag RJ, Waldman AS, Liskay RM (1989) Homologous recombination in mammalian cells. Annu Rev Genet 23:199–225
17. Borg J, Papadopoulos P, Georgitsi M et al (2010) Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet 42:801–805
18. Cai Y, Bak RO, Mikkelsen JG (2014) Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases. eLife 3:e01911
19. Canver MC, Smith EC, Sher F et al (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527:192–197
20. Carlson DF, Fahrenkrug SC, Hackett PB (2012) Targeting DNA with fingers and TALENs. Mol Ther Nucleic Acids 1:e3. doi:10.1038/mtna.2011.5
21. Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188:773–782
22. Cathomen T, Joung J (2008) Zinc-finger nucleases: the next generation emerges. Mol Ther 16:1200–1207
23. Chandrakasan S, Malik P (2014) Gene therapy for hemoglobinopathies. Hematol Oncol Clin North Am 28:199–216
24. Chang JC, Ye L, Kan YW (2006) Correction of the sickle cell mutation in embryonic stem cells. Proc Natl Acad Sci USA 103:1036–1040
25. Check E (2002) Gene therapy: a tragic setback. Nature 420:116–118
26. Choulika A, Perrin A, Dujon B, Nicolas JF (1995) Induction of homologous recombination in mammalian chromosomes by using the I-SceI system of Saccharomyces cerevisiae. Mol Cell Biol 15:1968–1973
27. Christian M, Cermak T, Doyle EL et al (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186:757–761
28. Chu VT, Weber T, Wefers B et al (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33:543–548
29. Collins FS, Metherall JE, Yamakawa M et al (1985) A point mutation in the A gamma-globin gene promoter in Greek hereditary persistence of fetal haemoglobin. Nature 313:325–326
30. Cong L, Ran FA, Cox D et al (2013) Multiplex genome engineering using CRISPR/Cas Systems. Science 339:819–823
31. Cornu TI, Thibodeau-Beganny S, Guhl E et al (2007) DNA-binding specificity is a major determinant of the activity and toxicity of zinc-finger nucleases. Mol Ther 16:352–358
32. Costa FC, Fedosyuk H, Neades R et al (2012) Induction of fetal hemoglobin in vivo mediated by a synthetic γ-globin zinc finger activator. Anemia 2012:e507894
33. Cottle RN, Lee CM, Archer D, Bao G (2015) Controlled delivery of β-globin-targeting TALENs and CRISPR/Cas9 into mammalian cells for genome editing using microinjection. Sci Rep 5:16031. doi:10.1038/srep16031
34. Cox DBT, Platt RJ, Zhang F (2015) Therapeutic genome editing: prospects and challenges. Nat Med 21:121–131
35. Cradick TJ, Fine EJ, Antico CJ, Bao G (2013) CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res 41:9584–9592
36. Deng W, Rupon JW, Krivega I et al (2014) Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158:849–860
37. Deng C, Capecchi MR (1992) Reexamination of gene targeting frequency as a function of the extent of homology between the targeting vector and the target locus. Mol Cell Biol 12:3365–3371
38. DeWitt M, Magis W, Bray NL et al (2016) Efficient correction of the sickle mutation in human hematopoietic stem cells using a Cas9 ribonucleoprotein complex. bioRxiv. doi:10.1101/036236
39. Dong A, Rivella S, Breda L (2013) Gene therapy for hemoglobinopathies: progress and challenges. Transl Res 161:293–306
40. Doyon Y, Vo TD, Mendel MC et al (2011) Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures. Nat Methods 8:74–79
41. Filipe A, Li Q, Deveaux S et al (1999) Regulation of embryonic/fetal globin genes by nuclear hormone receptors: a novel perspective on hemoglobin switching. EMBO J 18:687–697
42. Focosi D, Amabile G, Di Ruscio A et al (2014) Induced pluripotent stem cells in hematology: current and future applications. Blood Cancer J 4:e211
43. Frenette PS, Atweh GF (2007) Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest 117:850–858
44. Frock RL, Hu J, Meyers RM et al (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179–186
45. Fu Y, Sander JD, Reyon D et al (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32:279–284
46. Gaj T, Guo J, Kato Y et al (2012) Targeted gene knockout by direct delivery of zinc-finger nuclease proteins. Nat Methods 9:805–807
47. Galarneau G, Palmer CD, Sankaran VG et al (2010) Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 42:1049–1051
48. Geisinger JM, Turan S, Hernandez S et al (2016) In vivo blunt-end cloning through CRISPR/Cas9-facilitated non-homologous end-joining. Nucleic Acids Res. doi:10.1093/nar/gkv1542
49. Genovese P, Schiroli G, Escobar G et al (2014) Targeted genome editing in human repopulating hematopoietic stem cells. Nature 510:235–240
50. Goncz KK, Prokopishyn NL, Chow BL et al (2002) Application of SFHR to gene therapy of monogenic disorders. Gene Ther 9:691–694
51. Gräslund T, Li X, Magnenat L et al (2005) Exploring strategies for the design of artificial transcription factors: targeting sites proximal to known regulatory regions for the induction of γ-globin expression and the treatment of sickle cell disease. J Biol Chem 280:3707–3714
52. Hacein-Bey-Abina S, Garrigue A, Wang GP et al (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118:3132–3142
53. Händel EM, Alwin S, Cathomen T (2009) Expanding or restricting the target site repertoire of zinc-finger nucleases: the inter-domain linker as a major determinant of target site selectivity. Mol Ther 17:104–111
54. Hanna J, Wernig M, Markoulaki S et al (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318:1920–1923
55. Hassell KL (2010) Population estimates of sickle cell disease in the U.S. Am J Prev Med 38:S512–521
56. Hendrie PC, Russell DW (2005) Gene targeting with viral vectors. Mol Ther 12:9–17
57. Hoban MD, Cost GJ, Mendel MC et al (2015) Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125:2597–2604
58. Hockemeyer D, Soldner F, Beard C et al (2009) Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol 27:851–857
59. Holkers M, Maggio I, Henriques SFD et al (2014) Adenoviral vector DNA for accurate genome editing with engineered nucleases. Nat Methods 11:1051–1057
60. Hsu PD, Scott DA, Weinstein JA et al (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31:827–832
61. Huang X, Wang Y, Yan W et al (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 33:1470–1479
62. Iannone R, Casella JF, Fuchs EJ et al (2003) Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant 9:519–528
63. Ingram VM (1956) A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178:792–794
64. Isalan M (2012) Zinc-finger nucleases: how to play two good hands. Nat Methods 9:32–34
65. Jane SM, Nienhuis AW, Cunningham JM (1995) Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein. EMBO J 14:97–105
66. John A, Brylka H, Wiegreffe C et al (2012) Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development. Development 139:1831–1841
67. Johnson RD, Jasin M (2001) Double-strand-break-induced homologous recombination in mammalian cells. Biochem Soc Trans 29:196–201
68. Khan IF, Hirata RK, Russell DW (2011) AAV-mediated gene targeting methods for human cells. Nat Protoc 6:482–501
69. Kim C (2014) Disease modeling and cell based therapy with iPSC: future therapeutic option with fast and safe application. Blood Res 49:7–14
70. Kim S, Kim D, Cho SW et al (2014) Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res 24(6):1012–1019
71. Kim Y, Kweon J, Kim A et al (2013) A library of TAL effector nucleases spanning the human genome. Nat Biotechnol 31:251–258
72. Kim D, Bae S, Park J et al (2015) Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells. Nat Methods 12:237–243
73. Kleinstiver BP, Pattanayak V, Prew MS et al (2016) High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529:490–495
74. Kuo TY, Chen CY, Hsueh YP (2010) Bcl11A/CTIP1 mediates the effect of the glutamate receptor on axon branching and dendrite outgrowth. J Neurochem 114:1381–1392
75. LaFountaine JS, Fathe K, Smyth HDC (2015) Delivery and therapeutic applications of gene editing technologies ZFNs, TALENs, and CRISPR/Cas9. Int J Pharm 494:180–194
76. Lanzkron S, Strouse JJ, Wilson R et al (2008) Systematic review: hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med 148:939–955
77. Lanzkron S, Carroll CP, Haywood C (2013) Mortality rates and age at death from sickle cell disease: US, 1979–2005. Public Health Rep 128:110–116
78. Larochelle A, Dunbar CE (2008) HOXB4 and retroviral vectors: adding fuel to the fire. J Clin Invest 118:1350–1353
79. Lengerke C, Daley GQ (2010) Autologous blood cell therapies from pluripotent stem cells. Blood Rev 24:27–37
80. Levasseur DN, Ryan TM, Pawlik KM, Townes TM (2003) Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102:4312–4319
81. Li T, Huang S, Jiang WZ et al (2011a) TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain. Nucleic Acids Res 39:359–372
82. Li M, Suzuki K, Qu J et al (2011b) Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. Cell Res 21:1740–1744
83. Liang J, Chao R, Abil Z et al (2014) FairyTALE: a high-throughput TAL effector synthesis platform. ACS Synth Biol 3:67–73
84. Liang X, Potter J, Kumar S et al (2015a) Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J Biotechnol 208:44–53
85. Liang P, Xu Y, Zhang X et al (2015b) CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6:363–372
86. Lin S, Staahl BT, Alla RK, Doudna JA (2014) Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. eLife 3:e04766
87. Lin J, Chen H, Luo L et al (2015) Creating a monomeric endonuclease TALE-I-SceI with high specificity and low genotoxicity in human cells. Nucleic Acids Res 43:1112–1122
88. Liu P, Keller JR, Ortiz M et al (2003) Bcl11a is essential for normal lymphoid development. Nat Immunol 4:525–532
89. Liu J, Gaj T, Patterson JT et al (2014) Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. PLoS ONE 9:e85755
90. Locatelli F, Pagliara D (2012) Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. Pediatr Blood Cancer 59:372–376
91. Lombardo A, Genovese P, Beausejour CM et al (2007) Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol 25:1298–1306
92. Luo Y, Zhu D, Zhang Z et al (2015) Integrative analysis of CRISPR/Cas9 target sites in the human HBB gene. BioMed Res Int 2015:514709. doi:10.1155/2015/514709
93. Maggio I, Gonçalves MAFV (2015) Genome editing at the crossroads of delivery, specificity, and fidelity. Trends Biotechnol 33:280–291
94. Mali P, Yang L, Esvelt KM et al (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826
95. Maresca M, Lin VG, Guo N, Yang Y (2013) Obligate Ligation-Gated Recombination (ObLiGaRe): custom-designed nuclease-mediated targeted integration through nonhomologous end joining. Genome Res 23:539–546
96. Maruyama T, Dougan SK, Truttmann MC et al (2015) Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol 33:538–542
97. Menzel S, Garner C, Gut I et al (2007) A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet 39:1197–1199
98. Miller JC, Holmes MC, Wang J et al (2007) An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25:778–785
99. Mock U, Riecken K, Berdien B et al (2014) Novel lentiviral vectors with mutated reverse transcriptase for mRNA delivery of TALE nucleases. Sci Rep 4:6409
100. Mock U, Machowicz R, Hauber I et al (2015) mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucleic Acids Res 43:5560–5571
101. Moscou MJ, Bogdanove AJ (2009) A simple cipher governs DNA recognition by TAL effectors. Science 326:1501
102. Mussolino C, Morbitzer R, Lütge F et al (2011) A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res 39:9283–9293
103. Noordermeer D, de Laat W (2008) Joining the loops: beta-globin gene regulation. IUBMB Life 60:824–833
104. O’Geen H, Henry IM, Bhakta MS et al (2015) A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture. Nucleic Acids Res 43:3389–3404
105. Ochiai H (2015) Single-base pair genome editing in human cells by using site-specific endonucleases. Int J Mol Sci 16:21128–21137
106. Paradowski K (2015) Pathophysiology and perioperative management of sickle cell disease. J Perioper Pract 25:101–104
107. Pawliuk R, Westerman KA, Fabry ME et al (2001) Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294:2368–2371
108. 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 Ther 17:245–252
109. Pfeiffer P, Goedecke W, Obe G (2000) Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations. Mutagenesis 15:289–302
110. Piel FB (2016) The present and future global burden of the inherited disorders of hemoglobin. Hematol Oncol Clin North Am 30:327–341
111. Porteus MH (2006) Mammalian gene targeting with designed zinc finger nucleases. Mol Ther 13:438–446
112. Ramakrishna S, Kwaku Dad AB, Beloor J et al (2014) Gene disruption by cell-penetrating peptide-mediated delivery of Cas9 protein and guide RNA. Genome Res 24:1020–1027
113. Ramalingam S, Annaluru N, Kandavelou K, Chandrasegaran S (2014) TALEN-mediated generation and genetic correction of disease-specific human induced pluripotent stem cells. Curr Gene Ther 14:461–472
114. Ran FA, Hsu PD, Lin CY et al (2013a) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154:1380–1389
115. Ran FA, Hsu PD, Wright J et al (2013b) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308
116. Renneville A, Galen PV, Canver MC et al (2015) EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression. Blood 126:1930–1939
117. Ru R, Yao Y, Yu S et al (2013) Targeted genome engineering in human induced pluripotent stem cells by penetrating TALENs. Cell Regen 2:5
118. Sadelain M, Rivella S, Lisowski L et al (2004) Globin gene transfer for treatment of the β-thalassemias and sickle cell disease. Best Pract Res Clin Haematol 17:517–534
119. Sakuma T, Nakade S, Sakane Y et al (2016) MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems. Nat Protoc 11:118–133
120. Sebastiano V, Maeder ML, Angstman JF et al (2011) In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells 29:1717–1726
121. Sedgewick AE, Timofeev N, Sebastiani P et al (2008) BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies. Blood Cells Mol Dis 41:255–258
122. Serjeant GR (2013) The natural history of sickle cell disease. Cold Spring Harb Perspect Med 3:a011783
123. Shenoy S (2011) Hematopoietic stem cell transplantation for sickle cell disease: current practice and emerging trends. Hematol Am Soc Hematol Educ Program 2011:273–279
124. Singh VK, Kalsan M, Kumar N et al (2015) Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol 3:2. doi:10.3389/fcell.2015.00002
125. Slaymaker IM, Gao L, Zetsche B et al (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351:84–88
126. Slukvin II (2013) Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells. Blood 122:4035–4046
127. Smithies O, Gregg RG, Boggs SS et al (1985) Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature 317:230–234
128. Song J, Yang D, Xu J et al (2016) RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency. Nat Commun 7:10548. doi:10.1038/ncomms10548
129. Steinberg MH, Sebastiani P (2012) Genetic modifiers of sickle cell disease. Am J Hematol 87:795–803
130. Steinberg MH, Lu ZH, Barton FB et al (1997) Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Blood 89:1078–1088
131. Sun N, Zhao H (2013) Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Biotechnol Bioeng 110:1811–1821
132. Sun N, Zhao H (2014) Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. Biotechnol Bioeng 111:1048–1053
133. Sun N, Liang J, Abil Z, Zhao H (2012) Optimized TAL effector nucleases (TALENs) for use in treatment of sickle cell disease. Mol BioSyst 8:1255–1263
134. Sunshine HR, Hofrichter J, Eaton WA (1978) Requirement for therapeutic inhibition of sickle haemoglobin gelation. Nature 275:238–240
135. Suzuki K, Yu C, Qu J et al (2014) Targeted gene correction minimally impacts whole-genome mutational load in human-disease-specific induced pluripotent stem cell clones. Cell Stem Cell 15:31–36
136. Szczepek M, Brondani V, Büchel J et al (2007) Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat Biotechnol 25:786–793
137. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
138. Tebas P, Stein D, Tang WW et al (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370:901–910
139. Thein SL, Menzel S, Peng X et al (2007) Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci USA 104:11346–11351
140. Thomas KR, Capecchi MR (1987) Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51:503–512
141. Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4:346–358
142. Tsai SQ, Wyvekens N, Khayter C et al (2014) Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat Biotechnol 32:569–576
143. Tsai SQ, Zheng Z, Nguyen NT et al (2015) GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol 33:187–197
144. Tsang JCH, Yu Y, Burke S et al (2015) Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells. Genome Biol 16:178. doi:10.1186/s13059-015-0739-5
145. 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 β-thalassemia. Proc Natl Acad Sci USA 105:1620–1625
146. Urnov FD, Rebar EJ, Holmes MC et al (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11:636–646
147. van Dijk TB, Gillemans N, Pourfarzad F et al (2010) Fetal globin expression is regulated by Friend of Prmt1. Blood 116:4349–4352
148. Vasquez KM, Marburger K, Intody Z, Wilson JH (2001) Manipulating the mammalian genome by homologous recombination. Proc Natl Acad Sci USA 98:8403–8410
149. Voit RA, Hendel A, Pruett-Miller SM, Porteus MH (2014) Nuclease-mediated gene editing by homologous recombination of the human globin locus. Nucleic Acids Res 42:1365–1378
150. Wah DA, Bitinaite J, Schildkraut I, Aggarwal AK (1998) Structure of FokI has implications for DNA cleavage. Proc Natl Acad Sci USA 95:10564–10569
151. Walters MC, Patience M, Leisenring W et al (2001) Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 7:665–673
152. Wang L, Menendez P, Shojaei F et al (2005) Generation of hematopoietic repopulating cells from human embryonic stem cells independent of ectopic HOXB4 expression. J Exp Med 201:1603–1614
153. Wang X, Wang Y, Wu X et al (2015) Unbiased detection of off-target cleavage by CRISPR-Cas9 and TALENs using integrase-defective lentiviral vectors. Nat Biotechnol 33:175–178
154. Weatherall DJ, Clegg JB (2001) Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ 79:704–712
155. Wilber A, Tschulena U, Hargrove PW et al (2010) A zinc-finger transcriptional activator designed to interact with the gamma-globin gene promoters enhances fetal hemoglobin production in primary human adult erythroblasts. Blood 115:3033–3041
156. Wilber A, Hargrove PW, Kim YS et al (2011a) Therapeutic levels of fetal hemoglobin in erythroid progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer. Blood 117:2817–2826
157. Wilber A, Nienhuis AW, Persons DA (2011b) Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood 117:3945–3953
158. Woods NB, Bottero V, Schmidt M et al (2006) Gene therapy: therapeutic gene causing lymphoma. Nature 440:1123
159. Wright AV, Nuñez JK, Doudna JA (2016) Biology and applications of CRISPR systems: harnessing nature’s toolbox for genome engineering. Cell 164:29–44
160. Wu LC, Sun CW, Ryan TM et al (2006) Correction of sickle cell disease by homologous recombination in embryonic stem cells. Blood 108:1183–1188
161. Wu CJ, Gladwin M, Tisdale J et al (2007) Mixed haematopoietic chimerism for sickle cell disease prevents intravascular haemolysis. Br J Haematol 139:504–507
162. Xiao-Jie L, Hui-Ying X, Zun-Ping K et al (2015) CRISPR-Cas9: a new and promising player in gene therapy. J Med Genet 52:289–296
163. Xu J, Sankaran VG, Ni M et al (2010) Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev 24:783–798
164. Zhang X-B, Beard BC, Trobridge GD et al (2008) High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. J Clin Invest 118:1502–1510
165. Zhou W, Zhao Q, Sutton R et al (2004) The role of p22 NF-E4 in human globin gene switching. J Biol Chem 279:26227–26232
166. Zhou D, Liu K, Sun CW et al (2010) KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 42:742–744
167. Zou J, Mali P, Huang X et al (2011) Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 118:4599–4608