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Use of genome-editing tools to treat sickle cell disease

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Abstract

Recent advances in genome-editing techniques have made it possible to modify any desired DNA sequence by employing programmable nucleases. These next-generation genome-modifying tools are the ideal candidates for therapeutic applications, especially for the treatment of genetic disorders like sickle cell disease (SCD). SCD is an inheritable monogenic disorder which is caused by a point mutation in the β-globin gene. Substantial success has been achieved in the development of supportive therapeutic strategies for SCD, but unfortunately there is still a lack of long-term universal cure. The only existing curative treatment is based on allogeneic stem cell transplantation from healthy donors; however, this treatment is applicable to a limited number of patients only. Hence, a universally applicable therapy is highly desirable. In this review, we will discuss the three programmable nucleases that are commonly used for genome-editing purposes: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). We will continue by exemplifying uses of these methods to correct the sickle cell mutation. Additionally, we will present induction of fetal globin expression as an alternative approach to cure sickle cell disease. We will conclude by comparing the three methods and explaining the concerns about their use in therapy.

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References

  • Abil Z, Xiong X, Zhao H (2015) Synthetic biology for therapeutic applications. Mol Pharm 12:322–331

    Article  CAS  PubMed  Google Scholar 

  • Ackermann M, Liebhaber S, Klusmann JH, Lachmann N (2015) Lost in translation: pluripotent stem cell-derived hematopoiesis. EMBO Mol Med 7:1388–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aliyu ZY, Tumblin AR, Kato GJ (2006) Current therapy of sickle cell disease. Haematologica 91:7–10

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arora N, Daley GQ (2012) Pluripotent stem cells in research and treatment of hemoglobinopathies. Cold Spring Harb Perspect Med 2(4):a011841

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Barrangou R, Fremaux C, Deveau H et al (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315:1709–1712

    Article  CAS  PubMed  Google Scholar 

  • Bauer DE, Kamran SC, Orkin SH (2012) Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders. Blood 120:2945–2953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baum C, Düllmann J, Li Z et al (2003) Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 101:2099–2113

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bibikova M, Golic M, Golic KG, Carroll D (2002) Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161:1169–1175

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boch J, Bonas U (2010) Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol 48:419–436

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Bollag RJ, Waldman AS, Liskay RM (1989) Homologous recombination in mammalian cells. Annu Rev Genet 23:199–225

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai Y, Bak RO, Mikkelsen JG (2014) Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases. eLife 3:e01911

    Article  PubMed  PubMed Central  Google Scholar 

  • Canver MC, Smith EC, Sher F et al (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527:192–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188:773–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cathomen T, Joung J (2008) Zinc-finger nucleases: the next generation emerges. Mol Ther 16:1200–1207

    Article  CAS  PubMed  Google Scholar 

  • Chandrakasan S, Malik P (2014) Gene therapy for hemoglobinopathies. Hematol Oncol Clin North Am 28:199–216

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Check E (2002) Gene therapy: a tragic setback. Nature 420:116–118

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christian M, Cermak T, Doyle EL et al (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186:757–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Cong L, Ran FA, Cox D et al (2013) Multiplex genome engineering using CRISPR/Cas Systems. Science 339:819–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cox DBT, Platt RJ, Zhang F (2015) Therapeutic genome editing: prospects and challenges. Nat Med 21:121–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng W, Rupon JW, Krivega I et al (2014) Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158:849–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Google Scholar 

  • Dong A, Rivella S, Breda L (2013) Gene therapy for hemoglobinopathies: progress and challenges. Transl Res 161:293–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyon Y, Vo TD, Mendel MC et al (2011) Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures. Nat Methods 8:74–79

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frenette PS, Atweh GF (2007) Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest 117:850–858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Fu Y, Sander JD, Reyon D et al (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32:279–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • Genovese P, Schiroli G, Escobar G et al (2014) Targeted genome editing in human repopulating hematopoietic stem cells. Nature 510:235–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goncz KK, Prokopishyn NL, Chow BL et al (2002) Application of SFHR to gene therapy of monogenic disorders. Gene Ther 9:691–694

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hassell KL (2010) Population estimates of sickle cell disease in the U.S. Am J Prev Med 38:S512–521

    Article  PubMed  Google Scholar 

  • Hendrie PC, Russell DW (2005) Gene targeting with viral vectors. Mol Ther 12:9–17

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holkers M, Maggio I, Henriques SFD et al (2014) Adenoviral vector DNA for accurate genome editing with engineered nucleases. Nat Methods 11:1051–1057

    Article  CAS  PubMed  Google Scholar 

  • Hsu PD, Scott DA, Weinstein JA et al (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31:827–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Ingram VM (1956) A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178:792–794

    Article  CAS  PubMed  Google Scholar 

  • Isalan M (2012) Zinc-finger nucleases: how to play two good hands. Nat Methods 9:32–34

    Article  CAS  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson RD, Jasin M (2001) Double-strand-break-induced homologous recombination in mammalian cells. Biochem Soc Trans 29:196–201

    Article  CAS  PubMed  Google Scholar 

  • Khan IF, Hirata RK, Russell DW (2011) AAV-mediated gene targeting methods for human cells. Nat Protoc 6:482–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim C (2014) Disease modeling and cell based therapy with iPSC: future therapeutic option with fast and safe application. Blood Res 49:7–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim Y, Kweon J, Kim A et al (2013) A library of TAL effector nucleases spanning the human genome. Nat Biotechnol 31:251–258

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • Larochelle A, Dunbar CE (2008) HOXB4 and retroviral vectors: adding fuel to the fire. J Clin Invest 118:1350–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lengerke C, Daley GQ (2010) Autologous blood cell therapies from pluripotent stem cells. Blood Rev 24:27–37

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang J, Chao R, Abil Z et al (2014) FairyTALE: a high-throughput TAL effector synthesis platform. ACS Synth Biol 3:67–73

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Liang P, Xu Y, Zhang X et al (2015b) CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6:363–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Liu P, Keller JR, Ortiz M et al (2003) Bcl11a is essential for normal lymphoid development. Nat Immunol 4:525–532

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Locatelli F, Pagliara D (2012) Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. Pediatr Blood Cancer 59:372–376

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • Maggio I, Gonçalves MAFV (2015) Genome editing at the crossroads of delivery, specificity, and fidelity. Trends Biotechnol 33:280–291

    Article  CAS  PubMed  Google Scholar 

  • Mali P, Yang L, Esvelt KM et al (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moscou MJ, Bogdanove AJ (2009) A simple cipher governs DNA recognition by TAL effectors. Science 326:1501

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noordermeer D, de Laat W (2008) Joining the loops: beta-globin gene regulation. IUBMB Life 60:824–833

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ochiai H (2015) Single-base pair genome editing in human cells by using site-specific endonucleases. Int J Mol Sci 16:21128–21137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paradowski K (2015) Pathophysiology and perioperative management of sickle cell disease. J Perioper Pract 25:101–104

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Piel FB (2016) The present and future global burden of the inherited disorders of hemoglobin. Hematol Oncol Clin North Am 30:327–341

    Article  PubMed  Google Scholar 

  • Porteus MH (2006) Mammalian gene targeting with designed zinc finger nucleases. Mol Ther 13:438–446

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ran FA, Hsu PD, Wright J et al (2013b) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Renneville A, Galen PV, Canver MC et al (2015) EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression. Blood 126:1930–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serjeant GR (2013) The natural history of sickle cell disease. Cold Spring Harb Perspect Med 3:a011783

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Slaymaker IM, Gao L, Zetsche B et al (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351:84–88

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinberg MH, Sebastiani P (2012) Genetic modifiers of sickle cell disease. Am J Hematol 87:795–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinberg MH, Lu ZH, Barton FB et al (1997) Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Blood 89:1078–1088

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Sunshine HR, Hofrichter J, Eaton WA (1978) Requirement for therapeutic inhibition of sickle haemoglobin gelation. Nature 275:238–240

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas KR, Capecchi MR (1987) Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51:503–512

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urnov FD, Rebar EJ, Holmes MC et al (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11:636–646

    Article  CAS  PubMed  Google Scholar 

  • van Dijk TB, Gillemans N, Pourfarzad F et al (2010) Fetal globin expression is regulated by Friend of Prmt1. Blood 116:4349–4352

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vasquez KM, Marburger K, Intody Z, Wilson JH (2001) Manipulating the mammalian genome by homologous recombination. Proc Natl Acad Sci USA 98:8403–8410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Weatherall DJ, Clegg JB (2001) Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ 79:704–712

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilber A, Nienhuis AW, Persons DA (2011b) Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood 117:3945–3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woods NB, Bottero V, Schmidt M et al (2006) Gene therapy: therapeutic gene causing lymphoma. Nature 440:1123

    Article  CAS  PubMed  Google Scholar 

  • Wright AV, Nuñez JK, Doudna JA (2016) Biology and applications of CRISPR systems: harnessing nature’s toolbox for genome engineering. Cell 164:29–44

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We gratefully acknowledge financial support from the National Institutes of Health (1U54DK107965) and Centennial Chair Professorship (HZ) in the Department of Chemical and Biomolecular Engineering at the University of Illinois at Urbana-Champaign.

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Authors and Affiliations

  1. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Ipek Tasan, Surbhi Jain & Huimin Zhao

  2. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

  3. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

  4. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

  5. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

  6. Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

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  1. Ipek Tasan
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  2. Surbhi Jain
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Correspondence to Huimin Zhao.

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Tasan, I., Jain, S. & Zhao, H. Use of genome-editing tools to treat sickle cell disease. Hum Genet 135, 1011–1028 (2016). https://doi.org/10.1007/s00439-016-1688-0

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