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Review Article

基因治疗作为镰状细胞病的新前沿

卷 29, 期 3, 2022

发表于: 23 August, 2021

页: [453 - 466] 页: 14

弟呕挨: 10.2174/0929867328666210527092456

价格: $65

摘要

镰状细胞病（SCD）是由β珠蛋白基因的点突变引起的最常见的单基因疾病之一。这种突变导致血红蛋白（Hb）在氧合减少的条件下聚合，导致僵硬的镰状红细胞和溶血性贫血。这种明确定义的基本分子机制使SCD成为精确治疗的典型靶点。突变β珠蛋白及其下游病理生理学都是深入研究的药理学靶点。SCD也是一种非常适合基因治疗等生物干预的疾病。造血干细胞（HSC）移植和基因治疗平台（如慢病毒载体和基因编辑策略）的最新进展扩大了SCD患者的潜在治疗选择。本文综述了SCD精准治疗的最新进展以及自体HSC基因治疗SCD的临床前和临床进展。

关键词: 镰状细胞病，基因治疗，基因编辑，造血干细胞，干细胞移植，精准治疗。

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[1]
Kato, G.J.; Piel, F.B.; Reid, C.D.; Gaston, M.H.; Ohene-Frempong, K.; Krishnamurti, L.; Smith, W.R.; Panepinto, J.A.; Weatherall, D.J.; Costa, F.F.; Vichinsky, E.P. Sickle cell disease. Nat. Rev. Dis. Primers, 2018, 4, 18010.
[http://dx.doi.org/10.1038/nrdp.2018.10] [PMID: 29542687]
[2]
Hassell, K.L. Population estimates of sickle cell disease in the U.S. Am. J. Prev. Med., 2010, 38(4)(Suppl.), S512-S521.
[http://dx.doi.org/10.1016/j.amepre.2009.12.022] [PMID: 20331952]
[3]
Pauling, L.; Itano, H.A. Sickle cell anemia, a molecular disease. Sci., 1949, 109(2835), 443.
[PMID: 18213804]
[4]
Ware, R.E.; de Montalembert, M.; Tshilolo, L.; Abboud, M.R. Sickle cell disease. Lancet, 2017, 390(10091), 311-323.
[http://dx.doi.org/10.1016/S0140-6736(17)30193-9] [PMID: 28159390]
[5]
Nader, E.; Romana, M.; Connes, P. The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front. Immunol., 2020, 11, 454.
[http://dx.doi.org/10.3389/fimmu.2020.00454] [PMID: 32231672]
[6]
Taylor, S.M.; Parobek, C.M.; Fairhurst, R.M. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect. Dis., 2012, 12(6), 457-468.
[http://dx.doi.org/10.1016/S1473-3099(12)70055-5] [PMID: 22445352]
[7]
Ojodu, J.; Hulihan, M.M.; Pope, S.N.; Grant, A.M. Centers for Disease Control and Prevention (CDC). Incidence of sickle cell trait-United States, 2010. MMWR Morb. Mortal. Wkly. Rep., 2014, 63(49), 1155-1158.
[PMID: 25503918]
[8]
Thoreson, C.K.; O’Connor, M.Y.; Ricks, M.; Chung, S.T.; Sumner, A.E. Sickle Cell Trait from a Metabolic, Renal, and Vascular Perspective: Linking History, Knowledge, and Health. J. Racial Ethn. Health Disparities, 2015, 2(3), 330-335.
[http://dx.doi.org/10.1007/s40615-014-0077-4] [PMID: 26322267]
[9]
Naik, R.P.; Smith-Whitley, K.; Hassell, K.L.; Umeh, N.I.; de Montalembert, M.; Sahota, P.; Haywood, C., Jr; Jenkins, J.; Lloyd-Puryear, M.A.; Joiner, C.H.; Bonham, V.L.; Kato, G.J. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review. Ann. Intern. Med., 2018, 169(9), 619-627.
[http://dx.doi.org/10.7326/M18-1161] [PMID: 30383109]
[10]
Grosse, S.D.; Odame, I.; Atrash, H.K.; Amendah, D.D.; Piel, F.B.; Williams, T.N. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am. J. Prev. Med., 2011, 41(6)(Suppl. 4), S398-S405.
[http://dx.doi.org/10.1016/j.amepre.2011.09.013] [PMID: 22099364]
[11]
Lanzkron, S.; Carroll, C.P.; Haywood, C., Jr Mortality rates and age at death from sickle cell disease: U.S., 1979-2005. Public Health Rep., 2013, 128(2), 110-116.
[http://dx.doi.org/10.1177/003335491312800206] [PMID: 23450875]
[12]
Elmariah, H.; Garrett, M.E.; De Castro, L.M.; Jonassaint, J.C.; Ataga, K.I.; Eckman, J.R.; Ashley-Koch, A.E.; Telen, M.J. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol., 2014, 89(5), 530-535.
[http://dx.doi.org/10.1002/ajh.23683] [PMID: 24478166]
[13]
Pecker, L.H.; Naik, R.P. The current state of sickle cell trait: implications for reproductive and genetic counseling. Hematology (Am. Soc. Hematol. Educ. Program), 2018, 2018(1), 474-481.
[http://dx.doi.org/10.1182/asheducation-2018.1.474] [PMID: 30504348]
[14]
Obstetrics, A.C.o. ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet. Gynecol., 2007, 109(1), 229-237.
[http://dx.doi.org/10.1097/00006250-200701000-00055] [PMID: 17197616]
[15]
Xu, K.; Shi, Z.M.; Veeck, L.L.; Hughes, M.R.; Rosenwaks, Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA, 1999, 281(18), 1701-1706.
[http://dx.doi.org/10.1001/jama.281.18.1701] [PMID: 10328069]
[16]
Cordeiro Mitchell, C.N.; Pradhan, A.; Singh, B.; Naik, R.P.; Baker, V.L.; Lanzkron, S.M.; Christianson, M.S.; Pecker, L.H. Primary prevention of sickle cell disease using preimplantation genetic testing and in vitro fertilization is cost-effective. Am. J. Hematol., 2020.
[http://dx.doi.org/10.1002/ajh.25974] [PMID: 32818300]
[17]
Rai, P.; Ataga, K.I. Drug Therapies for the Management of Sickle Cell Disease. F1000 Res., 2020, 9, 9.
[http://dx.doi.org/10.12688/f1000research.22433.1] [PMID: 32765834]
[18]
Telen, M.J.; Malik, P.; Vercellotti, G.M. Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat. Rev. Drug Discov., 2019, 18(2), 139-158.
[http://dx.doi.org/10.1038/s41573-018-0003-2] [PMID: 30514970]
[19]
Saunthararajah, Y. Targeting sickle cell disease root-cause pathophysiology with small molecules. Haematologica, 2019, 104(9), 1720-1730.
[http://dx.doi.org/10.3324/haematol.2018.207530] [PMID: 31399526]
[20]
Odièvre, M.H.; Bony, V.; Benkerrou, M.; Lapouméroulie, C.; Alberti, C.; Ducrocq, R.; Jacqz-Aigrain, E.; Elion, J.; Cartron, J.P. Modulation of erythroid adhesion receptor expression by hydroxyurea in children with sickle cell disease. Haematologica, 2008, 93(4), 502-510.
[http://dx.doi.org/10.3324/haematol.12070] [PMID: 18322255]
[21]
Agrawal, R.K.; Patel, R.K.; Shah, V.; Nainiwal, L.; Trivedi, B. Hydroxyurea in sickle cell disease: drug review. Indian J. Hematol. Blood Transfus., 2014, 30(2), 91-96.
[http://dx.doi.org/10.1007/s12288-013-0261-4] [PMID: 24839362]
[22]
Dufu, K.; Patel, M.; Oksenberg, D.; Cabrales, P. GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions. Clin. Hemorheol. Microcirc., 2018, 70(1), 95-105.
[http://dx.doi.org/10.3233/CH-170340] [PMID: 29660913]
[23]
Vichinsky, E.; Hoppe, C.C.; Ataga, K.I.; Ware, R.E.; Nduba, V.; El-Beshlawy, A.; Hassab, H.; Achebe, M.M.; Alkindi, S.; Brown, R.C.; Diuguid, D.L.; Telfer, P.; Tsitsikas, D.A.; Elghandour, A.; Gordeuk, V.R.; Kanter, J.; Abboud, M.R.; Lehrer-Graiwer, J.; Tonda, M.; Intondi, A.; Tong, B.; Howard, J.; Investigators, H.T. HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N. Engl. J. Med., 2019, 381(6), 509-519.
[http://dx.doi.org/10.1056/NEJMoa1903212] [PMID: 31199090]
[24]
Blair, H.A. Voxelotor: First Approval. Drugs, 2020, 80(2), 209-215.
[http://dx.doi.org/10.1007/s40265-020-01262-7] [PMID: 32020554]
[25]
Oder, E.; Safo, M.K.; Abdulmalik, O.; Kato, G.J. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br. J. Haematol., 2016, 175(1), 24-30.
[http://dx.doi.org/10.1111/bjh.14264] [PMID: 27605087]
[26]
Embury, S.H.; Matsui, N.M.; Ramanujam, S.; Mayadas, T.N.; Noguchi, C.T.; Diwan, B.A.; Mohandas, N.; Cheung, A.T. The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood, 2004, 104(10), 3378-3385.
[http://dx.doi.org/10.1182/blood-2004-02-0713] [PMID: 15271798]
[27]
Matsui, N.M.; Borsig, L.; Rosen, S.D.; Yaghmai, M.; Varki, A.; Embury, S.H. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood, 2001, 98(6), 1955-1962.
[http://dx.doi.org/10.1182/blood.V98.6.1955] [PMID: 11535535]
[28]
Blair, H.A. Crizanlizumab: First Approval. Drugs, 2020, 80(1), 79-84.
[http://dx.doi.org/10.1007/s40265-019-01254-2] [PMID: 31933169]
[29]
Ataga, K.I.; Kutlar, A.; Kanter, J.; Liles, D.; Cancado, R.; Friedrisch, J.; Guthrie, T.H.; Knight-Madden, J.; Alvarez, O.A.; Gordeuk, V.R.; Gualandro, S.; Colella, M.P.; Smith, W.R.; Rollins, S.A.; Stocker, J.W.; Rother, R.P. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N. Engl. J. Med., 2017, 376(5), 429-439.
[http://dx.doi.org/10.1056/NEJMoa1611770] [PMID: 27959701]
[30]
Niihara, Y.; Miller, S.T.; Kanter, J.; Lanzkron, S.; Smith, W.R.; Hsu, L.L.; Gordeuk, V.R.; Viswanathan, K.; Sarnaik, S.; Osunkwo, I.; Guillaume, E.; Sadanandan, S.; Sieger, L.; Lasky, J.L.; Panosyan, E.H.; Blake, O.A.; New, T.N.; Bellevue, R.; Tran, L.T.; Razon, R.L.; Stark, C.W.; Neumayr, L.D.; Vichinsky, E.P. Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N. Engl. J. Med., 2018, 379(3), 226-235.
[http://dx.doi.org/10.1056/NEJMoa1715971] [PMID: 30021096]
[31]
Robinson, T.M.; Fuchs, E.J. Allogeneic stem cell transplantation for sickle cell disease. Curr. Opin. Hematol., 2016, 23(6), 524-529.
[http://dx.doi.org/10.1097/MOH.0000000000000282] [PMID: 27496639]
[32]
Eapen, M.; Brazauskas, R.; Walters, M.C.; Bernaudin, F.; Bo-Subait, K.; Fitzhugh, C.D.; Hankins, J.S.; Kanter, J.; Meerpohl, J.J.; Bolaños-Meade, J.; Panepinto, J.A.; Rondelli, D.; Shenoy, S.; Williamson, J.; Woolford, T.L.; Gluckman, E.; Wagner, J.E.; Tisdale, J.F. Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study. Lancet Haematol., 2019, 6(11), e585-e596.
[http://dx.doi.org/10.1016/S2352-3026(19)30154-1] [PMID: 31495699]
[33]
de la Fuente, J.; Dhedin, N.; Koyama, T.; Bernaudin, F.; Kuentz, M.; Karnik, L.; Socié, G.; Culos, K.A.; Brodsky, R.A.; DeBaun, M.R.; Kassim, A.A. Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative. Biol. Blood Marrow Transplant., 2019, 25(6), 1197-1209.
[http://dx.doi.org/10.1016/j.bbmt.2018.11.027] [PMID: 30500440]
[34]
Limerick, E.; Fitzhugh, C. Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease. J. Clin. Med., 2019, 8(11)E1997
[http://dx.doi.org/10.3390/jcm8111997] [PMID: 31731790]
[35]
Wagner, J.E. Cord blood 2.0: state of the art and future directions in transplant medicine. Blood Res., 2019, 54(1), 7-9.
[http://dx.doi.org/10.5045/br.2019.54.1.7] [PMID: 30956957]
[36]
Rafii, H.; Bernaudin, F.; Rouard, H.; Vanneaux, V.; Ruggeri, A.; Cavazzana, M.; Gauthereau, V.; Stanislas, A.; Benkerrou, M.; De Montalembert, M.; Ferry, C.; Girot, R.; Arnaud, C.; Kamdem, A.; Gour, J.; Touboul, C.; Cras, A.; Kuentz, M.; Rieux, C.; Volt, F.; Cappelli, B.; Maio, K.T.; Paviglianiti, A.; Kenzey, C.; Larghero, J.; Gluckman, E. Family cord blood banking for sickle cell disease: a twenty-year experience in two dedicated public cord blood banks. Haematologica, 2017, 102(6), 976-983.
[http://dx.doi.org/10.3324/haematol.2016.163055] [PMID: 28302713]
[37]
Abraham, A.; Cluster, A.; Jacobsohn, D.; Delgado, D.; Hulbert, M.L.; Kukadiya, D.; Murray, L.; Shenoy, S. Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial. Biol. Blood Marrow Transplant., 2017, 23(9), 1587-1592.
[http://dx.doi.org/10.1016/j.bbmt.2017.05.027] [PMID: 28578010]
[38]
Wagner, J.E., Jr; Brunstein, C.G.; Boitano, A.E.; DeFor, T.E.; McKenna, D.; Sumstad, D.; Blazar, B.R.; Tolar, J.; Le, C.; Jones, J.; Cooke, M.P.; Bleul, C.C. Phase I/II Trial of StemRegenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-Alone Graft. Cell Stem Cell, 2016, 18(1), 144-155.
[http://dx.doi.org/10.1016/j.stem.2015.10.004] [PMID: 26669897]
[39]
Miyoshi, H.; Blömer, U.; Takahashi, M.; Gage, F.H.; Verma, I.M. Development of a self-inactivating lentivirus vector. J. Virol., 1998, 72(10), 8150-8157.
[http://dx.doi.org/10.1128/JVI.72.10.8150-8157.1998] [PMID: 9733856]
[40]
Hacein-Bey-Abina, S.; Garrigue, A.; Wang, G.P.; Soulier, J.; Lim, A.; Morillon, E.; Clappier, E.; Caccavelli, L.; Delabesse, E.; Beldjord, K.; Asnafi, V.; MacIntyre, E.; Dal Cortivo, L.; Radford, I.; Brousse, N.; Sigaux, F.; Moshous, D.; Hauer, J.; Borkhardt, A.; Belohradsky, B.H.; Wintergerst, U.; Velez, M.C.; Leiva, L.; Sorensen, R.; Wulffraat, N.; Blanche, S.; Bushman, F.D.; Fischer, A.; Cavazzana-Calvo, M. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest., 2008, 118(9), 3132-3142.
[http://dx.doi.org/10.1172/JCI35700] [PMID: 18688285]
[41]
Ryu, B.Y.; Evans-Galea, M.V.; Gray, J.T.; Bodine, D.M.; Persons, D.A.; Nienhuis, A.W. An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation. Blood, 2008, 111(4), 1866-1875.
[http://dx.doi.org/10.1182/blood-2007-04-085506] [PMID: 17991809]
[42]
Escors, D.; Breckpot, K. Lentiviral vectors in gene therapy: their current status and future potential. Arch. Immunol. Ther. Exp. (Warsz.), 2010, 58(2), 107-119.
[http://dx.doi.org/10.1007/s00005-010-0063-4] [PMID: 20143172]
[43]
Milone, M.C.; O’Doherty, U. Clinical use of lentiviral vectors. Leukemia, 2018, 32(7), 1529-1541.
[http://dx.doi.org/10.1038/s41375-018-0106-0] [PMID: 29654266]
[44]
Morgan, R.A.; Unti, M.J.; Aleshe, B.; Brown, D.; Osborne, K.S.; Koziol, C.; Ayoub, P.G.; Smith, O.B.; O’Brien, R.; Tam, C.; Miyahira, E.; Ruiz, M.; Quintos, J.P.; Senadheera, S.; Hollis, R.P.; Kohn, D.B. Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small β-Globin Locus Control Region Elements. Mol. Ther., 2020, 28(1), 328-340.
[http://dx.doi.org/10.1016/j.ymthe.2019.09.020] [PMID: 31628051]
[45]
Sawado, T.; Halow, J.; Bender, M.A.; Groudine, M. The beta -globin locus control region (LCR) functions primarily by enhancing the transition from transcription initiation to elongation. Genes Dev., 2003, 17(8), 1009-1018.
[http://dx.doi.org/10.1101/gad.1072303] [PMID: 12672691]
[46]
Ghiaccio, V.; Chappell, M.; Rivella, S.; Breda, L. Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges. Mol. Diagn. Ther., 2019, 23(2), 173-186.
[http://dx.doi.org/10.1007/s40291-019-00383-4] [PMID: 30701409]
[47]
Novak, U.; Harris, E.A.; Forrester, W.; Groudine, M.; Gelinas, R. High-level beta-globin expression after retroviral transfer of locus activation region-containing human beta-globin gene derivatives into murine erythroleukemia cells. Proc. Natl. Acad. Sci. USA, 1990, 87(9), 3386-3390.
[http://dx.doi.org/10.1073/pnas.87.9.3386] [PMID: 2333288]
[48]
Karlsson, S.; Bodine, D.M.; Perry, L.; Papayannopoulou, T.; Nienhuis, A.W. Expression of the human beta-globin gene following retroviral-mediated transfer into multipotential hematopoietic progenitors of mice. Proc. Natl. Acad. Sci. USA, 1988, 85(16), 6062-6066.
[http://dx.doi.org/10.1073/pnas.85.16.6062] [PMID: 3413076]
[49]
Dzierzak, E.A.; Papayannopoulou, T.; Mulligan, R.C. 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.
[http://dx.doi.org/10.1038/331035a0] [PMID: 2893284]
[50]
Cone, R.D.; Weber-Benarous, A.; Baorto, D.; Mulligan, R.C. Regulated expression of a complete human beta-globin gene encoded by a transmissible retrovirus vector. Mol. Cell. Biol., 1987, 7(2), 887-897.
[http://dx.doi.org/10.1128/MCB.7.2.887] [PMID: 3029570]
[51]
McCune, S.L.; Reilly, M.P.; Chomo, M.J.; Asakura, T.; Townes, T.M. Recombinant human hemoglobins designed for gene therapy of sickle cell disease. Proc. Natl. Acad. Sci. USA, 1994, 91(21), 9852-9856.
[http://dx.doi.org/10.1073/pnas.91.21.9852] [PMID: 7937904]
[52]
Levasseur, D.N.; Ryan, T.M.; Reilly, M.P.; McCune, S.L.; Asakura, T.; Townes, T.M. A recombinant human hemoglobin with anti-sickling properties greater than fetal hemoglobin. J. Biol. Chem., 2004, 279(26), 27518-27524.
[http://dx.doi.org/10.1074/jbc.M402578200] [PMID: 15084588]
[53]
Negre, O.; Eggimann, A.V.; Beuzard, Y.; Ribeil, J.A.; Bourget, P.; Borwornpinyo, S.; Hongeng, S.; Hacein-Bey, S.; Cavazzana, M.; Leboulch, P.; Payen, E. Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β(A(T87Q))-Globin Gene. Hum. Gene Ther., 2016, 27(2), 148-165.
[http://dx.doi.org/10.1089/hum.2016.007] [PMID: 26886832]
[54]
Ribeil, J.A.; Hacein-Bey-Abina, S.; Payen, E.; Magnani, A.; Semeraro, M.; Magrin, E.; Caccavelli, L.; Neven, B.; Bourget, P.; El Nemer, W.; Bartolucci, P.; Weber, L.; Puy, H.; Meritet, J.F.; Grevent, D.; Beuzard, Y.; Chrétien, S.; Lefebvre, T.; Ross, R.W.; Negre, O.; Veres, G.; Sandler, L.; Soni, S.; de Montalembert, M.; Blanche, S.; Leboulch, P.; Cavazzana, M. Gene Therapy in a Patient with Sickle Cell Disease. N. Engl. J. Med., 2017, 376(9), 848-855.
[http://dx.doi.org/10.1056/NEJMoa1609677] [PMID: 28249145]
[55]
Urbinati, F.; Wherley, J.; Geiger, S.; Fernandez, B.C.; Kaufman, M.L.; Cooper, A.; Romero, Z.; Marchioni, F.; Reeves, L.; Read, E.; Nowicki, B.; Grassman, E.; Viswanathan, S.; Wang, X.; Hollis, R.P.; Kohn, D.B. Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease. Cytotherapy, 2017, 19(9), 1096-1112.
[http://dx.doi.org/10.1016/j.jcyt.2017.06.002] [PMID: 28733131]
[56]
Poletti, V.; Urbinati, F.; Charrier, S.; Corre, G.; Hollis, R.P.; Campo Fernandez, B.; Martin, S.; Rothe, M.; Schambach, A.; Kohn, D.B.; Mavilio, F. Pre-clinical Development of a Lentiviral Vector Expressing the Anti-sickling βAS3 Globin for Gene Therapy for Sickle Cell Disease. Mol. Ther. Methods Clin. Dev., 2018, 11, 167-179.
[http://dx.doi.org/10.1016/j.omtm.2018.10.014] [PMID: 30533448]
[57]
Sankaran, V.G.; Orkin, S.H. The switch from fetal to adult hemoglobin. Cold Spring Harb. Perspect. Med., 2013, 3(1)a011643
[http://dx.doi.org/10.1101/cshperspect.a011643] [PMID: 23209159]
[58]
Forget, B.G. Molecular basis of hereditary persistence of fetal hemoglobin. Ann. N. Y. Acad. Sci., 1998, 850, 38-44.
[http://dx.doi.org/10.1111/j.1749-6632.1998.tb10460.x] [PMID: 9668525]
[59]
Joly, P.; Lacan, P.; Garcia, C.; Couprie, N.; Francina, A. Identification and molecular characterization of four new large deletions in the beta-globin gene cluster. Blood Cells Mol. Dis., 2009, 43(1), 53-57.
[http://dx.doi.org/10.1016/j.bcmd.2009.01.017] [PMID: 19269866]
[60]
Pestina, T.I.; Hargrove, P.W.; Jay, D.; Gray, J.T.; Boyd, K.M.; Persons, D.A. Correction of murine sickle cell disease using gamma-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin. Mol. Ther., 2009, 17(2), 245-252.
[http://dx.doi.org/10.1038/mt.2008.259] [PMID: 19050697]
[61]
Perumbeti, A.; Higashimoto, T.; Urbinati, F.; Franco, R.; Meiselman, H.J.; Witte, D.; Malik, P. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood, 2009, 114(6), 1174-1185.
[http://dx.doi.org/10.1182/blood-2009-01-201863] [PMID: 19474450]
[62]
Kiem, H.P.; Arumugam, P.I.; Burtner, C.R.; Fox, C.F.; Beard, B.C.; Dexheimer, P.; Adair, J.E.; Malik, P. Pigtailed macaques as a model to study long-term safety of lentivirus vector-mediated gene therapy for hemoglobinopathies. Mol. Ther. Methods Clin. Dev., 2014, 1, 14055.
[http://dx.doi.org/10.1038/mtm.2014.55] [PMID: 26052523]
[63]
Norton, L.J.; Funnell, A.P.W.; Burdach, J.; Wienert, B.; Kurita, R.; Nakamura, Y.; Philipsen, S.; Pearson, R.C.M.; Quinlan, K.G.R.; Crossley, M. KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells. Blood Adv., 2017, 1(11), 685-692.
[http://dx.doi.org/10.1182/bloodadvances.2016002303] [PMID: 29296711]
[64]
Wienert, B.; Funnell, A.P.; Norton, L.J.; Pearson, R.C.; Wilkinson-White, L.E.; Lester, K.; Vadolas, J.; Porteus, M.H.; Matthews, J.M.; Quinlan, K.G.; Crossley, M. Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin. Nat. Commun., 2015, 6, 7085.
[http://dx.doi.org/10.1038/ncomms8085] [PMID: 25971621]
[65]
Martyn, G.E.; Wienert, B.; Yang, L.; Shah, M.; Norton, L.J.; Burdach, J.; Kurita, R.; Nakamura, Y.; Pearson, R.C.M.; Funnell, A.P.W.; Quinlan, K.G.R.; Crossley, M. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat. Genet., 2018, 50(4), 498-503.
[http://dx.doi.org/10.1038/s41588-018-0085-0] [PMID: 29610478]
[66]
Orkin, S.H.; Bauer, D.E. Emerging Genetic Therapy for Sickle Cell Disease. Annu. Rev. Med., 2019, 70, 257-271.
[http://dx.doi.org/10.1146/annurev-med-041817-125507] [PMID: 30355263]
[67]
Li, C.; Psatha, N.; Gil, S.; Wang, H.; Papayannopoulou, T.; Lieber, A. HDAd5/35++ Adenovirus Vector Expressing Anti-CRISPR Peptides Decreases CRISPR/Cas9 Toxicity in Human Hematopoietic Stem Cells. Mol. Ther. Methods Clin. Dev., 2018, 9, 390-401.
[http://dx.doi.org/10.1016/j.omtm.2018.04.008] [PMID: 30038942]
[68]
Li, C.; Psatha, N.; Sova, P.; Gil, S.; Wang, H.; Kim, J.; Kulkarni, C.; Valensisi, C.; Hawkins, R.D.; Stamatoyannopoulos, G.; Lieber, A. Reactivation of γ-globin in adult β-YAC mice after ex vivo and in vivo hematopoietic stem cell genome editing. Blood, 2018, 131(26), 2915-2928.
[http://dx.doi.org/10.1182/blood-2018-03-838540] [PMID: 29789357]
[69]
Liu, N.; Hargreaves, V.V.; Zhu, Q.; Kurland, J.V.; Hong, J.; Kim, W.; Sher, F.; Macias-Trevino, C.; Rogers, J.M.; Kurita, R.; Nakamura, Y.; Yuan, G.C.; Bauer, D.E.; Xu, J.; Bulyk, M.L.; Orkin, S.H. Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. Cell, 2018., 173(2), 430-442 e417.,
[http://dx.doi.org/10.1016/j.cell.2018.03.016]
[70]
Métais, J.Y.; Doerfler, P.A.; Mayuranathan, T.; Bauer, D.E.; Fowler, S.C.; Hsieh, M.M.; Katta, V.; Keriwala, S.; Lazzarotto, C.R.; Luk, K.; Neel, M.D.; Perry, S.S.; Peters, S.T.; Porter, S.N.; Ryu, B.Y.; Sharma, A.; Shea, D.; Tisdale, J.F.; Uchida, N.; Wolfe, S.A.; Woodard, K.J.; Wu, Y.; Yao, Y.; Zeng, J.; Pruett-Miller, S.; Tsai, S.Q.; Weiss, M.J. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv., 2019, 3(21), 3379-3392.
[http://dx.doi.org/10.1182/bloodadvances.2019000820] [PMID: 31698466]
[71]
Weber, L.; Frati, G.; Felix, T.; Hardouin, G.; Casini, A.; Wollenschlaeger, C.; Meneghini, V.; Masson, C.; De Cian, A.; Chalumeau, A.; Mavilio, F.; Amendola, M.; Andre-Schmutz, I.; Cereseto, A.; El Nemer, W.; Concordet, J.P.; Giovannangeli, C.; Cavazzana, M.; Miccio, A. Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Sci. Adv., 2020, 6(7)eaay9392
[http://dx.doi.org/10.1126/sciadv.aay9392] [PMID: 32917636]
[72]
Wu, Y.; Zeng, J.; Roscoe, B.P.; Liu, P.; Yao, Q.; Lazzarotto, C.R.; Clement, K.; Cole, M.A.; Luk, K.; Baricordi, C.; Shen, A.H.; Ren, C.; Esrick, E.B.; Manis, J.P.; Dorfman, D.M.; Williams, D.A.; Biffi, A.; Brugnara, C.; Biasco, L.; Brendel, C.; Pinello, L.; Tsai, S.Q.; Wolfe, S.A.; Bauer, D.E. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med., 2019, 25(5), 776-783.
[http://dx.doi.org/10.1038/s41591-019-0401-y] [PMID: 30911135]
[73]
Brendel, C.; Guda, S.; Renella, R.; Bauer, D.E.; Canver, M.C.; Kim, Y.J.; Heeney, M.M.; Klatt, D.; Fogel, J.; Milsom, M.D.; Orkin, S.H.; Gregory, R.I.; Williams, D.A. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J. Clin. Invest., 2016, 126(10), 3868-3878.
[http://dx.doi.org/10.1172/JCI87885] [PMID: 27599293]
[74]
Brendel, C.; Negre, O.; Rothe, M.; Guda, S.; Parsons, G.; Harris, C.; McGuinness, M.; Abriss, D.; Tsytsykova, A.; Klatt, D.; Bentler, M.; Pellin, D.; Christiansen, L.; Schambach, A.; Manis, J.; Trebeden-Negre, H.; Bonner, M.; Esrick, E.; Veres, G.; Armant, M.; Williams, D.A. Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Mol. Ther. Methods Clin. Dev., 2020, 17, 589-600.
[http://dx.doi.org/10.1016/j.omtm.2020.03.015] [PMID: 32300607]
[75]
Carroll, D. Genome engineering with targetable nucleases. Annu. Rev. Biochem., 2014, 83, 409-439.
[http://dx.doi.org/10.1146/annurev-biochem-060713-035418] [PMID: 24606144]
[76]
Shin, J.J.; Schröder, M.S.; Caiado, F.; Wyman, S.K.; Bray, N.L.; Bordi, M.; Dewitt, M.A.; Vu, J.T.; Kim, W.T.; Hockemeyer, D.; Manz, M.G.; Corn, J.E. Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells. Cell Rep., 2020, 32(9)108093
[http://dx.doi.org/10.1016/j.celrep.2020.108093] [PMID: 32877675]
[77]
Traxler, E.A.; Yao, Y.; Wang, Y.D.; Woodard, K.J.; Kurita, R.; Nakamura, Y.; Hughes, J.R.; Hardison, R.C.; Blobel, G.A.; Li, C.; Weiss, M.J. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med., 2016, 22(9), 987-990.
[http://dx.doi.org/10.1038/nm.4170] [PMID: 27525524]
[78]
Chang, K.H.; Smith, S.E.; Sullivan, T.; Chen, K.; Zhou, Q.; West, J.A.; Liu, M.; Liu, Y.; Vieira, B.F.; Sun, C.; Hong, V.P.; Zhang, M.; Yang, X.; Reik, A.; Urnov, F.D.; Rebar, E.J.; Holmes, M.C.; Danos, O.; Jiang, H.; Tan, S. Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells. Mol. Ther. Methods Clin. Dev., 2017, 4, 137-148.
[http://dx.doi.org/10.1016/j.omtm.2016.12.009] [PMID: 28344999]
[79]
Zeng, J.; Wu, Y.; Ren, C.; Bonanno, J.; Shen, A.H.; Shea, D.; Gehrke, J.M.; Clement, K.; Luk, K.; Yao, Q.; Kim, R.; Wolfe, S.A.; Manis, J.P.; Pinello, L.; Joung, J.K.; Bauer, D.E. Therapeutic base editing of human hematopoietic stem cells. Nat. Med., 2020, 26(4), 535-541.
[http://dx.doi.org/10.1038/s41591-020-0790-y] [PMID: 32284612]
[80]
Rees, H.A.; Liu, D.R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet., 2018, 19(12), 770-788.
[http://dx.doi.org/10.1038/s41576-018-0059-1] [PMID: 30323312]
[81]
Viprakasit, V.; Wiriyasateinkul, A.; Sattayasevana, B.; Miles, K.L.; Laosombat, V. Hb G-Makassar [beta6(A3)Glu-->Ala; codon 6 (GAG-->GCG)]: molecular characterization, clinical, and hematological effects. Hemoglobin, 2002, 26(3), 245-253.
[http://dx.doi.org/10.1081/HEM-120015028] [PMID: 12403489]
[82]
Dever, D.P.; Bak, R.O.; Reinisch, A.; Camarena, J.; Washington, G.; Nicolas, C.E.; Pavel-Dinu, M.; Saxena, N.; Wilkens, A.B.; Mantri, S.; Uchida, N.; Hendel, A.; Narla, A.; Majeti, R.; Weinberg, K.I.; Porteus, M.H. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature, 2016, 539(7629), 384-389.
[http://dx.doi.org/10.1038/nature20134] [PMID: 27820943]
[83]
Hoban, M.D.; Lumaquin, D.; Kuo, C.Y.; Romero, Z.; Long, J.; Ho, M.; Young, C.S.; Mojadidi, M.; Fitz-Gibbon, S.; Cooper, A.R.; Lill, G.R.; Urbinati, F.; Campo-Fernandez, B.; Bjurstrom, C.F.; Pellegrini, M.; Hollis, R.P.; Kohn, D.B. CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells. Mol. Ther., 2016, 24(9), 1561-1569.
[http://dx.doi.org/10.1038/mt.2016.148] [PMID: 27406980]
[84]
Park, S.H.; Lee, C.M.; Dever, D.P.; Davis, T.H.; Camarena, J.; Srifa, W.; Zhang, Y.; Paikari, A.; Chang, A.K.; Porteus, M.H.; Sheehan, V.A.; Bao, G. Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. Nucleic Acids Res., 2019, 47(15), 7955-7972.
[http://dx.doi.org/10.1093/nar/gkz475] [PMID: 31147717]
[85]
DeWitt, M.A.; Magis, W.; Bray, N.L.; Wang, T.; Berman, J.R.; Urbinati, F.; Heo, S.J.; Mitros, T.; Muñoz, D.P.; Boffelli, D.; Kohn, D.B.; Walters, M.C.; Carroll, D.; Martin, D.I.; Corn, J.E. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl. Med., 2016, 8(360)360ra134
[http://dx.doi.org/10.1126/scitranslmed.aaf9336] [PMID: 27733558]
[86]
Falanga, A.; Marchetti, M.; Evangelista, V.; Manarini, S.; Oldani, E.; Giovanelli, S.; Galbusera, M.; Cerletti, C.; Barbui, T. Neutrophil activation and hemostatic changes in healthy donors receiving granulocyte colony-stimulating factor. Blood, 1999, 93(8), 2506-2514.
[http://dx.doi.org/10.1182/blood.V93.8.2506] [PMID: 10194429]
[87]
Spiel, A.O.; Bartko, J.; Schwameis, M.; Firbas, C.; Siller-Matula, J.; Schuetz, M.; Weigl, M.; Jilma, B. Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial. Thromb. Haemost., 2011, 105(4), 655-662.
[http://dx.doi.org/10.1160/TH10-08-0530] [PMID: 21301783]
[88]
Canales, M.A.; Arrieta, R.; Gomez-Rioja, R.; Diez, J.; Jimenez-Yuste, V.; Hernandez-Navarro, F. Induction of a hypercoagulability state and endothelial cell activation by granulocyte colony-stimulating factor in peripheral blood stem cell donors. J. Hematother. Stem Cell Res., 2002, 11(4), 675-681.
[http://dx.doi.org/10.1089/15258160260194820] [PMID: 12201956]
[89]
Fitzhugh, C.D.; Hsieh, M.M.; Bolan, C.D.; Saenz, C.; Tisdale, J.F. Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy, 2009, 11(4), 464-471.
[http://dx.doi.org/10.1080/14653240902849788] [PMID: 19513902]
[90]
Broxmeyer, H.E.; Orschell, C.M.; Clapp, D.W.; Hangoc, G.; Cooper, S.; Plett, P.A.; Liles, W.C.; Li, X.; Graham-Evans, B.; Campbell, T.B.; Calandra, G.; Bridger, G.; Dale, D.C.; Srour, E.F. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J. Exp. Med., 2005, 201(8), 1307-1318.
[http://dx.doi.org/10.1084/jem.20041385] [PMID: 15837815]
[91]
Tisdale, J.F.; Pierciey, F.J., Jr; Bonner, M.; Thompson, A.A.; Krishnamurti, L.; Mapara, M.Y.; Kwiatkowski, J.L.; Shestopalov, I.; Ribeil, J.A.; Huang, W.; Asmal, M.; Kanter, J.; Walters, M.C. Safety and feasibility of hematopoietic progenitor stem cell collection by mobilization with plerixafor followed by apheresis vs bone marrow harvest in patients with sickle cell disease in the multi-center HGB-206 trial. Am. J. Hematol., 2020, 95(9), E239-E242.
[http://dx.doi.org/10.1002/ajh.25867] [PMID: 32401372]
[92]
Lagresle-Peyrou, C.; Lefrère, F.; Magrin, E.; Ribeil, J.A.; Romano, O.; Weber, L.; Magnani, A.; Sadek, H.; Plantier, C.; Gabrion, A.; Ternaux, B.; Félix, T.; Couzin, C.; Stanislas, A.; Tréluyer, J.M.; Lamhaut, L.; Joseph, L.; Delville, M.; Miccio, A.; André-Schmutz, I.; Cavazzana, M. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica, 2018, 103(5), 778-786.
[http://dx.doi.org/10.3324/haematol.2017.184788] [PMID: 29472357]
[93]
Boulad, F.; Shore, T.; van Besien, K.; Minniti, C.; Barbu-Stevanovic, M.; Fedus, S.W.; Perna, F.; Greenberg, J.; Guarneri, D.; Nandi, V.; Mauguen, A.; Yazdanbakhsh, K.; Sadelain, M.; Shi, P.A. Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica, 2018, 103(9), 1577.
[http://dx.doi.org/10.3324/haematol.2018.199414] [PMID: 30171018]
[94]
Esrick, E.B.; Manis, J.P.; Daley, H.; Baricordi, C.; Trébéden-Negre, H.; Pierciey, F.J.; Armant, M.; Nikiforow, S.; Heeney, M.M.; London, W.B.; Biasco, L.; Asmal, M.; Williams, D.A.; Biffi, A. Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Blood Adv., 2018, 2(19), 2505-2512.
[http://dx.doi.org/10.1182/bloodadvances.2018016725] [PMID: 30282642]
[95]
Hoggatt, J.; Singh, P.; Tate, T.A.; Chou, B.K.; Datari, S.R.; Fukuda, S.; Liu, L.; Kharchenko, P.V.; Schajnovitz, A.; Baryawno, N.; Mercier, F.E.; Boyer, J.; Gardner, J.; Morrow, D.M.; Scadden, D.T.; Pelus, L.M. Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell.Cell, 2018., 172(1-2), 191-204 e110.,
[http://dx.doi.org/10.1016/j.cell.2017.11.003]
[96]
Bernardo, M.E.; Aiuti, A. The Role of Conditioning in Hematopoietic Stem-Cell Gene Therapy. Hum. Gene Ther., 2016, 27(10), 741-748.
[http://dx.doi.org/10.1089/hum.2016.103] [PMID: 27530055]
[97]
Uchida, N.; Nassehi, T.; Drysdale, C.M.; Gamer, J.; Yapundich, M.; Demirci, S.; Haro-Mora, J.J.; Leonard, A.; Hsieh, M.M.; Tisdale, J.F. High-Efficiency Lentiviral Transduction of Human CD34+ Cells in High-Density Culture with Poloxamer and Prostaglandin E2. Mol. Ther. Methods Clin. Dev., 2019, 13, 187-196.
[http://dx.doi.org/10.1016/j.omtm.2019.01.005] [PMID: 30788387]
[98]
Jang, Y.; Kim, Y.S.; Wielgosz, M.M.; Ferrara, F.; Ma, Z.; Condori, J.; Palmer, L.E.; Zhao, X.; Kang, G.; Rawlings, D.J.; Zhou, S.; Ryu, B.Y. Optimizing lentiviral vector transduction of hematopoietic stem cells for gene therapy. Gene Ther., 2020, 27(12), 545-556.
[http://dx.doi.org/10.1038/s41434-020-0150-z] [PMID: 32341484]
[99]
Masiuk, K.E.; Zhang, R.; Osborne, K.; Hollis, R.P.; Campo-Fernandez, B.; Kohn, D.B. PGE2 and Poloxamer Synperonic F108 Enhance Transduction of Human HSPCs with a β-Globin Lentiviral Vector. Mol. Ther. Methods Clin. Dev., 2019, 13, 390-398.
[http://dx.doi.org/10.1016/j.omtm.2019.03.005] [PMID: 31024981]
[100]
Morgan, R.A.; Ma, F.; Unti, M.J.; Brown, D.; Ayoub, P.G.; Tam, C.; Lathrop, L.; Aleshe, B.; Kurita, R.; Nakamura, Y.; Senadheera, S.; Wong, R.L.; Hollis, R.P.; Pellegrini, M.; Kohn, D.B. Creating New β-Globin-Expressing Lentiviral Vectors by High-Resolution Mapping of Locus Control Region Enhancer Sequences. Mol. Ther. Methods Clin. Dev., 2020, 17, 999-1013.
[http://dx.doi.org/10.1016/j.omtm.2020.04.006] [PMID: 32426415]
[101]
Uchida, N.; Hsieh, M.M.; Raines, L.; Haro-Mora, J.J.; Demirci, S.; Bonifacino, A.C.; Krouse, A.E.; Metzger, M.E.; Donahue, R.E.; Tisdale, J.F. Development of a forward-oriented therapeutic lentiviral vector for hemoglobin disorders. Nat. Commun., 2019, 10(1), 4479.
[http://dx.doi.org/10.1038/s41467-019-12456-3] [PMID: 31578323]
[102]
Li, C.; Wang, H.; Georgakopoulou, A.; Gil, S.; Yannaki, E.; Lieber, A. In Vivo HSC Gene Therapy Using a Bi-modular HDAd5/35++ Vector Cures Sickle Cell Disease in a Mouse Model. Mol. Ther., 2020.
[http://dx.doi.org/10.1016/j.ymthe.2020.09.001] [PMID: 32949495]
[103]
Urbinati, F.; Campo Fernandez, B.; Masiuk, K.E.; Poletti, V.; Hollis, R.P.; Koziol, C.; Kaufman, M.L.; Brown, D.; Mavilio, F.; Kohn, D.B. Gene Therapy for Sickle Cell Disease: A Lentiviral Vector Comparison Study. Hum. Gene Ther., 2018, 29(10), 1153-1166.
[http://dx.doi.org/10.1089/hum.2018.061] [PMID: 30198339]
[104]
Pattabhi, S.; Lotti, S.N.; Berger, M.P.; Singh, S.; Lux, C.T.; Jacoby, K.; Lee, C.; Negre, O.; Scharenberg, A.M.; Rawlings, D.J. In Vivo Outcome of Homology-Directed Repair at the HBB Gene in HSC Using Alternative Donor Template Delivery Methods. Mol. Ther. Nucleic Acids, 2019, 17, 277- 288..
[http://dx.doi.org/10.1016/j.omtn.2019.05.025] [PMID: 31279229]
[105]
Romero, Z.; Lomova, A.; Said, S.; Miggelbrink, A.; Kuo, C.Y.; Campo-Fernandez, B.; Hoban, M.D.; Masiuk, K.E.; Clark, D.N.; Long, J.; Sanchez, J.M.; Velez, M.; Miyahira, E.; Zhang, R.; Brown, D.; Wang, X.; Kurmangaliyev, Y.Z.; Hollis, R.P.; Kohn, D.B. Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates. Mol. Ther.,, 2019, 27(8), 1389-1406.
[http://dx.doi.org/10.1016/j.ymthe.2019.05.014] [PMID: 31178391]

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