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Gene therapy of hematological disorders: current challenges

Abstract

Recent advances in genetic engineering technology and stem cell biology have spurred great interest in developing gene therapies for hereditary, as well as acquired hematological disorders. Currently, hematopoietic stem cell transplantation is used to cure disorders such as hemoglobinopathies and primary immunodeficiencies; however, this method is limited by the availability of immune-matched donors. Using autologous cells coupled with genome editing bypasses this limitation and therefore became the focus of many research groups aiming to develop efficient and safe genomic modification. Hence, gene therapy research has witnessed a noticeable growth in recent years with numerous successful achievements; however, several challenges have to be overcome before gene therapy becomes widely available for patients. In this review, I discuss tools used in gene therapy for hematological disorders, choices of target cells, and delivery vehicles with emphasis on current hurdles and attempts to solve them, and present examples of successful clinical trials to give a glimpse of current progress.

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References

  1. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T Lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. (80-) 1995. https://doi.org/10.1126/science.270.5235.475.

    CAS  PubMed  Article  Google Scholar 

  2. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006. https://doi.org/10.1016/j.cell.2006.07.024.

    CAS  PubMed  Article  Google Scholar 

  3. Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest. 2014; https://doi.org/10.1172/JCI72992.

    CAS  Article  Google Scholar 

  4. Papapetrou EP, Schambach A. Gene insertion into genomic safe harbors for human gene therapy. Mol Ther. 2016. https://doi.org/10.1038/mt.2016.38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Maeder ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther. 2016. https://doi.org/10.1038/mt.2016.10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature. 2016. https://doi.org/10.1038/nature16526.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. Rationally engineered Cas9 nucleases with improved specificity. Science (80-). 2016. https://doi.org/10.1126/science.aad5227.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, et al. Enhanced proofreading governs CRISPR-Cas9 targeting accuracy. Nature. 2017. https://doi.org/10.1038/nature24268.

    PubMed  PubMed Central  Article  Google Scholar 

  9. Vakulskas CA, Dever DP, Rettig GR, Turk R, Jacobi AM, Collingwood MA, et al. A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat Med. 2018. https://doi.org/10.1038/s41591-018-0137-0.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016. https://doi.org/10.1038/nature17946.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Richter M, Stone D, Miao C, Humbert O, Kiem HP, Papayannopoulou T, et al. In vivo hematopoietic stem cell transduction. Hematol Oncol Clin N. Am. 2017. https://doi.org/10.1016/j.hoc.2017.06.001.

    PubMed  PubMed Central  Article  Google Scholar 

  12. Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-Associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011. https://doi.org/10.1056/NEJMoa1108046.

    CAS  Article  Google Scholar 

  13. Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv. 2018. https://doi.org/10.1080/10717544.2018.1474964.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Brendel C, Goebel B, Daniela A, Brugman M, Kneissl S, Schwäble J, et al. CD133-targeted gene transfer into long-term repopulating hematopoietic stem cells. Mol Ther. 2015. https://doi.org/10.1038/mt.2014.173.

    CAS  PubMed  Article  Google Scholar 

  15. Meuwissen HJ, Gatti RA, Terasaki PI, Hong R, Good RA. Treatment of lymphopenic hypogammaglobulinemia and bone-marrow aplasia by transplantation of allogeneic marrow. N Engl J Med. 1969. https://doi.org/10.1056/NEJM196909252811302.

    CAS  Article  Google Scholar 

  16. Hoban MD, Cost GJ, Mendel MC, Romero Z, Kaufman ML, Joglekar AV, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015. https://doi.org/10.1182/blood-2014-12-615948.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010. https://doi.org/10.1038/nbt.1663.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Park B, Yoo KH, Kim C. Hematopoietic stem cell expansion and generation: he ways to make a breakthrough. Blood Res. 2015. https://doi.org/10.5045/br.2015.50.4.194.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010. https://doi.org/10.1038/nm.2080.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. de Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med. 2012. https://doi.org/10.1056/NEJMoa1207285.

    CAS  Article  Google Scholar 

  21. Ferreira MSV, Mousavi SH. Nanofiber technology in the ex vivo expansion of cord blood-derived hematopoietic stem cells. Nanomed Nanotechnol Biol Med. 2018. https://doi.org/10.1016/j.nano.2018.04.017.

    CAS  Article  Google Scholar 

  22. Dever DP, Bak RO, Reinisch A, Camarena J, Washington G, Nicolas CE, et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature. 2016. https://doi.org/10.1038/nature20134.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Hanna J, Wernig M, Markoulaki S, Sun C-W, Meissner A, Cassady JP, et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science. 2007. https://doi.org/10.1126/science.1152092.

    PubMed  Article  Google Scholar 

  24. Wahlster L, Daley GQ. Progress towards generation of human haematopoietic stem cells. Nat Cell Biol. 2016. https://doi.org/10.1038/ncb3419.

    CAS  PubMed  Article  Google Scholar 

  25. Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol. 2013. https://doi.org/10.1038/nbt.2678.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science (80-.). 2018. https://doi.org/10.1126/science.aar6711.

    CAS  PubMed  Article  Google Scholar 

  27. Batta K, Florkowska M, Kouskoff V, Lacaud G. Direct Reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Rep. 2014. https://doi.org/10.1016/j.celrep.2014.11.002.

    CAS  PubMed  Article  Google Scholar 

  28. Sandler VM, Lis R, Liu Y, Kedem A, James D, Elemento O, et al. Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature. 2014. https://doi.org/10.1038/nature13547.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Milone MC, O’Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018. https://doi.org/10.1038/s41375-018-0106-0.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Yu K-R, Natanson H, Dunbar CE. Gene editing of human hematopoietic stem and progenitor cells: promise and potential hurdles. Hum Gene Ther. 2016. https://doi.org/10.1089/hum.2016.107.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. VandenDriessche T, Chuah MK. Hemophilia gene therapy: ready for prime time? Hum Gene Ther. 2017. https://doi.org/10.1089/hum.2017.116.

    CAS  PubMed  Article  Google Scholar 

  32. Naso MF, Tomkowicz B, Perry WL, Strohl WR. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs. 2017. https://doi.org/10.1007/s40259-017-0234-5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Liang X, Potter J, Kumar S, Zou Y, Quintanilla R, Sridharan M, et al. Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J Biotechnol. 2015. https://doi.org/10.1016/j.jbiotec.2015.04.024.

    CAS  PubMed  Article  Google Scholar 

  34. De Ravin SS, Reik A, Liu P-Q, Li L, Wu X, Su L, et al. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol. 2016;34:424–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. Pestina TI, Hargrove PW, Jay D, Gray JT, Boyd KM, Persons DA. Correction of murine sickle cell disease using gamma-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin. Mol Ther. 2009. mt2008259 [pii]/r10.1038/mt.2008.259.

  36. Chang KH, Smith SE, Sullivan T, Chen K, Zhou Q, West JA, et al. Long-Term engraftment and fetal globin induction upon BCL11A gene editing in bone-marrow-derived CD34+ hematopoietic stem and progenitor cells. Mol Ther. 2017. https://doi.org/10.1016/j.omtm.2016.12.009.

    CAS  Article  Google Scholar 

  37. Ribeil J-A, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017. https://doi.org/10.1056/NEJMoa1609677.

    CAS  Article  Google Scholar 

  38. Jayavaradhan R, Malik P. Genetic therapies for sickle cell disease. Pediatr Clin N Am. 2018;65:465–80.

    Article  Google Scholar 

  39. Monahan PE, Sun J, Gui T, Hu G, Hannah WB, Wichlan DG, et al. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial. Hum Gene Ther. 2015. https://doi.org/10.1089/hum.2014.106.

    CAS  PubMed  Article  Google Scholar 

  40. Wang CX, Cannon PM. The clinical applications of genome editing in HIV. Blood. 2016. https://doi.org/10.1182/blood-2016-01-678144.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Maier DA, Brennan AL, Jiang S, Binder-Scholl GK, Lee G, Plesa G, et al. Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther. 2013. https://doi.org/10.1089/hum.2012.172.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013. https://doi.org/10.1038/srep02510.

  43. Huang Z, Tomitaka A, Raymond A, Nair M. Current application of CRISPR/Cas9 gene-editing technique to eradication of HIV/AIDS. Gene Ther. 2017. https://doi.org/10.1038/gt.2017.35.

    CAS  PubMed  Article  Google Scholar 

  44. Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M, Gate RE, et al. Generation of knock-in primary human T cells using. Proc Natl Acad Sci USA. 2015. https://doi.org/10.1073/pnas.1512503112.

    CAS  Article  Google Scholar 

  45. de Lima M, McMannis J, Gee A, Komanduri K, Couriel D, Andersson BS, et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant. 2008. https://doi.org/10.1038/sj.bmt.1705979.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Rizo A, Dontje B, Vellenga E, De Haan G, Sehuringa JJ. Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1. Blood. 2008. https://doi.org/10.1182/blood-2007-08-106666.

    PubMed  Article  CAS  Google Scholar 

  47. Nishino T, Miyaji K, Ishiwata N, Arai K, Yui M, Asai Y, et al. Ex vivo expansion of human hematopoietic stem cells by a small-molecule agonist of c-MPL. Exp Hematol. 2009. https://doi.org/10.1016/j.exphem.2009.09.001.

    PubMed  Article  CAS  Google Scholar 

  48. Csaszar E, Kirouac DC, Yu M, Wang W, Qiao W, Cooke MP, et al. Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell. 2012. https://doi.org/10.1016/j.stem.2012.01.003.

    CAS  PubMed  Article  Google Scholar 

  49. Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J, et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013. https://doi.org/10.1182/blood-2013-05-503177.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N, et al. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science (80-). 2014. https://doi.org/10.1126/science.1256337.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. 2014. https://doi.org/10.1172/JCI74556.

    CAS  Article  Google Scholar 

  52. Chaurasia P, Gajzer DC, Schaniel C, Souza SD, Hoffman R, D’Souza S, et al. Epigenetic reprogramming induces the expansion of cord blood stem cells. J Clin Invest. 2014. https://doi.org/10.1172/JCI70313.2378.

  53. Xie X-Q, Yang P, Zhang Y, Zhang P, Wang L, Ding Y, et al. Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion. Sci Rep. 2015. https://doi.org/10.1038/srep18115.

  54. Wagner JE, Brunstein CG, Boitano AE, Defor TE, McKenna D, Sumstad D, et al. 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. https://doi.org/10.1016/j.stem.2015.10.004.

    CAS  PubMed  Article  Google Scholar 

  55. Shen B, Zhang Y, Dai W, Ma Y, Jiang Y, Aguila J, et al. Ex-vivo expansion of nonhuman primate CD34+ cells by stem cell factor Sall4B. Stem Cell Res Ther. 2016. https://doi.org/10.1186/s13287-016-0413-1.

  56. Wang L, Guan X, Wang H, Shen B, Zhang Y, Ren Z, et al. A small-molecule/cytokine combination enhances hematopoietic stem cell proliferation via inhibition of cell differentiation. Stem Cell Res Ther. 2017. https://doi.org/10.1186/s13287-017-0625-z.

  57. Li Z, Qian P, Shao W, Shi H, He XC, Gogol M, et al. Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 2018. https://doi.org/10.1038/s41422-018-0072-0.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Zhao K, Zheng WW, Dong XM, Yin RH, Gao R, Li X, et al. EDAG promotes the expansion and survival of human CD34+cells. PLoS ONE. 2018. https://doi.org/10.1371/journal.pone.0190794.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. Guo B, Huang X, Lee MR, Lee SA, Broxmeyer HE. Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med. 2018. https://doi.org/10.1038/nm.4477.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Ledran MH, Krassowska A, Armstrong L, Dimmick I, Renström J, Lang R, et al. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches. Cell Stem Cell. 2008. https://doi.org/10.1016/j.stem.2008.06.001.

    CAS  PubMed  Article  Google Scholar 

  61. Woods N-B, Parker AS, Moraghebi R, Lutz MK, Firth AL, Brennand KJ, et al. Brief report: efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines. Stem Cells. 2011. https://doi.org/10.1002/stem.657.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Real PJ, Ligero G, Ayllon V, Ramos-Mejia V, Bueno C, Gutierrez-Aranda I, et al. SCL/TAL1 regulates hematopoietic specification from human embryonic stem cells. Mol Ther. 2012 https://doi.org/10.1038/mt.2012.49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Kennedy M, Awong G, Sturgeon CM, Ditadi A, LaMotte-Mohs R, Zúñiga-Pflücker JC, et al. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2012. https://doi.org/10.1016/j.celrep.2012.11.003.

    CAS  PubMed  Article  Google Scholar 

  64. Park TS, Zimmerlin L, Zambidis ET. Efficient and simultaneous generation of hematopoietic and vascular progenitors from human induced pluripotent stem cells. Cytom Part A. 2013. https://doi.org/10.1002/cyto.a.22090.

    Article  CAS  Google Scholar 

  65. Doulatov S, Vo LT, Chou SS, Kim PG, Arora N, Li H, et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell. 2013. https://doi.org/10.1016/j.stem.2013.09.002.

    CAS  PubMed  Article  Google Scholar 

  66. Ran D, Shia WJ, Lo MC, Fan JB, Knorr DA, Ferrell PI, et al. RUNX1a enhances hematopoietic lineage commitment from human embryonic stem cells and inducible pluripotent stem cells. Blood. 2013. https://doi.org/10.1182/blood-2012-08-451641.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Amabile G, Welner RS, Nombela-Arrieta C, D’Alise AM, Di Ruscio A, Ebralidze AK, et al. In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells. Blood. 2013. https://doi.org/10.1182/blood-2012-06-434407.

    PubMed  Article  CAS  Google Scholar 

  68. Suzuki N, Yamazaki S, Yamaguchi T, Okabe M, Masaki H, Takaki S, et al. Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. Mol Ther. 2013. https://doi.org/10.1038/mt.2013.71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Ramos-Mejía V, Navarro-Montero O, Ayllón V, Bueno C, Romero T, Real PJ, et al. HOXA9 promotes hematopoietic commitment of human embryonic stem cells. Blood. 2014. https://doi.org/10.1182/blood-2014-03-558825.

    CAS  PubMed  Article  Google Scholar 

  70. Sturgeon CM, Ditadi A, Awong G, Kennedy M, Keller G. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat Biotechnol. 2014. https://doi.org/10.1038/nbt.2915.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Gori JL, Butler JM, Chan YY, Chandrasekaran D, Poulos MG, Ginsberg M, et al. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. J Clin Invest. 2015. https://doi.org/10.1172/JCI79328.

    Article  Google Scholar 

  72. Jackson M, Ma R, Taylor AH, Axton RA, Easterbrook J, Kydonaki M, et al. Enforced expression of HOXB4 in human embryonic stem cells enhances the production of hematopoietic progenitors but has no effect on the maturation of red blood cells. Stem Cells Transl Med. 2016. https://doi.org/10.5966/sctm.2015-0324.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Saxena S, Rönn RE, Guibentif C, Moraghebi R, Woods NB. Cyclic AMP signaling through Epac axis modulates human hemogenic endothelium and enhances hematopoietic cell generation. Stem Cell Rep. 2016;6:692–703.

    CAS  Article  Google Scholar 

  74. Li X, Xia C, Wang T, Liu L, Zhao Q, Yang D, et al. Pyrimidoindole derivative UM171 enhances derivation of hematopoietic progenitor cells from human pluripotent stem cells. Stem Cell Res. 2017;21:32–39.

    CAS  PubMed  Article  Google Scholar 

  75. Sugimura R, Jha DK, Han A, Soria-Valles C, Da Rocha EL, Lu YF, et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature. 2017. https://doi.org/10.1038/nature22370.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Duan F, Huang R, Zhang F, Zhu Y, Wang L, Chen X, et al. Biphasic modulation of insulin signaling enables highly efficient hematopoietic differentiation from human pluripotent stem cells. Stem Cell Res Ther. 2018. https://doi.org/10.1186/s13287-018-0934-x.

  77. Tan Y-T, Ye L, Xie F, Beyer AI, Muench MO, Wang J, et al. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. Proc Natl Acad Sci USA. 2018. https://doi.org/10.1073/pnas.1718446115.

    CAS  Article  Google Scholar 

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I would like to thank Zahraa Al-Saif for her help in producing the illustrations in this article.

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Al-Saif, A.M. Gene therapy of hematological disorders: current challenges. Gene Ther 26, 296–307 (2019). https://doi.org/10.1038/s41434-019-0093-4

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