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Gene therapy using haematopoietic stem and progenitor cells

Nature Reviews Genetics volume 22, pages 216–234 (2021)Cite this article

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Abstract

Haematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and β-thalassaemia. Medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use, and the site-specific genome modification of HSPCs using gene editing techniques such as CRISPR–Cas9 has shown great clinical promise. Preclinical studies have shown engineered HSPCs could also be used to cross-correct non-haematopoietic cells in neurodegenerative metabolic diseases. Here, we review the most recent advances in HSPC gene therapy and discuss emerging strategies for using HSPC gene therapy for a range of diseases.

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Fig. 1: The haematopoietic hierarchy and genetic disorders.
Fig. 2: A timeline of HSPC gene therapy.
Fig. 3: Manufacturing of engineered HSPCs by gene addition and gene editing.
Fig. 4: HSPC gene therapy vector design and integration preferences.
Fig. 5: Gene editing techniques for HSPC gene therapy.
Fig. 6: HSPC-driven localized delivery of therapeutics in lysosomal storage diseases.

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References

  1. Chabannon, C. et al. Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Sci. Transl Med. 10, eaap9630 (2018).

    PubMed  Google Scholar 

  2. Carreras, E., Dufour, C., Mohty, M. & Kröger, N. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies (Springer, 2019).

  3. Gatti, R. A., Meuwissen, H. J., Allen, H. D., Hong, R. & Good, R. A. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 2, 1366–1369 (1968).

    CAS  PubMed  Google Scholar 

  4. Bach, F. H., Albertini, R. J., Joo, P., Anderson, J. L. & Bortin, M. M. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 2, 1364–1366 (1968).

    CAS  PubMed  Google Scholar 

  5. Styczynski, J. et al. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant. 55, 126–136 (2020).

    PubMed  Google Scholar 

  6. Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).

    PubMed  Google Scholar 

  7. Naldini, L. Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives. EMBO Mol. Med. 11, e99858 (2019).

    Google Scholar 

  8. Kohn, D. B. Gene therapy for blood diseases. Curr. Opin. Biotechnol. 60, 39–45 (2019).

    CAS  PubMed  Google Scholar 

  9. Bordignon, C. et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270, 470–475 (1995).

    CAS  PubMed  Google Scholar 

  10. Blaese, R. M. et al. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with CD34+ selected autologous peripheral blood cells transduced with a human ADA gene. Amendment to clinical research project, project 90-C-195, January 10, 1992. Hum. Gene Ther. 4, 521–527 (1993).

    CAS  PubMed  Google Scholar 

  11. Kohn, D. B. et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat. Med. 1, 1017–1023 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Blaese, R. M. et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270, 475–480 (1995).

    CAS  PubMed  Google Scholar 

  13. Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669–672 (2000). This study is one of the first demonstrations of clinically successful gene therapy in humans.

    CAS  PubMed  Google Scholar 

  14. Aiuti, A. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413 (2002). This study is the first demonstration of clinically successful gene therapy with conditioning.

    CAS  PubMed  Google Scholar 

  15. Howe, S. J. et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 118, 3143–3150 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hacein-Bey-Abina, S. et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256 (2003).

    PubMed  Google Scholar 

  17. Thornley, I. et al. Differences in cell cycle kinetics of candidate engrafting cells in human bone marrow and mobilized peripheral blood. Exp. Hematol. 29, 525–533 (2001).

    CAS  PubMed  Google Scholar 

  18. Steidl, U. et al. Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow-derived and circulating human CD34+ hematopoietic stem cells. Blood 99, 2037–2044 (2002).

    CAS  PubMed  Google Scholar 

  19. Lidonnici, M. R. et al. Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone. Haematologica 102, e120–e124 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. Basso-Ricci, L. et al. Multiparametric whole blood dissection: a one-shot comprehensive picture of the human hematopoietic system. Cytometry A 91, 952–965 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tucci, F. et al. Bone marrow harvesting from paediatric patients undergoing haematopoietic stem cell gene therapy. Bone Marrow Transpl. 54, 1995–2003 (2019).

    Google Scholar 

  22. Ferrua, F. et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 6, e239–e253 (2019).

    PubMed  PubMed Central  Google Scholar 

  23. Gertz, M. A. Current status of stem cell mobilization. Br. J. Haematol. 150, 647–662 (2010).

    CAS  PubMed  Google Scholar 

  24. Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018). This reports a clinical trial for β-thalassaemia reporting transfusion independence.

    CAS  PubMed  Google Scholar 

  25. Marktel, S. et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent β-thalassemia. Nat. Med. 25, 234–241 (2019). This reports one of the first clinical trials for β-thalassaemia using intrabone injection of a drug product, reporting transfusion independence in paediatric patients.

    CAS  PubMed  Google Scholar 

  26. Eichler, F. et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 377, 1630–1638 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rio, P. et al. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat. Med. 25, 1396–1401 (2019). This is a proof-of-principle study for the correction of bone marrow failure.

    CAS  PubMed  Google Scholar 

  28. Zonari, E. et al. Efficient Ex vivo engineering and expansion of highly purified human hematopoietic stem and progenitor cell populations for gene therapy. Stem Cell Rep. 8, 977–990 (2017).

    CAS  Google Scholar 

  29. Masiuk, K. E. et al. Improving gene therapy efficiency through the enrichment of human hematopoietic stem cells. Mol. Ther. 25, 2163–2175 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mulligan, R. C. The basic science of gene therapy. Science 260, 926–932 (1993).

    CAS  PubMed  Google Scholar 

  31. Miller, A. D., Miller, D. G., Garcia, J. V. & Lynch, C. M. Use of retroviral vectors for gene transfer and expression. Methods Enzymol. 217, 581–599 (1993).

    CAS  PubMed  Google Scholar 

  32. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996). This study describes the development of lentiviral vectors for gene therapy.

    CAS  PubMed  Google Scholar 

  33. Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009). This study represents the first clinical application of lentiviral-mediated gene therapy and demonstrates the correction of a neurometabolic disease.

    CAS  PubMed  Google Scholar 

  34. Hacein-Bey-Abina, S. et al. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N. Engl. J. Med. 371, 1407–1417 (2014). This study outlines the development of LTR-modified retroviral vectors to reduce risk of mutagenesis.

    PubMed  PubMed Central  Google Scholar 

  35. Biasco, L., Rothe, M., Schott, J. W. & Schambach, A. Integrating vectors for gene therapy and clonal tracking of engineered hematopoiesis. Hematol. Oncol. Clin. North Am. 31, 737–752 (2017).

    PubMed  Google Scholar 

  36. Porteus, M. H. A new class of medicines through DNA editing. N. Engl. J. Med. 380, 947–959 (2019).

    CAS  PubMed  Google Scholar 

  37. Lombardo, A. et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat. Biotechnol. 25, 1298–1306 (2007).

    CAS  PubMed  Google Scholar 

  38. Lombardo, A. & Naldini, L. Genome editing: a tool for research and therapy: targeted genome editing hits the clinic. Nat. Med. 20, 1101–1103 (2014).

    CAS  PubMed  Google Scholar 

  39. Dever, D. P. et al. CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Genovese, P. et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 510, 235–240 (2014). The studies by Genovese et al. (2014) and Dever et al. (2016) both provide evidence for efficient gene editing of human HSPCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Schiroli, G. et al. Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Sci. Transl Med. 9, eaan0820 (2017).

    PubMed  Google Scholar 

  42. Pavel-Dinu, M. et al. Gene correction for SCID-X1 in long-term hematopoietic stem cells. Nat. Commun. 10, 1634 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. Rai, R. et al. Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott-Aldrich syndrome. Nat. Commun. 11, 4034 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu, Y. et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25, 776–783 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. DeWitt, M. A. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl Med. 8, 360ra134 (2016).

    PubMed  PubMed Central  Google Scholar 

  46. Ferrari, S. et al. Efficient gene editing of human long-term hematopoietic stem cells validated by clonal tracking. Nat. Biotechnol. 38, 1298–1308 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hendel, A. et al. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat. Biotechnol. 33, 985–989 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hoban, M. D. et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125, 2597–2604 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Chang, K. H. 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. Methods Clin. Dev. 4, 137–148 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Corbacioglu, S. et al. Initial safety and efficacy results with a single dose of autologous CRISPR-CAS9 modified CD34+ hematopietic stem and progenitor cells in transfusion-dependent ß-thalassemia and sickle cell disease. HemaSphere 4, 101 (2020).

    Google Scholar 

  51. Hoban, M. D. et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol. Ther. 24, 1561–1569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Canver, M. C. et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192–197 (2015). This study provides a dissection of the BCL11A erythroid-specific enhancer as a target for gene editing.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Martyn, G. E. et al. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat. Genet. 50, 498–503 (2018).

    CAS  PubMed  Google Scholar 

  54. Metais, J. Y. et al. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv. 3, 3379–3392 (2019).

    PubMed  PubMed Central  Google Scholar 

  55. Wienert, B. et al. Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin. Nat. Commun. 6, 7085 (2015).

    CAS  PubMed  Google Scholar 

  56. Traxler, E. A. et al. A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Antoniani, C. et al. Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus. Blood 131, 1960–1973 (2018).

    CAS  PubMed  Google Scholar 

  58. Weber, L. et al. Editing a gamma-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Sci. Adv. 6, eaay9392 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 36, 765–771 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Galanello, R. et al. Erythropoiesis following bone marrow transplantation from donors heterozygous for beta-thalassaemia. Br. J. Haematol. 72, 561–566 (1989).

    CAS  PubMed  Google Scholar 

  61. Paciaroni, K. & Lucarelli, G. Hemopoietic stem cell transplantation failure followed by switch to stable production of fetal hemoglobin. Blood 119, 1091–1092 (2012).

    CAS  PubMed  Google Scholar 

  62. Rees, H. A. & Liu, D. R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet. 19, 770–788 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Anzalone, A. V., Koblan, L. W. & Liu, D. R. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38, 824–844 (2020).

    CAS  PubMed  Google Scholar 

  65. Piras, F. et al. Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells. EMBO Mol. Med. 9, 1198–1211 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Schiroli, G. et al. Precise gene editing preserves hematopoietic stem cell function following transient p53-mediated DNA damage response. Cell Stem Cell 24, 551–565.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mazurier, F., Gan, O. I., McKenzie, J. L., Doedens, M. & Dick, J. E. Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood 103, 545–552 (2004).

    CAS  PubMed  Google Scholar 

  68. Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 (2013). This study is the first to demonstrate the effectiveness of gene therapy for MLD, for which there is no other treatment.

    PubMed  Google Scholar 

  69. Colomer-Lluch, M., Ruiz, A., Moris, A. & Prado, J. G. Restriction factors: from intrinsic viral restriction to shaping cellular immunity against HIV-1. Front. Immunol. 9, 2876 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Petrillo, C. et al. Cyclosporine H overcomes innate immune restrictions to improve lentiviral transduction and gene editing in human hematopoietic stem cells. Cell stem Cell 23, 820–832.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Hofig, I. et al. Poloxamer Synperonic F108 improves cellular transduction with lentiviral vectors. J. Gene Med. 14, 549–560 (2012).

    PubMed  Google Scholar 

  72. Schott, J. W. et al. Enhancing lentiviral and alpharetroviral transduction of human hematopoietic stem cells for clinical application. Mol. Ther. Methods Clin. Dev. 14, 134–147 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang, C. X. et al. Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells. Blood 124, 913–923 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Heffner, G. C. et al. Prostaglandin E2 increases lentiviral vector transduction efficiency of adult human hematopoietic stem and progenitor cells. Mol. Ther. 26, 320–328 (2018).

    CAS  PubMed  Google Scholar 

  75. Bernardo, M. E. & Aiuti, A. The role of conditioning in hematopoietic stem cell gene therapy. Hum. Gene Ther. 27, 741–748 (2016).

    CAS  PubMed  Google Scholar 

  76. Rio, P. et al. Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. Blood 130, 1535–1542 (2017).

    CAS  PubMed  Google Scholar 

  77. Sessa, M. et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388, 476–487 (2016).

    CAS  PubMed  Google Scholar 

  78. Capotondo, A. et al. Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc. Natl Acad. Sci. USA 109, 15018–15023 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dalle, J. H. et al. State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015. Bone Marrow Transpl. 52, 1029–1035 (2017).

    Google Scholar 

  80. Kwon, H. S. et al. Anti-human CD117 antibody-mediated bone marrow niche clearance in nonhuman primates and humanized NSG mice. Blood 133, 2104–2108 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Palchaudhuri, R. et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat. Biotechnol. 34, 738–745 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Agarwal, R. et al. Toxicity-free hematopoietic stem cell engraftment achieved with anti-CD117 monoclonal antibody conditioning. Biol. Blood Marrow Transplant. 25, S92 (2019).

    Google Scholar 

  83. Crippa, S. et al. Bone marrow stromal cells from beta-thalassemia patients have impaired hematopoietic supportive capacity. J. Clin. Invest. 129, 1566–1580 (2019).

    PubMed  PubMed Central  Google Scholar 

  84. Aprile, A. et al. Hematopoietic stem cell function in beta-thalassemia is impaired and is rescued by targeting the bone marrow niche. Blood 136, 610–622 (2020).

    PubMed  PubMed Central  Google Scholar 

  85. Aiuti, A. et al. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat. Med. 8, 423–425 (2002).

    CAS  PubMed  Google Scholar 

  86. Cicalese, M. P. et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 128, 45–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gaspar, H. B. et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181–2187 (2004).

    CAS  PubMed  Google Scholar 

  88. Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447–458 (2009).

    CAS  PubMed  Google Scholar 

  89. Hacein-Bey Abina, S. et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA 313, 1550–1563 (2015).

    PubMed  Google Scholar 

  90. Kohn, D. B. et al. Lentiviral gene therapy for X-linked chronic granulomatous disease. Nat. Med. 26, 200–206 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Wei, Q. & Frenette, P. S. Niches for hematopoietic stem cells and their progeny. Immunity 48, 632–648 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kfoury, Y. & Scadden, D. T. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16, 239–253 (2015).

    CAS  PubMed  Google Scholar 

  93. Tormin, A. et al. CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood 117, 5067–5077 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  95. Abarrategi, A. et al. Modeling the human bone marrow niche in mice: from host bone marrow engraftment to bioengineering approaches. J. Exp. Med. 215, 729–743 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Reinisch, A., Hernandez, D. C., Schallmoser, K. & Majeti, R. Generation and use of a humanized bone-marrow-ossicle niche for hematopoietic xenotransplantation into mice. Nat. Protoc. 12, 2169–2188 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. de Lima, M. et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N. Engl. J. Med. 367, 2305–2315 (2012).

    PubMed  PubMed Central  Google Scholar 

  98. Ball, L. M. et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110, 2764–2767 (2007).

    CAS  PubMed  Google Scholar 

  99. Biffi, A. et al. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood 117, 5332–5339 (2011).

    CAS  PubMed  Google Scholar 

  100. Cattoglio, C. et al. Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 110, 1770–1778 (2007).

    CAS  PubMed  Google Scholar 

  101. Felice, B. et al. Transcription factor binding sites are genetic determinants of retroviral integration in the human genome. PLoS ONE 4, e4571 (2009).

    PubMed  PubMed Central  Google Scholar 

  102. Biasco, L. et al. Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. EMBO Mol. Med. 3, 89–101 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Cattoglio, C. et al. High-definition mapping of retroviral integration sites identifies active regulatory elements in human multipotent hematopoietic progenitors. Blood 116, 5507–5517 (2010).

    CAS  PubMed  Google Scholar 

  104. De Ravin, S. S. et al. Enhancers are major targets for murine leukemia virus vector integration. J. Virol. 88, 4504–4513 (2014).

    PubMed  PubMed Central  Google Scholar 

  105. Bushman, F. D. Retroviral insertional mutagenesis in humans: evidence for four genetic mechanisms promoting expansion of cell clones. Mol. Ther. 28, 352–356 (2020). This is an up-to-date review summarizing mechanisms of vector-mediated genotoxicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Aiuti, A. et al. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J. Clin. Invest. 117, 2233–2240 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, G. P. et al. Dynamics of gene-modified progenitor cells analyzed by tracking retroviral integration sites in a human SCID-X1 gene therapy trial. Blood 115, 4356–4366 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Braun, C. J. et al. Gene therapy for Wiskott-Aldrich syndrome–long-term efficacy and genotoxicity. Sci. Transl Med. 6, 227ra233 (2014).

    Google Scholar 

  109. Ott, M. G. et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat. Med. 12, 401–409 (2006).

    CAS  PubMed  Google Scholar 

  110. Gabriel, R. et al. Comprehensive genomic access to vector integration in clinical gene therapy. Nat. Med. 15, 1431–1436 (2009).

    CAS  PubMed  Google Scholar 

  111. Biasco, L., Rothe, M., Buning, H. & Schambach, A. Analyzing the genotoxicity of retroviral vectors in hematopoietic cell gene therapy. Mol. Ther. Methods Clin. Dev. 8, 21–30 (2018).

    CAS  PubMed  Google Scholar 

  112. Hacein-Bey-Abina, S. et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415–419 (2003).

    CAS  PubMed  Google Scholar 

  113. Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467, 318–322 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341, 1233151 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. European Medicines Agency. Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (EMA, 2008).

  116. Biasco, L. et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19, 107–119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Xu, S., Kim, S., Chen, I. S. Y. & Chou, T. Modeling large fluctuations of thousands of clones during hematopoiesis: the role of stem cell self-renewal and bursty progenitor dynamics in rhesus macaque. PLoS Comput. Biol. 14, e1006489 (2018).

    PubMed  PubMed Central  Google Scholar 

  118. Scala, S. et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat. Med. 24, 1683–1690 (2018).

    CAS  PubMed  Google Scholar 

  119. Ochs, H. D. & Hagin, D. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ann. Allergy Asthma Immunol. 112, 489–495 (2014).

    PubMed  Google Scholar 

  120. Tangye, S. G. et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J. Clin. Immunol. 40, 24–64 (2020).

    PubMed  PubMed Central  Google Scholar 

  121. Gennery, A. R. & Lankester, A. Long term outcome and immune function after hematopoietic stem cell transplantation for primary immunodeficiency. Front. Pediatrics 7, 381 (2019).

    Google Scholar 

  122. Pai, S. Y. et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N. Engl. J. Med. 371, 434–446 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Castagnoli, R., Delmonte, O. M., Calzoni, E. & Notarangelo, L. D. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front. Pediatrics 7, 295 (2019).

    Google Scholar 

  124. Buckley, R. H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu. Rev. Immunol. 22, 625–655 (2004).

    CAS  PubMed  Google Scholar 

  125. Wada, T. & Candotti, F. Somatic mosaicism in primary immune deficiencies. Curr. Opin. Allergy Clin. Immunol. 8, 510–514 (2008).

    PubMed  Google Scholar 

  126. Fischer, A. & Hacein-Bey-Abina, S. Gene therapy for severe combined immunodeficiencies and beyond. J. Exp. Med.217, e20190607 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Touzot, F. et al. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1. Blood 125, 3563–3569 (2015).

    CAS  PubMed  Google Scholar 

  128. Wiekmeijer, A. S. et al. Overexpression of LMO2 causes aberrant human T-cell development in vivo by three potentially distinct cellular mechanisms. Exp. Hematol. 44, 838–849 e839 (2016).

    CAS  PubMed  Google Scholar 

  129. De Ravin, S. S. et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci. Transl Med. 8, 335ra357 (2016).

    Google Scholar 

  130. Mamcarz, E. et al. Lentiviral gene therapy combined with low-dose busulfan in infants with SCID-X1. N. Engl. J. Med. 380, 1525–1534 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Gaspar, H. B. et al. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci. Transl Med. 3, 97ra80 (2011).

    PubMed  Google Scholar 

  132. Shaw, K. L. et al. Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. J. Clin. Invest. 127, 1689–1699 (2017).

    PubMed  PubMed Central  Google Scholar 

  133. Aiuti, A., Roncarolo, M. G. & Naldini, L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol. Med. 9, 737–740 (2017). This work provides the history of clinical development for the first approved HSPC-based gene therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Cassani, B. et al. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood 114, 3546–3556 (2009).

    CAS  PubMed  Google Scholar 

  135. Kohn, D. B. et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J. Allergy Clin. Immunol. 143, 852–863 (2019).

    PubMed  Google Scholar 

  136. Cavazzana, M., Bushman, F. D., Miccio, A., Andre-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. 18, 447–462 (2019).

    CAS  PubMed  Google Scholar 

  137. Migliavacca, M. et al. First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature. Front. Immunol. 9, 113 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Thrasher, A. J. & Burns, S. O. WASP: a key immunological multitasker. Nat. Rev. Immunol. 10, 182–192 (2010).

    CAS  PubMed  Google Scholar 

  139. Sereni, L. et al. Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol. 144, 825–838 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Weisser, M. et al. Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions. J. Allergy Clin. Immunol. 138, 219–228 e219 (2016).

    CAS  PubMed  Google Scholar 

  141. Benjelloun, F. et al. Stable and functional lymphoid reconstitution in Artemis-deficient mice following lentiviral Artemis gene transfer into hematopoietic stem cells. Mol. Ther. 16, 1490–1499 (2008).

    CAS  PubMed  Google Scholar 

  142. Pike-Overzet, K. et al. Successful RAG1-SCID gene therapy depends on the level of RAG1 expression. J. Allergy Clin. Immunol. 134, 242–243 (2014).

    CAS  PubMed  Google Scholar 

  143. Morgan, R. A. et al. Improved titer and gene transfer by lentiviral vectors using novel, small beta-globin locus control region elements. Mol. Ther. 28, 328–340 (2020).

    CAS  PubMed  Google Scholar 

  144. Angelucci, E. et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 99, 811–820 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. Schuessler-Lenz, M., Enzmann, H. & Vamvakas, S. Regulators’ advice can make a difference: European Medicines Agency approval of Zynteglo for beta thalassemia. Clin. Pharmacol. Ther. 107, 492–494 (2020).

    PubMed  Google Scholar 

  146. Scaramuzza, S. et al. Clinical outcomes from a phase I/II gene therapy trial for patients affected by severe transfusion dependent β-thalassemia: two years follow-up. Mol. Ther. 28 (Suppl. 1), 168 (2020).

    Google Scholar 

  147. Sundd, P., Gladwin, M. T. & Novelli, E. M. Pathophysiology of sickle cell disease. Annu. Rev. Pathol. 14, 263–292 (2019).

    CAS  PubMed  Google Scholar 

  148. Park, S. Y. et al. Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversed by blood transfusion. Blood 135, 2071–2084 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sankaran, V. G. et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322, 1839–1842 (2008).

    CAS  PubMed  Google Scholar 

  150. Bauer, D. E. et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342, 253–257 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ribeil, J. A. et al. Gene therapy in a patient with sickle cell disease. N. Engl. J. Med. 376, 848–855 (2017). This study describes the first gene therapy trial for SCD.

    CAS  PubMed  Google Scholar 

  152. Kanter, J. et al. Resolution of sickle cell disease manifestations in patients treated with lentiglobin gene therapy: updated results from the phase 1/2 Hgb-206 group C study. Blood 134, 990 (2019).

    Google Scholar 

  153. Tisdale, F. J. et al. Resolution of sickle cell disease (SCD) manifestations in patients treated with lentiglobin gene therapy: Updated results from the phase 1/2 HGB-206 group C study. Mol. Ther. 28, 553 (2020).

    Google Scholar 

  154. Malik, P. et al. Gene therapy for sickle cell anemia using a modified gamma globin lentivirus vector and reduced intensity conditioning transplant shows promising correction of the disease phenotype. Blood 132, 1021 (2018).

    Google Scholar 

  155. Brendel, C. et al. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J. Clin. Invest. 126, 3868–3878 (2016).

    PubMed  PubMed Central  Google Scholar 

  156. Esrick E. B. et al. Validation of BCL11A as therapeutic target in sickle cell disease: results from the adult cohort of a pilot/feasibility gene therapy trial inducing sustained expression of fetal hemoglobin using post-transcriptional gene silencing. Blood 134 (Suppl. 2), LBA-5 (2019).

  157. Garcia-Gomez, M. et al. Safe and efficient gene therapy for pyruvate kinase deficiency. Mol. Ther. 24, 1187–1198 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Roman-Rodriguez, F. J. et al. NHEJ-mediated repair of CRISPR-Cas9-induced DNA breaks efficiently corrects mutations in HSPCs from patients with Fanconi anemia. Cell Stem Cell 25, 607–621.e7 (2019).

    CAS  PubMed  Google Scholar 

  159. Bellettato, C. M. et al. Inborn errors of metabolism involving complex molecules: lysosomal and peroxisomal storage diseases. Pediatr. Clin. North Am. 65, 353–373 (2018).

    PubMed  Google Scholar 

  160. Orchard, P. J. & Wagner, J. E. Leukodystrophy and gene therapy with a dimmer switch. N. Engl. J. Med. 364, 572–573 (2011).

    CAS  PubMed  Google Scholar 

  161. Krivit, W. & Whitley, C. B. Bone marrow transplantation for genetic diseases. N. Engl. J. Med. 316, 1085–1087 (1987).

    CAS  PubMed  Google Scholar 

  162. Bergner, C. G. et al. Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Glia 67, 1196–1209 (2019).

    PubMed  PubMed Central  Google Scholar 

  163. Biffi, A. Hematopoietic gene therapies for metabolic and neurologic diseases. Hematol. Oncol. Clin. North Am. 31, 869–881 (2017).

    PubMed  Google Scholar 

  164. Moser, H. W. et al. X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 31, 227–239 (2000).

    CAS  PubMed  Google Scholar 

  165. Krivit, W., Sung, J. H., Shapiro, E. G. & Lockman, L. A. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 4, 385–392 (1995).

    CAS  PubMed  Google Scholar 

  166. Taylor, M. et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses: past, present, and future. Biol. Blood Marrow Transplant. 25, e226–e246 (2019).

    PubMed  PubMed Central  Google Scholar 

  167. Yamada, T. et al. Therapeutic effects of normal cells on ABCD1 deficient cells in vitro and hematopoietic cell transplantation in the X-ALD mouse model. J. Neurolog. Sci. 218, 91–97 (2004).

    CAS  Google Scholar 

  168. Fumagalli, F. et al. Lentiviral (LV) hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD). J. Inherit. Metab. Dis. 42, 7 (2019).

    Google Scholar 

  169. Platt, F. M., d’Azzo, A., Davidson, B. L., Neufeld, E. F. & Tifft, C. J. Lysosomal storage diseases. Nat. Rev. Dis. Primers 4, 27 (2018).

    PubMed  Google Scholar 

  170. Visigalli, I. et al. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 116, 5130–5139 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Sergijenko, A. et al. Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. Mol. Ther. 21, 1938–1949 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Gentner, B. Extensive metabolic correction of Hurler disease by hematopoietic stem cell-based gene therapy: preliminary results from a phase I/II trial. Blood 134, 607 (2019).

    Google Scholar 

  173. Meneghini, V. et al. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy. EMBO Mol. Med. 8, 489–510 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Marco, S., Haurigot, V. & Bosch, F. In vivo gene therapy for mucopolysaccharidosis type III (Sanfilippo syndrome): a new treatment horizon. Hum. Gene Ther. 30, 1211–1221 (2019).

    CAS  PubMed  Google Scholar 

  175. Capotondo, A. et al. Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells. Sci. Adv. 3, e1701211 (2017).

    PubMed  PubMed Central  Google Scholar 

  176. Peake, R. W. et al. Newborn screening for lysosomal storage disorders: quo vadis? Clin. Chem. 62, 1430–1438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Ben Nasr, M. et al. PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. Sci. Transl Med. 9, eaam7543 (2017).

    PubMed  Google Scholar 

  178. Escobar, G. et al. Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens. Nat. Commun. 9, 2896 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Richter, M. et al. In vivo hematopoietic stem cell transduction. Hematol. Oncol. Clin. North Am. 31, 771–785 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. Tsai, S. Q. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat. Biotechnol. 33, 187–197 (2015).

    CAS  PubMed  Google Scholar 

  181. Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Ledford, H. Quest to use CRISPR against disease gains ground. Nature 577, 156 (2020).

    CAS  PubMed  Google Scholar 

  184. De Luca, M. et al. Advances in stem cell research and therapeutic development. Nat. Cell Biol. 21, 801–811 (2019).

    PubMed  Google Scholar 

  185. Poletti, V. & Mavilio, F. Interactions between retroviruses and the host cell genome. Mol. Ther. Methods Clin. D. 8, 31–41 (2018).

    CAS  Google Scholar 

  186. Wienert, B., Martyn, G. E., Funnell, A. P., Quinlan, K. G. & Crossley, M. Wake-up sleepy gene: reactivating fetal globin for β-haemoglobinopathies. Trends Genet. 34, 927–940 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Fondazione Telethon and the European Commission (SCIDNET, E-Rare EUROCID) for support. A.A. is the recipient of the Else Kröner Fresenius Prize for Medical Research 2020. A.J.T. is supported by the Wellcome Trust and the UK National Institute for Health Research biomedical research centres at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. A.A. and A.T. are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (project ID no. 739543) and the Inborn Error Working Party of EBMT. The authors thank F. Tucci for her help with the preparation of Table 1 and M. E. Bernardo, F. Fumagalli, A. Gritti and S. Scala, for their critical review of the figures and manuscript.

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Authors and Affiliations

  1. Vita-Salute San Raffaele University, Milan, Italy

    Giuliana Ferrari & Alessandro Aiuti

  2. San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Giuliana Ferrari & Alessandro Aiuti

  3. Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK

    Adrian J. Thrasher

  4. Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    Adrian J. Thrasher

  5. Pediatric Immunohematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Alessandro Aiuti

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All authors researched the literature, provided substantial contributions to discussions of the content, and reviewed and/or edited the manuscript before submission.

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Correspondence to Alessandro Aiuti.

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Competing interests

The San Raffaele Telethon Institute for Gene Therapy is a joint venture between Fondazione Telethon and Ospedale San Raffaele. Gene therapies for adenosine deaminase-deficient severe combined immunodeficiency, Wiskott–Aldrich syndrome, metachromatic leukodystrophy, β-thalassaemia and mucopolysaccharidosis type I developed at the San Raffaele Telethon Institute for Gene Therapy were licensed to Orchard Therapeutics in 2018 and 2019. A.A. is the principal investigator in the above-mentioned clinical trials. A.J.T has equity in and is on the scientific advisory board for Orchard Therapeutics and receives consultancy payments from Rocket Pharmaceuticals.

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Related links

New gene therapy to treat rare genetic disorder metachromatic leukodystrophy: https://www.ema.europa.eu/en/news/new-gene-therapy-treat-rare-genetic-disorder-metachromatic-leukodystrophy

Potential adverse reaction to gene therapy in a patient treated with Strimvelis for the treatment of ADA-SCID: https://www.telethon.it/en/stories-and-news/news/from-telethonfoundation/potential-adverse-event-after-gene-therapy-for-ada-scid

Glossary

Allogeneic

Relating to or denoting that the source of cells, tissues or organs for transplant is from an individual genetically different from the recipient.

Primary immunodeficiencies

(PIDs). Mendelian genetic disorders caused by defects in the development and/or function of immune cells. Currently, more than 300 genes have been identified that cause adaptive and/or innate immune cell defects.

Chronic granulomatous disease

(CGD). A disease caused by dysfunction of the phagocyte NADPH oxidase, a membrane-bound enzyme complex required for effective killing of bacteria and fungi.

Leukapheresis

A procedure that separates white blood cells, including haematopoietic stem cells, from the blood. White cells are collected from the donor and other blood fractions are returned to the circulation.

Mobilizing agents

Drugs that induce transient mobilization of haematopoietic stem cells from the bone marrow to the circulation so that they can be collected by leukapheresis.

Myeloablative conditioning

High-dose chemotherapy that destroys haematopoietic cells in the bone marrow and severely reduces the number of blood cells. Usually followed by haematopoietic stem and progenitor cell transplantation or gene therapy to rebuild the bone marrow.

Oligoclonality

A quality associated with clones derived from one or a few cells or molecules.

Iron chelation therapy

Pharmacological depletion of toxic iron accumulation in organs.

Stress erythropoiesis

The rapid development of new red blood cells stimulated in response to acute anaemia.

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Ferrari, G., Thrasher, A.J. & Aiuti, A. Gene therapy using haematopoietic stem and progenitor cells. Nat Rev Genet 22, 216–234 (2021). https://doi.org/10.1038/s41576-020-00298-5

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