Preloader

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

  • 1.

    Taher, A. T., Weatherall, D. J. & Cappellini, M. D. Thalassaemia. Lancet 391, 155–167 (2018).

    PubMed 

    Google Scholar 

  • 2.

    Weatherall, D. J. & Clegg, J. B. The Thalassemia Syndrome (Blackwell Scientific, 1981).

  • 3.

    Kountouris, P. et al. IthaGenes: an interactive database for haemoglobin variations and epidemiology. PLoS ONE 9, e103020 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 4.

    Orkin, S. & Nathan, D. G. Hematology of Infancy and Childhood (W. B. Saunders, 1998).

  • 5.

    Stamatoyannopoulos, G. The Molecular Basis of Blood Diseases (W.B. Saunders, 2001).

  • 6.

    Borgna-Pignatti, C. et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 89, 1187–1193 (2004).

    PubMed 

    Google Scholar 

  • 7.

    Ladis, V. et al. Survival in a large cohort of Greek patients with transfusion-dependent β thalassaemia and mortality ratios compared to the general population. Eur. J. Haematol. 86, 332–338 (2011).

    PubMed 

    Google Scholar 

  • 8.

    Mancuso, A., Sciarrino, E., Renda, M. C. & Maggio, A. A prospective study of hepatocellular carcinoma incidence in thalassemia. Hemoglobin 30, 119–124 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 9.

    Sadelain, M. et al. Therapeutic options for patients with severe β-thalassemia: the need for globin gene therapy. Hum. Gene Ther. 18, 1–9 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • 10.

    Lucarelli, G., Isgro, A., Sodani, P. & Gaziev, J. Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. Cold Spring Harb. Perspect. Med. 2, a011825 (2012).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 11.

    Baronciani, D. et al. Hematopoietic cell transplantation in thalassemia and sickle cell disease: report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry: 2000–2017. Blood 132, 168 (2018).

    Google Scholar 

  • 12.

    Fitzhugh, C. D., Abraham, A. & Hsieh, M. M. Alternative donor/unrelated donor transplants for the β-thalassemia and sickle cell disease. Adv. Exp. Med. Biol. 1013, 123–153 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 13.

    Weatherall, D. J. The challenge of haemoglobinopathies in resource-poor countries. Br. J. Haematol. 154, 736–744 (2011).

    PubMed 

    Google Scholar 

  • 14.

    Mansilla-Soto, J., Riviere, I., Boulad, F. & Sadelain, M. Cell and gene therapy for the β-thalassemias: advances and prospects. Hum. Gene Ther. 27, 295–304 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 15.

    Ferrari, G., Thrasher, A. J. & Aiuti, A. Gene therapy using haematopoietic stem and progenitor cells. Nat. Rev. Genet. 22, 216–234 (2020).

  • 16.

    Magrin, E., Miccio, A. & Cavazzana, M. Lentiviral and genome-editing strategies for the treatment of β-hemoglobinopathies. Blood 134, 1203–1213 (2019).

    PubMed 

    Google Scholar 

  • 17.

    Drysdale, C. M. et al. Hematopoietic-stem-cell-targeted gene-addition and gene-editing strategies for β-hemoglobinopathies. Cell Stem Cell 28, 191–208 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 18.

    Persons, D. A. & Tisdale, J. F. Gene therapy for the hemoglobin disorders. Semin. Hematol. 41, 279–286 (2004).

    CAS 
    PubMed 

    Google Scholar 

  • 19.

    Sadelain, M. Recent advances in globin gene transfer for the treatment of β-thalassemia and sickle cell anemia. Curr. Opin. Hematol. 13, 142–148 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 20.

    May, C. et al. Therapeutic haemoglobin synthesis in β-thalassaemic mice expressing lentivirus-encoded human β-globin. Nature 406, 82–86 (2000).

    CAS 
    PubMed 

    Google Scholar 

  • 21.

    May, C., Rivella, S., Chadburn, A. & Sadelain, M. Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene. Blood 99, 1902–1908 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 22.

    Rivella, S., May, C., Chadburn, A., Riviere, I. & Sadelain, M. A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer. Blood 101, 2932–2939 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 23.

    Lisowski, L. & Sadelain, M. Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in β-thalassemic mice. Blood 110, 4175–4178 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 24.

    Perumbeti, A. & Malik, P. Therapy for β-globinopathies: a brief review and determinants for successful and safe correction. Ann. N. Y. Acad. Sci. 1202, 36–44 (2010).

    CAS 
    PubMed 

    Google Scholar 

  • 25.

    Quek, L. & Thein, S. L. Molecular therapies in β-thalassaemia. Br. J. Haematol. 136, 353–365 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • 26.

    Boulad, F. et al. Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation. Blood 123, 1483–1486 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 27.

    Felfly, H. & Trudel, M. Successful correction of murine sickle cell disease with reduced stem cell requirements reinforced by fractionated marrow infusions. Br. J. Haematol. 148, 646–658 (2010).

    PubMed 

    Google Scholar 

  • 28.

    Bartelink, I. H. et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 3, e526–e536 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 29.

    Hu, J. et al. Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo. Blood 121, 3246–3253 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 30.

    Villa, E. et al. The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway. Cell Death Dis. 11, 1041 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 31.

    Berry, C. C., Ocwieja, K. E., Malani, N. & Bushman, F. D. Comparing DNA integration site clusters with scan statistics. Bioinformatics 30, 1493–1500 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 32.

    Yoon, J. K. et al. HIV proviral DNA integration can drive T cell growth ex vivo. Proc. Natl Acad. Sci. USA 117, 32880–32882 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 33.

    Katano, H. et al. Integration of HIV-1 caused STAT3-associated B cell lymphoma in an AIDS patient. Microbes Infect. 9, 1581–1589 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 34.

    Bushman, F. D. Retroviral insertional mutagenesis in humans: evidence for four genetic mechanisms promoting expansion of cell clones. Mol. Ther. 28, 352–356 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 35.

    Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • 36.

    Schneiderman, J. et al. Interim results from the phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) studies of betibeglogene autotemcel gene therapy (LentiGlobin) for the treatment of transfusion-dependent β-thalassemia. Biol. Blood Marrow Transplant. 26, S87–S88 (2020).

    Google Scholar 

  • 37.

    Frangoul, H. et al. Safety and efficacy of CTX001 in patients with transfusion-dependent β-thalassemia and sickle cell disease: early results from the Climb THAL-111 and Climb SCD-121 studies of autologous CRISPR–CAS9-modified CD34+ hematopoietic stem and progenitor cells. Blood 136, 3–4 (2020).

    Google Scholar 

  • 38.

    Grochow, L. B. et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother. Pharmacol. 25, 55–61 (1989).

    CAS 
    PubMed 

    Google Scholar 

  • 39.

    Lawson, R., Staatz, C. E., Fraser, C. J. & Hennig, S. Review of the pharmacokinetics and pharmacodynamics of intravenous busulfan in paediatric patients. Clin. Pharmacokinet. 60, 17–51 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 40.

    Strouse, C. et al. Risk score for the development of veno-occlusive disease after allogeneic hematopoietic cell transplant. Biol. Blood Marrow Transpl. 24, 2072–2080 (2018).

    Google Scholar 

  • 41.

    Marktel, S. et al. Platelet transfusion refractoriness in highly immunized β thalassemia children undergoing stem cell transplantation. Pediatr. Transpl. 14, 393–401 (2010).

    CAS 

    Google Scholar 

  • 42.

    Saito, A. M. et al. Lower costs associated with hematopoietic cell transplantation using reduced intensity vs high-dose regimens for hematological malignancy. Bone Marrow Transpl. 40, 209–217 (2007).

    CAS 

    Google Scholar 

  • 43.

    Svahn, B. M., Alvin, O., Ringden, O., Gardulf, A. & Remberger, M. Costs of allogeneic hematopoietic stem cell transplantation. Transplantation 82, 147–153 (2006).

    PubMed 

    Google Scholar 

  • 44.

    La Nasa, G. et al. Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia. Blood 122, 2262–2270 (2013).

    PubMed 

    Google Scholar 

  • 45.

    Jones, R. J. & DeBaun, M. R. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both or neither. Blood 138, 942–947 (2021).

  • 46.

    Hsieh, M. M. et al. Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease. Blood Adv. 4, 2058–2063 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 47.

    Li, Y. et al. Myeloid neoplasms in the setting of sickle cell disease: an intrinsic association with the underlying condition rather than a coincidence; report of 4 cases and review of the literature. Mod. Pathol. 32, 1712–1726 (2019).

    PubMed 

    Google Scholar 

  • 48.

    Seminog, O. O., Ogunlaja, O. I., Yeates, D. & Goldacre, M. J. Risk of individual malignant neoplasms in patients with sickle cell disease: English national record linkage study. J. R. Soc. Med. 109, 303–309 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 49.

    Brunson, A. et al. Increased risk of leukemia among sickle cell disease patients in California. Blood 130, 1597–1599 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 50.

    Grimley, M. et al. Early results from a phase 1/2 study of Aru-1801 gene therapy for sickle cell disease (SCD): manufacturing process enhancements improve efficacy of a modified gamma globin lentivirus vector and reduced intensity conditioning transplant. Blood 136, 20–21 (2020).

  • 51.

    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, 169 (2020).

    Google Scholar 

  • 52.

    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).

    CAS 
    PubMed 

    Google Scholar 

  • 53.

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

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 54.

    Bank, A., Dorazio, R. & Leboulch, P. A phase I/II clinical trial of β-globin gene therapy for β-thalassemia. Ann. N. Y. Acad. Sci. 1054, 308–316 (2005).

    CAS 
    PubMed 

    Google Scholar 

  • 55.

    Ikeda, K., Mason, P. J. & Bessler, M. 3′UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice. Blood 117, 5860–5869 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 56.

    Murakami, Y. et al. Deregulated expression of HMGA2 is implicated in clonal expansion of PIGA deficient cells in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 156, 383–387 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • 57.

    Yu, K. R. et al. HMGA2 regulates the in vitro aging and proliferation of human umbilical cord blood-derived stromal cells through the mTOR/p70S6K signaling pathway. Stem Cell Res. 10, 156–165 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • 58.

    Bottardi, S., Ross, J., Pierre-Charles, N., Blank, V. & Milot, E. Lineage-specific activators affect β-globin locus chromatin in multipotent hematopoietic progenitors. EMBO J. 25, 3586–3595 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 59.

    Jimenez, G., Griffiths, S. D., Ford, A. M., Greaves, M. F. & Enver, T. Activation of the β-globin locus control region precedes commitment to the erythroid lineage. Proc. Natl Acad. Sci. USA 89, 10618–10622 (1992).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 60.

    Schumm, M. et al. Isolation of highly purified autologous and allogeneic peripheral CD34+ cells using the CliniMACS device. J. Hematother. 8, 209–218 (1999).

    CAS 
    PubMed 

    Google Scholar 

  • 61.

    Alter, B. P., Rappeport, J. M., Huisman, T. H., Schroeder, W. A. & Nathan, D. G. Fetal erythropoiesis following bone marrow transplantation. Blood 48, 843–853 (1976).

    CAS 
    PubMed 

    Google Scholar 

  • 62.

    Yang, S. et al. A simple and effective method to generate lentiviral vectors for ex vivo gene delivery to mature human peripheral blood lymphocytes. Hum. Gene Ther. Methods 23, 73–83 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 63.

    Charrier, S. et al. Quantification of lentiviral vector copy numbers in individual hematopoietic colony-forming cells shows vector dose-dependent effects on the frequency and level of transduction. Gene Ther. 18, 479–487 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • 64.

    Shear, H. L. et al. Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism. Blood 92, 2520–2526 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • 65.

    Berry, C. C. et al. INSPIIRED: quantification and visualization tools for analyzing integration site distributions. Mol. Ther. Methods Clin. Dev. 4, 17–26 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 66.

    Sherman, E. et al. INSPIIRED: a pipeline for quantitative analysis of sites of new DNA integration in cellular genomes. Mol. Ther. Methods Clin. Dev. 4, 39–49 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 67.

    Berry, C. C. et al. Estimating abundances of retroviral insertion sites from DNA fragment length data. Bioinformatics 28, 755–762 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Source link