Gene-Edited Haematopoietic Stem Cells for the Treatment of Inherited Haemoglobinopathies
DOI:
https://doi.org/10.5281/zenodo.22274335Keywords:
Haematopoietic stem cells; Gene editing; Sickle cell disease; Beta-thalassaemia; Fetal haemoglobinAbstract
Background: Sickle cell disease and beta-thalassaemia are the commonest monogenic disorders worldwide; the Global
Burden of Disease 2021 analysis estimated 7.74 million people living with sickle cell disease.
Objective: To set out what the primary trial data show for lentiviral gene addition and nuclease editing of autologous
haematopoietic stem cells, and what they leave open.
Methods: Narrative review of registrational trials, preclinical editing studies and safety reports.
Findings: In severe sickle cell disease, 29 of 30 evaluable patients (97%) were free of vaso-occlusive crises for at least 12
months, from 44 infused. In transfusion-dependent beta-thalassaemia, 32 of 35 (91%) achieved transfusion independence
from 52 infused, with mean haemoglobin 13.1 g/dL.
Conclusions: The evidence supports durable correction by two distinct routes in small single-arm trials, but not long-term
safety: the leukaemia signal is unexplained and off-target quantification incomplete.
References
Piel, F.B., Steinberg, M.H., Rees, D.C. (2017) Sickle Cell Disease. New England Journal of Medicine, 376(16): 1561-1573.
Taher, A.T., Weatherall, D.J., Cappellini, M.D. (2018) Thalassaemia. The Lancet, 391(10116): 155-167.
Ferrari, G., Thrasher, A.J., Aiuti, A. (2021) Gene therapy using haematopoietic stem and progenitor cells. Nature Reviews Genetics, 22(4): 216-234.
Thomson, A.M., McHugh, T.A., Oron, A.P., Teply, C., Lonberg, N., Vilchis Tella, V., et al. (2023) Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. The Lancet Haematology, 10(8): e585-e599.
Sankaran, V.G., Menne, T.F., Xu, J., Akie, T.E., Lettre, G., Van Handel, B., et al. (2008) Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A. Science, 322(5909): 1839-1842.
Bauer, D.E., Kamran, S.C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., et al. (2013) An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. Science, 342(6155): 253-257.
Canver, M.C., Smith, E.C., Sher, F., Pinello, L., Sanjana, N.E., Shalem, O., et al. (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature, 527(7577): 192-197.
Traxler, E.A., Yao, Y., Wang, Y.-D., Woodard, K.J., Kurita, R., Nakamura, Y., et al. (2016) A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nature Medicine, 22(9): 987-990.
Weber, L., Frati, G., Felix, T., Hardouin, G., Casini, A., Wollenschlaeger, C., et al. (2020) Editing a gamma-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Science Advances, 6(7): eaay9392.
Frangoul, H., Altshuler, D., Cappellini, M.D., Chen, Y.-S., Domm, J., Eustace, B.K., et al. (2021) CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. New England Journal of Medicine, 384(3): 252-260.
Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M.Y., Molinari, L., et al. (2024) Exagamglogene Autotemcel for Severe Sickle Cell Disease. New England Journal of Medicine, 390(18): 1649-1662.
Locatelli, F., Lang, P., Wall, D., Meisel, R., Corbacioglu, S., Li, A.M., et al. (2024) Exagamglogene Autotemcel for Transfusion-Dependent beta-Thalassemia. New England Journal of Medicine, 390(18): 1663-1676.
Esrick, E.B., Lehmann, L.E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M.F., et al. (2021) Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. New England Journal of Medicine, 384(3): 205-215.
Sharma, A., Boelens, J.J., Cancio, M., Hankins, J.S., Bhad, P., Azizy, M., et al. (2023) CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. New England Journal of Medicine, 389(9): 820-832.
Fu, B., Liao, J., Chen, S., Li, W., Wang, Q., Hu, J., et al. (2022) CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric beta0/beta0 transfusion-dependent beta-thalassemia. Nature Medicine, 28(8): 1573-1580.
Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., et al. (2010) Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature, 467(7313): 318-322.
Ribeil, J.-A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M., Magrin, E., et al. (2017) Gene Therapy in a Patient with Sickle Cell Disease. New England Journal of Medicine, 376(9): 848-855.
Thompson, A.A., Walters, M.C., Kwiatkowski, J.L., Rasko, J.E.J., Ribeil, J.-A., Hongeng, S., et al. (2018) Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. New England Journal of Medicine, 378(16): 1479-1493.
Locatelli, F., Thompson, A.A., Kwiatkowski, J.L., Porter, J.B., Thrasher, A.J., Hongeng, S., et al. (2022) Betibeglogene Autotemcel Gene Therapy for Non-beta0/beta0 Genotype beta-Thalassemia. New England Journal of Medicine, 386(5): 415-427.
Kanter, J., Walters, M.C., Krishnamurti, L., Mapara, M.Y., Kwiatkowski, J.L., Rifkin-Zenenberg, S., et al. (2022) Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. New England Journal of Medicine, 386(7): 617-628.
Magrin, E., Semeraro, M., Hebert, N., Joseph, L., Magnani, A., Chalumeau, A., et al. (2022) Long-term outcomes of lentiviral gene therapy for the beta-hemoglobinopathies: the HGB-205 trial. Nature Medicine, 28(1): 81-88.
Dever, D.P., Bak, R.O., Reinisch, A., Camarena, J., Washington, G., Nicolas, C.E., et al. (2016) CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature, 539(7629): 384-389.
Wu, Y., Zeng, J., Roscoe, B.P., Liu, P., Yao, Q., Lazzarotto, C.R., et al. (2019) Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nature Medicine, 25(5): 776-783.
Newby, G.A., Yen, J.S., Woodard, K.J., Mayuranathan, T., Lazzarotto, C.R., Li, Y., et al. (2021) Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature, 595(7866): 295-302.
Mayuranathan, T., Newby, G.A., Feng, R., Yao, Y., Mayberry, K.D., Lazzarotto, C.R., et al. (2023) Potent and uniform fetal hemoglobin induction via base editing. Nature Genetics, 55(7): 1210-1220.
Zeng, J., Wu, Y., Ren, C., Bonanno, J., Shen, A.H., Shea, D., et al. (2020) Therapeutic base editing of human hematopoietic stem cells. Nature Medicine, 26(4): 535-541.
Everette, K.A., Newby, G.A., Levine, R.M., Mayberry, K., Jang, Y., Mayuranathan, T., et al. (2023) Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nature Biomedical Engineering, 7(5): 616-628.
Hsieh, M.M., Bonner, M., Pierciey, F.J., Uchida, N., Rottman, J., Demopoulos, L., et al. (2020) Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease. Blood Advances, 4(9): 2058-2063.
Goyal, S., Tisdale, J., Schmidt, M., Kanter, J., Jaroscak, J., Whitney, D., et al. (2022) Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease. New England Journal of Medicine, 386(2): 138-147.
Jones, R.J., DeBaun, M.R. (2021) Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither. Blood, 138(11): 942-947.
Cromer, M.K., Barsan, V.V., Jaeger, E., Wang, M., Hampton, J.P., Chen, F., et al. (2022) Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells. Nature Communications, 13(1): 4724.
Basu, A., Winn, A.N., Johnson, K.M., Jiao, B., Devine, B., Hankins, J.S., et al. (2024) Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States. Annals of Internal Medicine, 177(2): 155-164.
