Genetic Engineering in Hematopoietic Stem Cells for β-Hemoglobinopathies Treatment: Advances, Challenges, and Clinical Translation
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Abstract
β-hemoglobinopathies rank among the most prevalent inherited blood disorders globally. Traditional management strategies are primarily palliative and often associated with significant challenges, including iron overload and limited long-term efficacy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for transfusion-dependent patients, but its broader applicability is constrained by factors that limit its use. Utilizing viral vectors and gene-editing tools, particularly CRISPR-Cas9 technology, researchers have developed therapies that target the root causes of these disorders. These innovative approaches have demonstrated substantial therapeutic potential, accompanied by favorable safety profiles, in clinical settings. Since the initial investigations, the genome editing tool has rapidly advanced for genetic abnormalities, particularly monogenic blood diseases, including β-hemoglobinopathies. This method suggests an approach with lower concerns in viral gene integration and insertional mutagenesis issues. This review comprehensively surveys the therapeutic strategies for β-thalassemia and sickle cell disease (SCD) currently in preclinical and clinical development, with a focus on the evolving treatment paradigm. Looking forward, critical research priorities include optimizing the efficiency and specificity of gene-editing platforms and pioneering novel delivery systems to guarantee both therapeutic efficacy and clinical safety.
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3. Cavazzana M, Miccio A, Andre-Schmutz I, et al. Gene replacement therapy for hemoglobinopathies: clinical benefit & challenges for widespread utilization. Cell Gene Ther Insights. 2018 ; 4(7):653-664.
4. Flint J, Harding RM, Boyce AJ, et al. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol . 1998;11(1):1-51.
5. Lippi G, Mattiuzzi C. Updated worldwide epidemiology of inherited erythrocyte disorders. Acta Haematol. 2020;143(3):196-203.
6. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018:4:18010.
7. Sakuno G, Kato JM, Carricondo PC. Hemoglobinopathies and Coagulopathies. Diseases of the Retina and Vitreous: Clinical & Surgical Practice and Innovations: Springer; 2024. p. 1-14.
8. Thomson AM, McHugh TA, Oron AP, et al. 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. 2023;10(8):e585-e99.
9. Ochocinski D, Dalal M, Black LV, et al. Life-threatening infectious complications in sickle cell disease: a concise narrative review. Front Pediatr. 2020;8:38.
10. Segura EER, Ayoub PG, Hart KL, et al. Gene therapy for β-hemoglobinopathies: From discovery to clinical trials. Viruses. 2023;15(3):713.
11. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33(3):259-71.
12. Wang L, Li L, Ma Y, et al. Reactivation of γ-globin expression through Cas9 or base editor to treat β-hemoglobinopathies. Cell Res. 2020;30(3):276-8.
13. Kim A, Dean A. Chromatin loop formation in the β-globin locus and its role in globin gene transcription. Mol Cells. 2012;34(1):1-5.
14. Noordermeer D, De Wit E, Klous P, et al. Variegated gene expression caused by cell-specific long-range DNA interactions. Nat Cell Biol. 2011;13(8):944-51.
15. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23(1):1-8.
16. Khandros E, Blobel GA. Elevating fetal hemoglobin: recently discovered regulators and mechanisms. Blood. 2024;144(8):845-52.
17. Donze D, Townes TM, Bieker JJ. Role of Erythroid Kruppel-like Factor in Human γ-to β-Globin Gene Switching. J Biol Chem. 1995;270(4):1955-9.
18. Perrine SP, Mankidy R, Boosalis MS, et al. Erythroid Kruppel‐like factor (EKLF) is recruited to the γ‐globin gene promoter as a co‐activator and is required for γ‐globin gene induction by short‐chain fatty acid derivatives. Eur J Haematol. 2009;82(6):466-76.
19. Parkins AC, Sharpe AH, Orkin SH. Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature. 1995;375(6529):318-22.
20. Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42(9):801-5.
21. Deng W, Lee J, Wang H, et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012;149(6):1233-44.
22. Caulier AL, Sankaran VG. Molecular and cellular mechanisms that regulate human erythropoiesis. Blood. 2022;139(16):2450-9.
23. Vakoc CR, Letting DL, Gheldof N, et al. Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1. Mol Cell. 2005;17(3):453-62.
24. Shivdasani RA, Mayer EL, Orkin SH. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995;373(6513):432-4.
25. Porcher C, Chagraoui H, Kristiansen MS. SCL/TAL1: a multifaceted regulator from blood development to disease. Blood. 2017;129(15):2051-60.
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| Files | ||
| Issue | Vol 19 No 4 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Gene therapy; CRISPR/Cas; β-thalassemia; Sickle cell anemia; Clinical trials | ||
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How to Cite
1.
Taebi S, Eskandari F, Kohandani M, Manoochehrabadi T, Nasiri H. Genetic Engineering in Hematopoietic Stem Cells for β-Hemoglobinopathies Treatment: Advances, Challenges, and Clinical Translation. Int J Hematol Oncol Stem Cell Res. 2025;19(4):399-423.
