Aplicación de la técnica de repeticiones palindrómicas cortas agrupadas y regularmente interespaciadas (CRISPR) como terapia alternativa en la beta-talasemia mayor
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Published:
Jul 4, 2025
Keywords:
beta-Thalassemia, gene therapy, gene editing, CRISPR, Cooley’s anemia, blood transfusion.
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Abstract
Introduction: Beta-thalassemia major is a severe hereditary hemoglobinopathy caused by mutations in the HBB gene, which encodes the beta chain of hemoglobin. These mutations drastically reduce the production of functional hemoglobin, leading to severe chronic anemia. As an alternative to regular transfusion treatments, a promising gene therapy based on CRISPR/Cas9 technology has been investigated with the aim of correcting these mutations and offering a potential cure. Objective: Analyze the efficacy of the CRISPR/Cas9 technique as a therapeutic approach for beta-thalassemia major, highlighting its benefits and limitations. Methodology: A systematic review of studies published between 2020 and 2025 was conducted using the PRISMA methodology. Results: CRISPR/Cas9-based therapies in numerous studies primarily focused on editing the BCL11A gene, resulting in increased production of HbF. Additionally, other investigations targeted the β039 gene, achieving an increase in both HbF and HbA levels. Conclusion: Genetic therapy has shown effectiveness in more than 90% of patients with beta-thalassemia major, demonstrating that increased levels of HbF help patients achieve transfusion independence. However, certain limitations remain, such as the prohibitive cost and limited accessibility of treatment, particularly in regions with a high prevalence of the disease. General Area of Study: Clinical Laboratory. Specific area of study: Molecular biology. Type of study: Systematic bibliographic review.
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Cevallos Saá, B. S., & Rosero Freire, D. A. (2025). Aplicación de la técnica de repeticiones palindrómicas cortas agrupadas y regularmente interespaciadas (CRISPR) como terapia alternativa en la beta-talasemia mayor. Anatomía Digital, 8(3), 29-47. https://doi.org/10.33262/anatomiadigital.v8i3.3447
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Articulos de revisión bibliográfica
References
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8. Noor FA, Sultana N, Bhuyan GS, Islam MT, Hossain M, Sarker SK, et al. Nationwide carrier detection and molecular characterization of β-thalassemia and hemoglobin E variants in Bangladeshi population. Orphanet Journal of Rare Diseases [Internet]. 2020 [cited 2025 March 27];15(1):15. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6961315/
9. Eren R, Karlsmaz A, Aslan C, Dogu MH, Altlndal S, Yokus O, et al. Beta Thalassemia Minor: Patients Are Not Tired but Depressed and Anxious. Medical Principles and Practice [Internet]. 2020 [cited 2025 March 27];30(1):69-72. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7923903/
10. Baird DC, Batten SH, Sparks SK. Alpha- and Beta-thalassemia: Rapid Evidence Review. American Family Physician [Internet]. 2022 [cited 2025 March 31]; 105(3):272-280. Available from: https://pubmed.ncbi.nlm.nih.gov/35289581/
11. Khan I, Shaikh H. Beta Thalassemia Major (Cooley Anemia). StatPearls [Internet]. 2023 [cited 2025 March 31]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK557522/
12. Morgan M, Schambach A. Successful treatment of transfusion-dependent β-thalassemia: multiple paths to reach potential cure. Signal Transduction and Targeted Therapy [Internet]. 2025 [cited 2025 April 8];10(55):1–2. Available from: https://www.nature.com/articles/s41392-025-02135-9
13. Kargar M, Kaydani GA, Keikhaei B, Saki N, Jalalifar M.A. Association between HLA-DRB1*04, HLA-DQB1*03, and HLA-DQB1*06 with alloimmunization in transfusion-dependent patients with thalassemia: the first case-control study in Iran. Annals of Hematology [Internet]. 2025 [cited 2025 April 7]. Available from: https://pubmed.ncbi.nlm.nih.gov/40100392/
14. Mohammed AWA, Al-absi B, Elkhalifa AME, Alhamidi AH, Abdelrahman M. Red blood cell alloimmunization in blood transfusion-dependent β thalassemia major patients in Sana’a City-Yemen. Scientific Reports [Internet]. 2024 [cited 2025 April 8]. Available from: https://www.nature.com/articles/s41598-024-51561-2
15. Rahmayani S, Cahyadi A, Andarsini MR, Arumsari DK, Efendi F, Ugrasena IDG. Blood transfusion compliance in children with transfusion-dependent Thalassemia. Edelweiss Applied Science and Technology [Internet]. 2025 [cited 2025 April 9];9(1):856–866. Available from: https://learning-gate.com/index.php/2576-8484/article/view/4265
16. Gobbo A, Longo F, Cattaneo CA, Verrienti M, Marzi G, Chamekh F, et al. iFGF23 Plasma Levels in Transfusion-Dependent β-Thalassemia: Insights into Bone and Iron Metabolism. Journal of Clinical Medicine [Internet]. 2025 [cited 2025 April 8];14(6):1834. Available from: https://www.mdpi.com/2077-0383/14/6/1834/htm
17. Selim C, Çiftçiler R, Eroğlu Küçükdiler AH, Keklik Karadağ F, Soyer N. Effect of Iron Accumulation on Bone Mineral Density in Patients Diagnosed with Transfusion-Dependent Thalassemia. International Journal of Clinical Practice [Internet]. 2025 [cited 2025 April 9]; Available from: https://onlinelibrary.wiley.com/doi/full/10.1155/ijcp/5411059
18. Harshita, Singh Narang G, Malhotra P. Impact of chelation therapy on serum zinc levels in transfusion dependent thalassemia patients. Sri Lanka Journal of Child Health [Internet]. 2025 [cited 2025 April 8];54(1):53–57. Available from: https://sljch.sljol.info/articles/10.4038/sljch.v54i1.11141
19. Aydinok Y. Highlights on the Luspatercept Treatment in Thalassemia. Thalassemia Reports [Internet]. 2023 [cited 2025 April 6];13(1):77–84. Available from: https://www.mdpi.com/2039-4365/13/1/8
20. Chen S, Liu Y, Yin X, Lu Q, Du X, Huang R, et al. Transfusion burden and willingness to pay for temporary alleviation of anemia status in transfusion-dependent beta-thalassemia patients in China. BMC health services research [Internet]. 2024 [cited 2025 April 8];24(1215). Available from: https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-024-11547-2
21. Mensah C, Sheth S. When should gene therapy be considered for transfusion-dependent β-thalassemia patients? Hematology: The American Society of Hematology Education Program [Internet]. 2023 [cited 2025 April 27];2023(1):121-124. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10727019/
22. Locatelli F, Cavazzana M, Frangoul H, Fuente J de la, Algeri M, Meisel R. Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside. Molecular Therapy [Internet]. 2024 [cited 2025 April 26];32(5):1202–1218. Available from: https://www.cell.com/action/showFullText?pii=S1525001624001461
23. Thuret I, Ruggeri A, Angelucci E, Chabannon C. Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia. Stem Cells Translational Medicine [Internet]. 2022 [cited 2025 May 4];11(4):407-414. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9052404/
24. Wang L, Siwko S, Li D. Waking up the silenced beauty: CRISPR/Cas9 mediated reactivation of fetal hemoglobin genes to treat severe beta-thalassemia in young patients. Life Medicine [Internet]. 2023 [cited 2025 May 11];2(2): lnad009. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11749768/
25. Cosenza LC, Zuccato C, Zurlo M, Gambari R, Finotti A. Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin. Genes [Internet]. 2022 [cited 2025 May 11];13(10):1727. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601852/
26. Gambari R, Gamberini MR, Cosenza LC, Zuccato C, Finotti A. A β-Thalassemia Cell Biobank: Updates, Further Validation in Genetic and Therapeutic Research and Opportunities During (and after) the COVID-19 Pandemic. Journal of Clinical Medicine [Internet]. 2025 [cited 2025 May 11];14(1):289. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11722022/
27. Christakopoulos GE, Telange R, Yen J, Weiss MJ. Gene therapy and gene editing for β thalassemia. Hematology/oncology clinics of North America [Internet]. 2023 [cited 2025 May 11];37(2):433-477. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10355137/
28. Langer AL, Esrick EB. β-Thalassemia: evolving treatment options beyond transfusion and iron chelation. Hematology: The American Society of Hematology Education Program [Internet]. 2021 [cited 2025 May 11];2021(1):600-606. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8791140/
29. Kerwash E, Johnston JD. Casgevy: Innovative Medicinal Products Require Innovative Approaches to Regulatory Assessment. Pharmaceutics [Internet]. 2024 [cited 2025 May 11];16(7):906. Available from: https://www.mdpi.com/1999-4923/16/7/906/htm
30. Enache OM, Rendo V, Abdusamad M, Lam D, Davison D, Pal S, et al. Cas9 activates the p53 pathway and selects p53-inactivating mutations. Nature genetics [Internet]. 2020 [cited 2025 May 21];52(7):662-668. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7343612/
31. Dixon P. Pueden ser rentables los medicamentos de alto coste? El caso de Casgevy para la anemia de células falciformes y la beta-talasemia. Centro de Medicina Basada en la Evidencia (CEBM), Universidad de Oxford [Internet]. 2024 [cited 2025 May 20]. Available from: https://www-cebm-ox-ac-uk.translate.goog/news/views/can-high-cost-drugs-be-good-value-the-case-of-casgevy-for-sickle-cell-disease-and-beta-thalassemia-1?_x_tr_sl=en&_x_tr_tl=es&_x_tr_hl=es&_x_tr_pto=tc
32. Xu W, Zhang S, Qin H, Yao K. From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine. Journal of Translational Medicine [Internet]. 2024 [cited 2025 May 21];22(1133):1–43. Available from: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05957-3
2. Cosenza LC, Gasparello J, Romanini N, Zurlo M, Zuccato C, Gambari R, et al. Efficient CRISPR-Cas9-based genome editing of β-globin gene on erythroid cells from homozygous β039-thalassemia patients. Molecular Therapy Methods and Clinical Development [Internet]. 2021 [cited 2025 May 20]; 21:507-523. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8091488/
3. Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta Thalassemia. Stat Pearls [Internet]. 2023 [cited 2025 March 25]; Available from: https://pubmed.ncbi.nlm.nih.gov/30285376/
4. Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of β‐thalassemia. European Journal of Hematology [Internet]. 2020 [cited 2025 March 25];105(6):692-703. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7692954/
5. Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. New England Journal of Medicine [Internet]. 2021 [cited 2025 April 23];384(3):252–260. Available from: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2031054
6. Langer AL. Beta-Thalassemia. GeneReviews® [Internet]. 2000 [cited 2025 March 27]; Available from: https://pubmed.ncbi.nlm.nih.gov/20301599/
7. Sahoo S, Sahu N, Das P, Senapati U. Effect of megaloblastic anemia on hemoglobin A 2 and diagnosis of β-thalassemia trait. Indian Journal of Pathology and Microbiology [Internet]. 2023 [cited 2025 March 27];66(2):327–331. Available from: https://pubmed.ncbi.nlm.nih.gov/37077076/
8. Noor FA, Sultana N, Bhuyan GS, Islam MT, Hossain M, Sarker SK, et al. Nationwide carrier detection and molecular characterization of β-thalassemia and hemoglobin E variants in Bangladeshi population. Orphanet Journal of Rare Diseases [Internet]. 2020 [cited 2025 March 27];15(1):15. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6961315/
9. Eren R, Karlsmaz A, Aslan C, Dogu MH, Altlndal S, Yokus O, et al. Beta Thalassemia Minor: Patients Are Not Tired but Depressed and Anxious. Medical Principles and Practice [Internet]. 2020 [cited 2025 March 27];30(1):69-72. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7923903/
10. Baird DC, Batten SH, Sparks SK. Alpha- and Beta-thalassemia: Rapid Evidence Review. American Family Physician [Internet]. 2022 [cited 2025 March 31]; 105(3):272-280. Available from: https://pubmed.ncbi.nlm.nih.gov/35289581/
11. Khan I, Shaikh H. Beta Thalassemia Major (Cooley Anemia). StatPearls [Internet]. 2023 [cited 2025 March 31]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK557522/
12. Morgan M, Schambach A. Successful treatment of transfusion-dependent β-thalassemia: multiple paths to reach potential cure. Signal Transduction and Targeted Therapy [Internet]. 2025 [cited 2025 April 8];10(55):1–2. Available from: https://www.nature.com/articles/s41392-025-02135-9
13. Kargar M, Kaydani GA, Keikhaei B, Saki N, Jalalifar M.A. Association between HLA-DRB1*04, HLA-DQB1*03, and HLA-DQB1*06 with alloimmunization in transfusion-dependent patients with thalassemia: the first case-control study in Iran. Annals of Hematology [Internet]. 2025 [cited 2025 April 7]. Available from: https://pubmed.ncbi.nlm.nih.gov/40100392/
14. Mohammed AWA, Al-absi B, Elkhalifa AME, Alhamidi AH, Abdelrahman M. Red blood cell alloimmunization in blood transfusion-dependent β thalassemia major patients in Sana’a City-Yemen. Scientific Reports [Internet]. 2024 [cited 2025 April 8]. Available from: https://www.nature.com/articles/s41598-024-51561-2
15. Rahmayani S, Cahyadi A, Andarsini MR, Arumsari DK, Efendi F, Ugrasena IDG. Blood transfusion compliance in children with transfusion-dependent Thalassemia. Edelweiss Applied Science and Technology [Internet]. 2025 [cited 2025 April 9];9(1):856–866. Available from: https://learning-gate.com/index.php/2576-8484/article/view/4265
16. Gobbo A, Longo F, Cattaneo CA, Verrienti M, Marzi G, Chamekh F, et al. iFGF23 Plasma Levels in Transfusion-Dependent β-Thalassemia: Insights into Bone and Iron Metabolism. Journal of Clinical Medicine [Internet]. 2025 [cited 2025 April 8];14(6):1834. Available from: https://www.mdpi.com/2077-0383/14/6/1834/htm
17. Selim C, Çiftçiler R, Eroğlu Küçükdiler AH, Keklik Karadağ F, Soyer N. Effect of Iron Accumulation on Bone Mineral Density in Patients Diagnosed with Transfusion-Dependent Thalassemia. International Journal of Clinical Practice [Internet]. 2025 [cited 2025 April 9]; Available from: https://onlinelibrary.wiley.com/doi/full/10.1155/ijcp/5411059
18. Harshita, Singh Narang G, Malhotra P. Impact of chelation therapy on serum zinc levels in transfusion dependent thalassemia patients. Sri Lanka Journal of Child Health [Internet]. 2025 [cited 2025 April 8];54(1):53–57. Available from: https://sljch.sljol.info/articles/10.4038/sljch.v54i1.11141
19. Aydinok Y. Highlights on the Luspatercept Treatment in Thalassemia. Thalassemia Reports [Internet]. 2023 [cited 2025 April 6];13(1):77–84. Available from: https://www.mdpi.com/2039-4365/13/1/8
20. Chen S, Liu Y, Yin X, Lu Q, Du X, Huang R, et al. Transfusion burden and willingness to pay for temporary alleviation of anemia status in transfusion-dependent beta-thalassemia patients in China. BMC health services research [Internet]. 2024 [cited 2025 April 8];24(1215). Available from: https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-024-11547-2
21. Mensah C, Sheth S. When should gene therapy be considered for transfusion-dependent β-thalassemia patients? Hematology: The American Society of Hematology Education Program [Internet]. 2023 [cited 2025 April 27];2023(1):121-124. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10727019/
22. Locatelli F, Cavazzana M, Frangoul H, Fuente J de la, Algeri M, Meisel R. Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside. Molecular Therapy [Internet]. 2024 [cited 2025 April 26];32(5):1202–1218. Available from: https://www.cell.com/action/showFullText?pii=S1525001624001461
23. Thuret I, Ruggeri A, Angelucci E, Chabannon C. Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia. Stem Cells Translational Medicine [Internet]. 2022 [cited 2025 May 4];11(4):407-414. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9052404/
24. Wang L, Siwko S, Li D. Waking up the silenced beauty: CRISPR/Cas9 mediated reactivation of fetal hemoglobin genes to treat severe beta-thalassemia in young patients. Life Medicine [Internet]. 2023 [cited 2025 May 11];2(2): lnad009. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11749768/
25. Cosenza LC, Zuccato C, Zurlo M, Gambari R, Finotti A. Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin. Genes [Internet]. 2022 [cited 2025 May 11];13(10):1727. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601852/
26. Gambari R, Gamberini MR, Cosenza LC, Zuccato C, Finotti A. A β-Thalassemia Cell Biobank: Updates, Further Validation in Genetic and Therapeutic Research and Opportunities During (and after) the COVID-19 Pandemic. Journal of Clinical Medicine [Internet]. 2025 [cited 2025 May 11];14(1):289. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11722022/
27. Christakopoulos GE, Telange R, Yen J, Weiss MJ. Gene therapy and gene editing for β thalassemia. Hematology/oncology clinics of North America [Internet]. 2023 [cited 2025 May 11];37(2):433-477. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10355137/
28. Langer AL, Esrick EB. β-Thalassemia: evolving treatment options beyond transfusion and iron chelation. Hematology: The American Society of Hematology Education Program [Internet]. 2021 [cited 2025 May 11];2021(1):600-606. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8791140/
29. Kerwash E, Johnston JD. Casgevy: Innovative Medicinal Products Require Innovative Approaches to Regulatory Assessment. Pharmaceutics [Internet]. 2024 [cited 2025 May 11];16(7):906. Available from: https://www.mdpi.com/1999-4923/16/7/906/htm
30. Enache OM, Rendo V, Abdusamad M, Lam D, Davison D, Pal S, et al. Cas9 activates the p53 pathway and selects p53-inactivating mutations. Nature genetics [Internet]. 2020 [cited 2025 May 21];52(7):662-668. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7343612/
31. Dixon P. Pueden ser rentables los medicamentos de alto coste? El caso de Casgevy para la anemia de células falciformes y la beta-talasemia. Centro de Medicina Basada en la Evidencia (CEBM), Universidad de Oxford [Internet]. 2024 [cited 2025 May 20]. Available from: https://www-cebm-ox-ac-uk.translate.goog/news/views/can-high-cost-drugs-be-good-value-the-case-of-casgevy-for-sickle-cell-disease-and-beta-thalassemia-1?_x_tr_sl=en&_x_tr_tl=es&_x_tr_hl=es&_x_tr_pto=tc
32. Xu W, Zhang S, Qin H, Yao K. From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine. Journal of Translational Medicine [Internet]. 2024 [cited 2025 May 21];22(1133):1–43. Available from: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05957-3