Современные подходы к лечению β-талассемии: от переливания крови до генной терапии

Бета-талассемия – наследственное заболевание, обусловленное патогенными вариантами в гене HBB, которые ведут к нарушению синтеза β-цепей глобина, приводящему к неэффективному эритропоэзу, развитию микроцитарной гипохромной анемии и комплексу системных осложнений. В статье рассмотрены современные стратегии терапии этого состояния. Адекватная гемотрансфузионная поддержка в сочетании с регулярной хелаторной терапией традиционно остается основой стандартного лечения. В современной практике также применяются другие методы консервативной терапии, например, направленные на индукцию фетального гемоглобина, стимуляцию эритропоэза и другие звенья патогенеза. Аллогенная трансплантация гемопоэтических стволовых клеток до недавнего времени являлась единственным методом, способным обеспечить полное излечение β-талассемии, однако ее применение ограничено доступностью полностью совместимого донора и рисками трансплантационных осложнений, в том числе высокий риск неприживления трансплантата при данной патологии, реакции «трансплантат против хозяина». Развитие генной терапии, направленной на восстановление синтеза β-глобина или индукцию экспрессии фетального гемоглобина, открывает перспективы функционального излечения без необходимости выполнения аллогенной трансплантации гемопоэтических стволовых клеток, что преодолевает многие ее ограничения, в том числе отсутствие оптимального донора, реакции «трансплантат против хозяина» и отторжение трансплантата. В обзоре представлен анализ существующих методов лечения, их ограничений и возможностей клинического применения генной терапии при β-талассемии.

1. Kattamis A., Forni G. L., Aydinok Y., Viprakasit V. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol. 2020;105(6):692–703. doi: 10.1111/ejh.13512. PMID: 32886826.

2. Regional desk review of haemoglobinopathies with an emphasis on thalassaemia and accessibility and availability of safe blood and blood products as per these patients’ requirement in South-East Asia under universal health coverage [Electronic resource]. URL: https://www.who.int/publications/i/item/9789290228516 (appeal date 20.10.2025).

3. Хачатурян А.Г., Назаров В.Д., Дубина И.А., Лапин С.В., Сидоренко Д.В., Вильгельми А.А., Первакова М.Ю., Эмануэль В.Л. К вопросу об актуальности молекулярно-генетической диагностики β-талассемии в Российской Федерации. Российский журнал детской гематологии и онкологии. 2024;11(4):89–97. doi: 10.21682/2311-1267-2024-11-4-89-97.

4. Sankaran V.G., Orkin S.H. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013;3(1):а011643. doi: 10.1101/cshperspect.a011643. PMID: 23209159.

5. Farmakis D., Porter J., Taher A., Domenica Cappellini M., Angastiniotis M., Eleftheriou A. 2021 Thalassaemia international federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere. 2022;6(8):e732. doi: 10.1097/HS9.0000000000000732. PMID: 35928543.

6. Jaing T.H., Chang T.Y., Chen S.H., Lin C.W., Wen Y.C., Chiu C.C. Molecular genetics of β-thalassemia: a narrative review. Medicine (Baltimore). 2021;100(45):e27522. doi: 10.1097/MD.0000000000027522.

7. Musallam K.M., Vitrano A., Meloni A., Addario Pollina S., Di Marco V., Hussain Ansari S., Filosa A., Ricchi P., Ceci A., Daar S., Vlachaki E., Singer S.T., Naserullah Z.A., Pepe A., Scondotto S., Dardanoni G., Karimi M., El-Beshlawy A., Hajipour M., Bonifazi F., Vichinsky E., Taher A.T., Sankaran V.G., Maggio A.; International Working Group on Thalassemia (IWG-THAL). Primary HBB gene mutation severity and long-term outcomes in a global cohort of β-thalassaemia. Br J Haematol. 2022;196(2):414–23. doi: 10.1111/bjh.17897. PMID: 34697800.

8. Saliba A.N., Musallam K.M., Taher A.T. How I treat non-transfusiondependent β-thalassemia. Blood. 2023;142(11):949–60. doi: 10.1182/blood.2023020683. PMID: 37478396.

9. Cao A., Galanello R. Beta-thalassemia. Genet Med. 2010;12(2):61–76. doi: 10.1097/GIM.0b013e3181cd68ed. PMID: 20098328.

10. Lekawanvijit S., Chattipakorn N. Iron overload thalassemic cardiomyopathy: iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity. Can J Cardiol. 2009;25(4):213–21. doi: 10.1016/s0828-282x(09)70064-9. PMID: 19340344.

11. Borgna-Pignatti C., Vergine G., Lombardo T., Cappellini M.D., Cianciulli P., Maggio A., Renda D., Lai M.E., Mandas A., Forni G., Piga A., Bisconte M.G. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124(1):114–7. doi: 10.1046/j.1365-2141.2003.04732.x. PMID: 14675416.

12. Borgna-Pignatti C., Rugolotto S., De Stefano P., Zhao H., Cappellini M.D., Del Vecchio G.C., Romeo M.A., Forni G.L., Gamberini M.R., Ghilardi R., Piga A., Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187–93. PMID: 15477202.

13. Cappellini M.D., Cohen A., Porter J. Guidelines for the management of transfusion dependent thalassaemia. 3rd ed. Nicosia Thalass Int Fed. [Internet]. 2014.

14. Porter J.B. Practical management of iron overload. Br J Haematol. 2001;115(2):239–52. doi: 10.1046/j.1365-2141.2001.03195.x. PMID: 11703317.

15. Taher A.T., Musallam K.M., Cappellini M.D. β-thalassemias. N Engl J Med. 2021;384(8):727–43. doi: 10.1056/NEJMra2021838. PMID: 33626255.

16. Ali S., Mumtaz S., Shakir H.A., Khan M., Tahir H.M., Mumtaz S., Mughal T.A., Hassan A., Kazmi S.A.R., Sadia, Irfan M., Khan M.A. Current status of beta-thalassemia and its treatment strategies. Mol Genet Genomic Med. 2021;9(12):e1788. doi: 10.1002/mgg3.1788. Epub 2021 Nov 5. PMID: 34738740.

17. Ruivard M., Lobbes H. Diagnosis and treatment of iron overload. La Rev. Médecine Interne. 2023;44(12):656–61. doi: 10.1016/j. revmed.2023.07.002. Epub 2023 Jul 26. PMID: 37507250.

18. Taher A.T., Cappellini M.D. How I manage medical complications of β-thalassemia in adults. Blood. 2018;132(17):1781–91. doi: 10.1182/blood-2018-06-818187. Epub 2018 Sep 11. PMID: 30206117.

19. Bajwa H., Basit H. Thalassemia. StatPearls [Internet]. 2025.

20. Dragomir M., Petrescu D.G.E., Manga G.E., Călin G.A., Vasilescu C. Patients after splenectomy: old risks and new perspectives. Chirurgia (Bucur). 2016;111(5):393–9. doi: 10.21614/chirurgia.111.5.393. PMID: 27819637.

21. Theocharaki K., Anastasiadi A.T., Delicou S., Tzounakas V.L., Barla I., Rouvela S., Kazolia E., Tzafa G., Mpekoulis G., Gousdovas T., Pavlou E., Kostopoulos I.V., Velentzas A.D., Simantiris N., Xydaki A., Vassilaki N., Voskaridou E., Aggeli I.K., Nomikou E., Tsitsilonis O., Papageorgiou E., Thomaidis N., Gikas E., Politou M., Komninaka V., Antonelou M.H. Cellular and biochemical heterogeneity contributes to the phenotypic diversity of transfusiondependent β-thalassemia. Blood Adv. 2025;9(9):2091–107. doi: 10.1182/bloodadvances.2024015232. PMID: 39928952.

22. Bacon E.R., Dalyot N., Filon D., Schreiber L., Rachmilewitz E.A., Oppenheim A. Hemoglobin switching in humans is accompanied by changes in the ratio of the transcription factors, GATA-1 and SP1. Mol Med. 1995;1(3):297–305. doi: 10.1007/BF03401554. PMID: 8529108.

23. Huang T., Jiang H., Tang G., Li J., Huang X., Huang Z., Zhang H. Effi cacy and safety of hydroxyurea therapy on patients with β-thalassemia: a systematic review and meta-analysis. Front Med (Lausanne). 2025;11:1480831. doi: 10.3389/fmed.2024.1480831. PMID: 39882530.

24. Markham A. Luspatercept: fi rst approval. Drugs. 2020;80(1):85–90. doi: 10.1007/s40265-019-01251-5. PMID: 31939073.

25. Musallam K.M., Sheth S., Cappellini M.D., Kattamis A., Kuo K.H.M., Taher A.T. Luspatercept for transfusion-dependent β-thalassemia: time to get real. Ther Adv Hematol. 2023;14:20406207231195594. doi: 10.1177/20406207231195594. PMID: 37645382.

26. Cappellini M.D., Viprakasit V., Taher A.T., Georgiev P., Kuo K.H.M., Coates T., Voskaridou E., Liew H.K., Pazgal-Kobrowski I., Forni G.L., Perrotta S., Khelif A., Lal A., Kattamis A., Vlachaki E., Origa R., Aydinok Y., Bejaoui M., Ho P.J., Chew L.P., Bee P.C., Lim S.M., Lu M.Y., Tantiworawit A., Ganeva P., Gercheva L., Shah F., Neufeld E.J., Thompson A., Laadem A., Shetty J.K., Zou J., Zhang J., Miteva D., Zinger T, Linde P.G., Sherman M.L., Hermine O., Porter J., Piga A.; BELIEVE Investigators. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382(13):1219–31. doi: 10.1056/NEJMoa1910182. PMID: 32212518.

27. Baronciani D., Angelucci E., Potschger U., Gaziev J., Yesilipek A., Zecca M., Orofi no M.G., Giardini C., Al-Ahmari A., Marktel S., de la Fuente J., Ghavamzadeh A., Hussein A.A., Targhetta C., Pilo F., Locatelli F., Dini G., Bader P., Peters C. Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000–2010. Bone Marrow Transplant. 2016;51(4):536–41. doi: 10.1038/bmt.2015.293. Epub 2016 Jan 11. PMID: 26752139.

28. Vellaichamy Swaminathan V., Ravichandran N., Ramanan K.M., Meena S.K., Varla H., Ramakrishnan B., Jayakumar I., Uppuluri R., Raj R. Augmented immunosuppression and PTCY-based haploidentical hematopoietic stem cell transplantation for thalassemia major. Pediatr Transplant. 2021;25(2):e13893. doi: 10.1111/petr.13893. PMID: 33111490.

29. Khandelwal P., Yeh R.F., Yu L., Lane A., Dandoy C.E., El-Bietar J., Davies S.M., Grimley M.S. Graft-versus-host disease prophylaxis with abatacept reduces severe acute graft-versus-host disease in allogeneic hematopoietic stem cell transplant for beta-thalassemia major with busulfan, fl udarabine, and thiotepa. Transplantation. 2021;105(4):891–6. doi: 10.1097/TP.0000000000003327. PMID: 32467478.

30. Lüftinger R., Zubarovskaya N., Galimard J.E., Cseh A., Salzer E., Locatelli F., Algeri M., Yesilipek A., de la Fuente J., Isgrò A., Alseraihy A., Angelucci E., Smiers F.J., La La Nasa G., Zecca M., Fisgin T., Unal E., Kleinschmidt K., Peters C., Lankester A., Corbacioglu S.; EBMT Pediatric Diseases, Inborn Errors Working Parties. Busulfan–fl udarabine- or treosulfan–fl udarabine-based myeloablative conditioning for children with thalassemia major. Ann Hematol. 2022;101(3):655–65. doi: 10.1007/s00277-021-04732-4. PMID: 34999929.

31. Peters C. Allogeneic hematopoietic stem cell transplantation to cure transfusion-dependent thalassemia: timing matters! Biol Blood Marrow Transpl. 2018;24(6):1107–8. doi: 10.1016/j.bbmt.2018.04.023. PMID: 29704543.

32. Mulas O., Mola B., Caocci G., La Nasa G. Conditioning regimens in patients with β-thalassemia who underwent hematopoietic stem cell transplantation: a scoping review. J Clin Med. 2022;11(4):907. doi: 10.3390/jcm11040907. PMID: 35207178.

33. Mathews V., George B., Deotare U., Lakshmi K.M., Viswabandya A., Daniel D., Chandy M., Srivastava A. A new stratifi cation strategy that identifi es a subset of class III patients with an adverse prognosis among children with beta thalassemia major undergoing a matched related allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(8):889–94. doi: 10.1016/j.bbmt.2007.05.004. PMID: 17640592.

34. Bernardo M.E., Piras E., Vacca A., Giorgiani G., Zecca M., Bertaina A., Pagliara D., Contoli B., Pinto R.M., Caocci G., Mastronuzzi A., La Nasa G., Locatelli F. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reducedtoxicity conditioning regimen based on the use of treosulfan. Blood. 2012;120(2):473–6. doi: 10.1182/blood-2012-04-423822. PMID: 22645178.

35. Dzierzak E.A., Papayannopoulou T., Mulligan R.C. Lineage-specifi c expression of a human beta-globin gene in murine bone marrow transplant recipients reconstituted with retrovirus-transduced stem cells. Nature. 1988;331(6151):35–41. doi: 10.1038/331035a0. PMID: 2893284.

36. Ellis J., Pasceri P., Tan-Un K.C., Wu X., Harper A., Fraser P., Grosveld F. Evaluation of beta-globin gene therapy constructs in single copy transgenic mice. Nucleic Acids Res. 1997;25(6):1296–302. doi: 10.1093/nar/25.6.1296. PMID: 9092642.

37. May C., Rivella S., Callegari J., Heller G., Gaensler K.M., Luzzatto L., Sadelain M. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature. 2000;406(6791):82–6. doi: 10.1038/35017565. PMID: 10894546.

38. Persons D.A., Hargrove P.W., Allay E.R., Hanawa H., Nienhuis A.W. The degree of phenotypic correction of murine beta-thalassemia intermedia following lentiviral-mediated transfer of a human gammaglobin gene is infl uenced by chromosomal position eff ects and vector copy number. Blood. 2003;101(6):2175–83. doi: 10.1182/blood-2002-07-2211. PMID: 12411297.

39. Imren S., Payen E., Westerman K.A., Pawliuk R., Fabry M.E., Eaves C.J., Cavilla B., Wadsworth L.D., Beuzard Y., Bouhassira E.E., Russell R., London I.M., Nagel R.L., Leboulch P., Humphries R.K. Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci U S A. 2002;99(22):14380–5. doi: 10.1073/pnas.212507099. PMID: 12391330.

40. Negre O., Eggimann A.V., Beuzard Y., Ribeil J.A., Bourget P., Borwornpinyo S., Hongeng S., Hacein-Bey S., Cavazzana M., Leboulch P., Payen E. Gene therapy of the β-hemoglobinopathies by lentiviral transfer of the β(A(T87Q))-globin gene. Hum Gene Ther. 2016;27(2):148–65. doi: 10.1089/hum.2016.007. PMID: 26886832.

41. Cavazzana-Calvo M., Payen E., Negre O., Wang G., Hehir K., Fusil F., Down J., Denaro M., Brady T., Westerman K., Cavallesco R., Gillet-Legrand B., Caccavelli L., Sgarra R., Maouche-Chrétien L., Bernaudin F., Girot R., Dorazio R., Mulder G.J., Polack A., Bank A., Soulier J., Larghero J., Kabbara N., Dalle B., Gourmel B., Socie G., Chrétien S., Cartier N., Aubourg P., Fischer A., Cornetta K., Galacteros F., Beuzard Y., Gluckman E., Bushman F., Hacein-BeyAbina S., Leboulch P. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010;467(7313):318–22. doi: 10.1038/nature09328. PMID: 20844535.

42. Thompson A.A., Walters M.C., Kwiatkowski J., Rasko J.E.J., Ribeil J.A., Hongeng S., Magrin E., Schiller G.J., Payen E., Semeraro M., Moshous D., Lefrere F., Puy H., Bourget P., Magnani A., Caccavelli L., Diana J.S., Suarez F., Monpoux F., Brousse V., Poirot C., Brouzes C., Meritet J.F., Pondarré C., Beuzard Y., Chrétien S., Lefebvre T., Teachey D.T., Anurathapan U., Ho P.J., von Kalle C., Kletzel M., Vichinsky E., Soni S., Veres G., Negre O., Ross R.W., Davidson D., Petrusich A., Sandler L., Asmal M., Hermine O., De Montalembert M., Hacein-Bey-Abina S., Blanche S., Leboulch P., Cavazzana M. Gene therapy in patients with transfusiondependent β-thalassemia. N Engl J Med. 2018;378(16):1479–93. doi: 10.1056/NEJMoa1705342. PMID: 29669226.

43. Locatelli F., Thompson A.A., Kwiatkowski J.L., Porter J.B., Thrasher A.J., Hongeng S., Sauer M.G., Thuret I., Lal A., Algeri M., Schneiderman J., Olson T.S., Carpenter B., Amrolia P.J., Anurathapan U., Schambach A., Chabannon C., Schmidt M., Labik I., Elliot H., Guo R., Asmal M., Colvin R.A., Walters M.C. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415–27. doi: 10.1056/NEJMoa2113206. PMID: 34891223.

44. Kwiatkowski J.L., Walters M.C., Hongeng S., Yannaki E., Kulozik A.E., Kunz J.B., Sauer M.G., Thrasher A.J., Thuret I., Lal A., Tao G., Ali S., Thakar H.L., Elliot H., Lodaya A., Lee J., Colvin R.A., Locatelli F., Thompson A.A. Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial. Lancet. 2024;404(10468):2175–86. doi: 10.1016/S0140-6736(24)01884-1. PMID: 39527960.

45. Rubin R. New gene therapy for β-thalassemia. JAMA. 2022;328(11):1030. doi: 10.1001/jama.2022.14709. PMID: 36125483.

46. Pflaum (Kempler) C. FDA approves fi rst gene therapies to treat patients with sickle cell disease [Electronic resource]. FDA News Release. 2023. URL: https://www.fda.gov/news-events/pressannouncements/fda-approves-fi rst-gene-therapies-treat-patientssickle-cell-disease.

47. Kiem H.P., Rumugam P., Christopher B., Adair J.E., Beard B.C., Fox C., Malik P. Safety of a gamma globin expressing lentivirus vector in a non-human primate model for gene therapy of sickle cell disease. Blood. 2013;122(21):2896. doi: 10.1182/blood.V122.21.2896.2896.

48. Drakopoulou E., Georgomanoli M., Lederer C.W., Panetsos F., Kleanthous M., Voskaridou E., Valakos D., Papanikolaou E., Anagnou N.P. The optimized γ-globin lentiviral vector GGHI-mB-3D leads to nearly therapeutic HbF levels in vitro in CD34+ cells from sickle cell disease patients. Viruses. 2022;14(12):2716. doi: 10.3390/v14122716. PMID: 36560719.

49. Shen Y., Li R., Teichert K., Montbleau K.E., Verboon J.M., Voit R.A., Sankaran V.G. Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing. PLoS Genet. 2021;17(10):e1009835. doi: 10.1371/journal.pgen.1009835. PMID: 34634037.

50. Krivega I., Dean A. LDB1-mediated enhancer looping can be established independent of mediator and cohesin. Nucleic Acids Res. 2017;45(14):8255–68. doi: 10.1093/nar/gkx433. PMID: 28520978.

51. Doerfl er P.A., Feng R., Li Y., Palmer L.E., Porter S.N., Bell H.W., Crossley M., Pruett-Miller S.M., Cheng Y., Weiss M.J. Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin. Nat Genet. 2021;53(8):1177–86. doi: 10.1038/s41588-021-00904-0. PMID: 34341563.

52. Han Y., Tan X., Jin T., Zhao S., Hu L., Zhang W., Kurita R., Nakamura Y., Liu J., Li D., Zhang Z., Fang X., Huang S. CRISPR/ Cas9-based multiplex genome editing of BCL11A and HBG effi ciently induces fetal hemoglobin expression. Eur J Pharmacol. 2022;918:174788. doi: 10.1016/j.ejphar.2022.174788. PMID: 35093321.

53. Liu N., Hargreaves V.V., Zhu Q., Kurland J.V., Hong J., Kim W., Sher F., Macias-Trevino C., Rogers J.M., Kurita R., Nakamura Y., Yuan G.C., Bauer D.E., Xu J., Bulyk M.L., Orkin S.H. Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell. 2018;173(2):430–42.e17. doi: 10.1016/j.cell.2018.03.016. PMID: 29606353.

54. Martyn G.E., Wienert B., Yang L., Shah M., Norton L.J., Burdach J., Kurita R., Nakamura Y., Pearson R.C.M., Funnell A.P.W., Quinlan K.G.R., Crossley M. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat Genet. 2018;50(4):498–503. doi: 10.1038/s41588-018-0085-0. PMID: 29610478.

55. Traxler E.A., Yao Y., Wang Y.D., Woodard K.J., Kurita R., Nakamura Y., Hughes J.R., Hardison R.C., Blobel G.A., Li C., Weiss M.J. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat Med. 2016;22(9):987–90. doi: 10.1038/nm.4170. PMID: 27525524.

56. Wollenschlaeger C., Meneghini V., Masson C., De Cian A., Chalumeau A., Mavilio F., Amendola M., Andre-Schmutz I., Cereseto A., El Nemer W., Concordet J.P., Giovannangeli C., Cavazzana M., Miccio A. Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Sci Adv. 2020;6(7):eaay9392. doi: 10.1126/sciadv.aay9392. PMID: 32917636.

57. Métais J.Y., Doerfl er P.A., Mayuranathan T., Bauer D.E., Fowler S.C., Hsieh M.M., Katta V., Keriwala S., Lazzarotto C.R., Luk K., Neel M.D., Perry S.S., Peters S.T., Porter S.N., Ryu B.Y., Sharma A., Shea D., Tisdale J.F., Uchida N., Wolfe S.A., Woodard K.J., Wu Y., Yao Y., Zeng J., Pruett-Miller S., Tsai S.Q., Weiss M.J. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv. 2019;3(21):3379–92. doi: 10.1182/bloodadvances.2019000820. PMID: 31698466.

58. Sharma A., Boelens J.J., Cancio M., Hankins J.S., Bhad P., Azizy M., Lewandowski A., Zhao X., Chitnis S., Peddinti R., Zheng Y., Kapoor N., Ciceri F., Maclachlan T., Yang Y., Liu Y., Yuan J., Naumann U., Yu V.W.C., Stevenson S.C., De Vita S., LaBelle J.L. CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease. N Engl J Med. 2023;389(9):820–32. doi: 10.1056/NEJMoa2215643. PMID: 37646679.

59. Bauer D.E., Kamran S.C., Lessard S., Xu J., Fujiwara Y., Lin C., Shao Z., Canver M.C., Smith E.C., Pinello L., Sabo P.J., Vierstra J., Voit R.A., Yuan G.C., Porteus M.H., Stamatoyannopoulos J.A., Lettre G., Orkin S.H. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253–7. doi: 10.1126/science.1242088. PMID: 24115442.

60. Gamage U., Warnakulasuriya K., Hansika S., Silva G.N. CRISPR gene therapy: a promising one-time therapeutic approach for transfusiondependent β-thalassemia – CRISPR-Cas9 gene editing for β-thalassemia. Thalass Rep. 2023;13:51–69. doi: 10.3390/thalassrep13010006.

61. Holmes M.C., Reik A., Rebar E.J., Miller J.C., Zhou Y., Zhang L., Li P., Vaidya S. A potential therapy for beta-thalassemia (ST-400) and sickle cell disease (BIVV003). Biol Blood Marrow Transplant. 2018;24(3):172. doi: 10.1016/j.bbmt.2017.12.105.

62. Walters M.C., Smith A.R., Schiller G.J., Esrick E.B., Williams D.A., Gogoleva T., Rouy D., Cockroft B.M., Vercellotti G.M. Updated Results of a Phase 1/2 clinical study of zinc fi nger nuclease-mediated editing of BCL11A in autologous hematopoietic stem cells for transfusion-dependent beta thalassemia. Blood. 2021;138(1):3974. doi: 10.1182/blood-2021-147907.

63. Frangoul H., Altshuler D., Cappellini M.D., Chen Y.S., Domm J., Eustace B.K., Foell J., de la Fuente J., Grupp S., Handgretinger R., Ho T.W., Kattamis A., Kernytsky A., Lekstrom-Himes J., Li A.M., Locatelli F., Mapara M.Y., de Montalembert M., Rondelli D., Sharma A., Sheth S., Soni S., Steinberg M.H., Wall D., Yen A., Corbacioglu S. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252–60. doi: 10.1056/NEJMoa2031054. PMID: 33283989.

64. Frangoul H., Locatelli F., Sharma A., Bhatia M., Mapara M., Molinari L., Wall D., Liem R.I., Telfer P., Shah A.J., Cavazzana M., Corbacioglu S., Rondelli D., Meisel R., Dedeken L., Lobitz S., de Montalembert M., Steinberg M.H., Walters M.C., Eckrich M.J., Imren S., Bower L., Simard C., Zhou W., Xuan F., Morrow P.K., Hobbs W.E., Grupp S.A.; CLIMB SCD-121 Study Group. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649–62. doi: 10.1056/NEJMoa2309676. PMID: 38661449.

65. Frangoul H., Locatelli F., Lang P., Meisel R., Wall D., Corbacioglu S., Li A., de la Fuente J., Shah A.J., Carpenter B., Kwiatkowski J.L., Mapara M., Liem R., Capellini M.D., Algeri M., Kattamis A., Sheth S., Grupp S.A., Merkeley H., Kuo K.H.M., Rupprecht J., Kohli P., Xu G., Ross L., Tong B., Hobbs W. Durable clinical benefi ts in transfusion-dependent beta-talassemia with Exagamglogene autotemcel. Transplant Cell Ther. 2025;31(2):252. doi: 10.1016/j.jtct.2025.01.383.

66. Hanna R., Frangoul H., McKinney C., Pineiro L., Mapara M., Dalal J., Chang K.-H., Jaskolka M., Kim K., Farrington D.L., Wally M., Mei B., Lawal A., Afonja O.O., Walters M.C. AsCas12a gene editing of HBG1/2 promoters with EDIT-301 results in rapid and sustained normalization of hemoglobin and increased fetal hemoglobin in patients with severe sickle cell disease and transfusion-dependent beta-thalassemia. Blood. 2023;142(1):4996. doi: 10.1182/blood-2023-187397.

67. Frangoul H., Hanna R., Walters M.C., Chang K.-H., Jaskolka M., Kim K., Yu Q., Badamosi N., Mei B., Afonja O., Thompson A. ReniCel, an investigational AsCas12a gene-edited cell medicine, led to successful engraftment, increased hemoglobin, and reduced transfusion dependence in patients with transfusion dependent betathalassemia treated in the edithal trial. Transplant Cell Ther. 2025;31(2):254–5.

68. Пятиизбянцев Т.А., Шакирова А.И., Сергеев В.С., Лепик К.В., Попова М.О., Кулагин А.Д. Новая программируемая нуклеаза eBCL11A-FMPU-TALEN для генной терапии серповидноклеточных болезней и β-талассемии. Гематология и трансфузиология. 2024;69(приложение 2).

69. Frangoul H., Stults A., Bruce K., Domm J., Carroll C., Aide S., Duckworth M., Evans M., McManus M. Best Practices in gene therapy for sickle cell disease and transfusion-dependent β-thalassemia. Transplant Cell Ther. 2025;31(6):352.e1–10. doi: 10.1016/j.jtct.2025.02.025.