地中海贫血基因治疗研究进展及思考

doi:10.3969/j.issn.1674-8115.2025.05.002

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (5): 540-548.doi: 10.3969/j.issn.1674-8115.2025.05.002

地中海贫血基因治疗研究进展及思考

高欣洁(), 刘艳(), 王大威()

上海血液学研究所，组学与疾病全国重点实验室，国家转化医学研究中心（上海），上海交通大学医学院附属瑞金医院，上海 200025

收稿日期:2024-12-26 接受日期:2025-04-23 出版日期:2025-05-28 发布日期:2025-05-22
通讯作者: 刘　艳，高级工程师，博士；电子信箱：ly30689@rjh.com.cn
王大威，副研究员，博士；电子信箱：wangdawei@shsmu.edu.cn。
作者简介:高欣洁（2001—），女，硕士生；电子信箱：gxj0701@sjtu.edu.cn。
基金资助:
国家自然科学基金(82450107);中央高校基本科研专项资金(YG2022QN013);中国工程院咨询研究项目(2021-DFY-2)

Research progress and considerations for thalassemia gene therapy

GAO Xinjie(), LIU Yan(), WANG Dawei()

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received:2024-12-26 Accepted:2025-04-23 Online:2025-05-28 Published:2025-05-22
Contact: LIU Yan, E-mail: ly30689@rjh.com.cn
WANG Dawei, E-mail: wangdawei@shsmu.edu.cn.
Supported by:
National Natural Science Foundation of China(82450107);Fundamental Research Funds for the Central Universities(YG2022QN013);Chinese Academy of Engineering Consulting Research Project(2021-DFY-2)

摘要/Abstract

摘要：

地中海贫血的传统治疗方式为定期输血和异基因造血干细胞移植（allogenic hematopoietic stem cell transplantation，allo-HSCT）。近年兴起的基因修饰自体造血干细胞移植是治愈输血依赖型地中海贫血（transfusion dependent thalassemia，TDT）的新策略，有望替代传统治疗手段，使TDT患者终身受益。地中海贫血基因治疗现有2种技术路线：将外源性β-珠蛋白基因转导造血干细胞（hematopoietic stem cell，HSC）的基因添加；利用CRISPR-Cas9系统重新激活γ-珠蛋白表达的基因编辑。该文结合已获批上市的药物和临床试验的研究进展，具体分析了2种路线各自的优势与局限性，讨论了目前地中海贫血基因治疗药物的有效性和安全性，以及干细胞体外扩增与干性维持、载体递送介导体内基因修饰等关联技术的未来攻克方向。在实现临床转化层面，该文就工艺开发困境、临床试验开展、监管审批流程、商业化及支付体系等临床试验面临的现阶段挑战，进行深入思考并阐述可行性解决方案。

关键词: 地中海贫血, 基因治疗, 自体造血干细胞移植, 基因编辑, 转化医学

Abstract:

Traditional treatment modalities for thalassemia include regular blood transfusions and allogenic hematopoietic stem cell transplantation (allo-HSCT). In recent years, autologous transplantation of gene-modified hematopoietic stem cells has emerged as a new curative strategy for transfusion-dependent thalassemia (TDT),which has the potential to replace conventional treatments, and provide lifelong benefits for patients. There are two existing technical approaches for gene therapy of β-thalassemia: gene addition, which involves transducing exogenous β-globin genes into hematopoietic stem cells (HSCs), and gene editing, which utilizes CRISPR-Cas9 or other editing systems to re-activate the expression of γ-globin gene. This article summarizes the marketed products and research progress in clinical trials, aiming to analyze the respective advantages and limitations of these two approaches, and discusses the effectiveness and safety of current gene therapies for β-thalassemia, as well as the future directions for associated technologies, including ex vivo HSC expansion with maintenance of stemness and vector-mediated in vivo gene modification. In terms of clinical translational medicine, this article provides in-depth insights into promising solutions for contemporary challenges confronted in clinical trials, including process development challenges, clinical trial conduct, regulatory approval processes, commercialization and payment systems.

Key words: thalassemia, gene therapy, autologous hematopoietic stem-cell transplantation, gene editing, translational medicine

中图分类号:

R556.7

高欣洁, 刘艳, 王大威. 地中海贫血基因治疗研究进展及思考[J]. 上海交通大学学报（医学版）, 2025, 45(5): 540-548.

GAO Xinjie, LIU Yan, WANG Dawei. Research progress and considerations for thalassemia gene therapy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 540-548.

图/表 2

参考文献 60

1	KATTAMIS A, KWIATKOWSKI J L, AYDINOK Y. Thalassaemia[J]. Lancet, 2022, 399(10343): 2310-2324.
2	中华医学会血液学分会红细胞疾病贫血学组. 中国输血依赖型β地中海贫血诊断与治疗指南(2022年版)[J]. 中华血液学杂志, 2022, 43(11): 889-896.
	Red Blood Cell Diseases (Anemia) Group, Chinese Society of Hematology, Chinese Medical Association. Chinese guideline for diagnosis and treatment of transfusion dependent β-thalassemia (2022)[J]. Chinese Journal of Hematology, 2022, 43(11): 889-896.
3	LAL A, LOCATELLI F, KWIATKOWSKI J L, et al. Northstar-3: interim results from a phase 3 study evaluating lentiglobin gene therapy in patients with transfusion-dependent β-thalassemia and either a β⁰ or IVS-I-110 mutation at both alleles of the HBB gene[J]. Blood, 2019, 134: 815.
4	LOCATELLI F, LANG P, WALL D, et al. Exagamglogene autotemcel for transfusion-dependent β- thalassemia[J]. N Engl J Med, 2024, 390(18): 1663-1676.
5	PIEL F B, WEATHERALL D J. The α-thalassemias[J]. N Engl J Med, 2014, 371(20): 1908-1916.
6	KATTAMIS A, FORNI G L, AYDINOK Y, et al. Changing patterns in the epidemiology of β-thalassemia[J]. Eur J Haematol, 2020, 105(6): 692-703.
7	WANG W D, HU F, ZHOU D H, et al. Thalassaemia in China[J]. Blood Rev, 2023, 60: 101074.
8	中华医学会医学遗传学分会遗传病临床实践指南撰写组. β-地中海贫血的临床实践指南[J]. 中华医学遗传学杂志, 2020, 37(3): 243-251.
	Writing Group for Practice Guidelines for Diagnosis and Treatment of Genetic Diseases, Medical Genetics Branch of Chinese Medical Associatio. Clinical practice guidelines for β-thalassemia [J]. Chinese Journal of Medical Genetics, 2020, 37(3): 243-251.
9	ZHEN X M, MING J, ZHANG R Q, et al. Economic burden of adult patients with β-thalassaemia major in mainland China[J]. Orphanet J Rare Dis, 2023, 18(1): 252.
10	陈辉, 贾玉艳, 黄粤, 等. 地中海贫血基因治疗进展和现状[J]. 广西医科大学学报, 2024, 41(1): 1-10.
	CHEN H, JIA Y Y, HUANG Y, et al. Progress and current status of gene therapy for thalassemia[J]. Journal of Guangxi Medical University, 2024, 41(1): 1-10.
11	MARKTEL S, SCARAMUZZA S, CICALESE M P, et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent β-thalassemia[J]. Nat Med, 2019, 25(2): 234-241.
12	THOMPSON A A, WALTERS M C, KWIATKOWSKI J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia[J]. N Engl J Med, 2018, 378(16): 1479-1493.
13	LOCATELLI F, THOMPSON A A, KWIATKOWSKI J L, et al. Betibeglogene autotemcel gene therapy for non-β⁰/β⁰ genotype β-thalassemia[J]. N Engl J Med, 2022, 386(5): 415-427.
14	HAN N. Interim results of gene therapy using optimized LentiHBB^T87Q vector in five Chinese patients with transfusion dependent β-thalassemia[C]//EHA2024 Hybrid Congress. Madrid, Spain: EHA Library, 2024: 1517.
15	LI S Q, LING S K, WANG D W, et al. Modified lentiviral globin gene therapy for pediatric β⁰/β⁰ transfusion-dependent β-thalassemia: a single-center, single-arm pilot trial[J]. Cell Stem Cell, 2024, 31(7): 961-973.e8.
16	HUANG J Q, ZHANG Y M, LIANG L, et al. Gene therapy of transfusion-dependent β-thalassemia patients with quick engraftment of reinfused hematopoietic stem cells: an investigator-initiated trial of KL003[J]. Blood, 2023, 142: 4998.
17	WALTERS M C, SMITH A R, SCHILLER G J, et al. Updated results of a phase 1/2 clinical study of zinc finger nuclease-mediated editing of BCL11A in autologous hematopoietic stem cells for transfusion-dependent β thalassemia[J]. Blood, 2021, 138(Supplement 1): 3974.
18	FRANGOUL H, HANNA R, WALTERS M C, et al. Reni-cel, the first AsCas12a gene-edited cell therapy, shows promising preliminary results in key clinical outcomes in transfusion-dependent β- thalassemia patients treated in the EdiThaltrial[C]//EHA2024 Hybrid Congress. Madrid, Spain: EHA Library, 2024: 1476.
19	SHI J, FANG R G, GAO Z, et al. Preliminary safety and efficacy results of EDI001: an investigator initiated trial on CRISPR/Cas9-modified autologous CD34⁺ hematopoietic stem and progenitor cells for patients with transfusion dependent β-thalassemia[J]. Blood, 2022, 140(Supplement 1): 10652-10653.
20	ZHENG B, LIU R R, ZHANG X H, et al. Efficacy and safety of brl-101, CRISPR-Cas9-mediated gene editing of the BCL11A enhancer in transfusion-dependent β-thalassemia[J]. Blood, 2023, 142: 4995.
21	LIU R R, WANG L, XU H, et al. Safety and efficacy of RM-001 (autologous HBG1/2 promoter-modified CD34⁺ hematopoietic stem and progenitor cells) in patients with transfusion-dependent β-thalassemia[J]. Blood, 2023, 142: 4994.
22	KUSCU C, ARSLAN S, SINGH R, et al. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease[J]. Nat Biotechnol, 2014, 32(7): 677-683.
23	MORGAN R A, UNTI M J, ALESHE B, et al. Improved titer and gene transfer by lentiviral vectors using novel, small β-globin locus control region elements[J]. Mol Ther, 2020, 28(1): 328-340.
24	GIOMMETTI A, PAPANIKOLAOU E. Advancements in hematopoietic stem cell gene therapy: a journey of progress for viral transduction[J]. Cells, 2024, 13(12): 1039.
25	SEGURA E E R, AYOUB P G, HART K L, et al. Gene therapy for β-hemoglobinopathies: from discovery to clinical trials[J]. Viruses, 2023, 15(3): 713.
26	GAMBARI R. Alternative options for DNA-based experimental therapy of β-thalassemia[J]. Expert Opin Biol Ther, 2012, 12(4): 443-462.
27	BREDA L, PAPP T E, TRIEBWASSER M P, et al. In vivo hematopoietic stem cell modification by mRNA delivery[J]. Science, 2023, 381(6656): 436-443.
28	ESRICK E B, LEHMANN L E, BIFFI A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease[J]. N Engl J Med, 2021, 384(3): 205-215.
29	LIU B Y, BRENDEL C, VINJAMUR D S, et al. Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat β-hemoglobinopathies[J]. Mol Ther, 2022, 30(8): 2693-2708.
30	CAVAZZANA-CALVO M, PAYEN E, NEGRE O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia[J]. Nature, 2010, 467(7313): 318-322.
31	DUNCAN C N, BLEDSOE J R, GRZYWACZ B, et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy[J]. N Engl J Med, 2024, 391(14): 1287-1301.
32	POESCHLA E M. Integrase, LEDGF/p75 and HIV replication[J]. Cell Mol Life Sci, 2008, 65(9): 1403-1424.
33	DORMIANI K, MIR MOHAMMAD SADEGHI H, SADEGHI-ALIABADI H, et al. Long-term and efficient expression of human β-globin gene in a hematopoietic cell line using a new site-specific integrating non-viral system[J]. Gene Ther, 2015, 22(8): 663-674.
34	PFEIFER A, BRANDON E P, KOOTSTRA N, et al. Delivery of the Cre recombinase by a self-deleting lentiviral vector: efficient gene targeting in vivo[J]. Proc Natl Acad Sci USA, 2001, 98(20): 11450-11455.
35	BAHAL R, ALI MCNEER N, QUIJANO E, et al. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery[J]. Nat Commun, 2016, 7: 13304.
36	LAZARIS V M, SIMANTIRAKIS E, STAVROU E F, et al. Non-viral episomal vector mediates efficient gene transfer of the β-globin gene into K562 and human haematopoietic progenitor cells[J]. Genes (Basel), 2023, 14(9): 1774.
37	STAVROU E F, SIMANTIRAKIS E, VERRAS M, et al. Episomal vectors based on S/MAR and the β-globin replicator, encoding a synthetic transcriptional activator, mediate efficient γ-globin activation in haematopoietic cells[J]. Sci Rep, 2019, 9(1): 19765.
38	REES H A, MINELLA A C, BURNETT C A, et al. CRISPR-derived genome editing therapies: progress from bench to bedside[J]. Mol Ther, 2021, 29(11): 3125-3139.
39	ENACHE O M, RENDO V, ABDUSAMAD M, et al. Cas9 activates the p53 pathway and selects for p53-inactivating mutations[J]. Nat Genet, 2020, 52(7): 662-668.
40	ANTONIOU P, MICCIO A, BRUSSON M. Base and prime editing technologies for blood disorders[J]. Front Genome Ed, 2021, 3: 618406.
41	HRYHOROWICZ M, LIPIŃSKI D, ZEYLAND J. Evolution of CRISPR/cas systems for precise genome editing[J]. Int J Mol Sci, 2023, 24(18): 14233.
42	WU Z W, ZHANG Y F, YU H P, et al. Programmed genome editing by a miniature CRISPR-Cas12f nuclease[J]. Nat Chem Biol, 2021, 17(11): 1132-1138.
43	FERRARI S, JACOB A, CESANA D, et al. Choice of template delivery mitigates the genotoxic risk and adverse impact of editing in human hematopoietic stem cells[J]. Cell Stem Cell, 2022, 29(10): 1428-1444.e9.
44	LAMSFUS-CALLE A, DANIEL-MORENO A, UREÑA-BAILÉN G, et al. Universal gene correction approaches for β-hemoglobinopathies using CRISPR-Cas9 and adeno-associated virus serotype 6 donor templates[J]. CRISPR J, 2021, 4(2): 207-222.
45	NUALKAEW T, JEARAWIRIYAPAISARN N, HONGENG S, et al. Restoration of correct β^IVS2-654-globin mRNA splicing and HbA production by engineered U7 snRNA in β-thalassaemia/HbE erythroid cells[J]. Sci Rep, 2019, 9(1): 7672.
46	KYLE CROMER M, CAMARENA J, MARTIN R M, et al. Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells[J]. Nat Med, 2021, 27(4): 677-687.
47	PAVANI G, FABIANO A, LAURENT M, et al. Correction of β-thalassemia by CRISPR/Cas9 editing of the α-globin locus in human hematopoietic stem cells[J]. Blood Adv, 2021, 5(5): 1137-1153.
48	LU D, XU Z L, PENG Z Y, et al. Induction of fetal hemoglobin by introducing natural hereditary persistence of fetal hemoglobin mutations in the γ-globin gene promoters for genome editing therapies for β-thalassemia[J]. Front Genet, 2022, 13: 881937.
49	SHYR D C, LOWSKY R, MILLER W, et al. One year follow-up on the first patient treated with nula-cel: an autologous CRISPR/Cas9 gene corrected CD34⁺ cell product to treat sickle cell disease[J]. Blood, 2023, 142: 5000.
50	ZHANG H K, SUN R L, FEI J, et al. Correction of β-thalassemia IVS-II-654 mutation in a mouse model using prime editing[J]. Int J Mol Sci, 2022, 23(11): 5948.
51	UCHIDA N, TISDALE J F, DONAHUE R E, et al. A single dose of CD117 antibody drug conjugate enables hematopoietic stem cell based gene therapy in nonhuman Primates[J]. Biol Blood Marrow Transplant, 2020, 26(3): S6.
52	NGUYEN G N, EVERETT J K, KAFLE S, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells[J]. Nat Biotechnol, 2021, 39(1): 47-55.
53	WANG H J, GEORGAKOPOULOU A, PSATHA N, et al. In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia[J]. J Clin Invest, 2019, 129(2): 598-615.
54	LI C, WANG H J, GEORGAKOPOULOU A, et al. In vivo HSC gene therapy using a bi-modular HDAd5/35++ vector cures sickle cell disease in a mouse model[J]. Mol Ther, 2021, 29(2): 822-837.
55	PASCHOUDI K, YANNAKI E, PSATHA N. Precision editing as a therapeutic approach for β-hemoglobinopathies[J]. Int J Mol Sci, 2023, 24(11): 9527.
56	LI C, GEORGAKOPOULOU A, MISHRA A, et al. In vivo HSPC gene therapy with base editors allows for efficient reactivation of fetal γ-globin in β-YAC mice[J]. Blood Adv, 2021, 5(4): 1122-1135.
57	MEAKER G A, WILKINSON A C. Ex vivo hematopoietic stem cell expansion technologies: recent progress, applications, and open questions[J]. Exp Hematol, 2024, 130: 104136.
58	LI Y H, HE M, ZHANG W S, et al. Expansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche[J]. Nat Commun, 2023, 14(1): 2207.
59	WANG H J, GEORGAKOPOULOU A, NIZAMIS E, et al. Auto-expansion of in vivo HDAd-transduced hematopoietic stem cells by constitutive expression of tHMGA2[J]. Mol Ther Methods Clin Dev, 2024, 32(3): 101319.
60	CORBACIOGLU S, FRANGOUL H, LOCATELLI F, et al. Defining curative endpoints for transfusion-dependent β-thalassemia in the era of gene therapy and gene editing[J]. Am J Hematol, 2024, 99(3): 422-429.

Drug product	Sponsor	Status and clinical trial identifier	Participant/n	Clinical trial result
Lentivirus-mediated β-globin gene addition
Zynteglo	Bluebird Bio	Phase Ⅰ/Ⅱ, NCT01745120	22	Transfusion independence (TI) occurred in 12 patients with non-β⁰/β⁰ genotype and 3 patients with β⁰/β⁰ genotype or IVS1-110 homozygous mutation^[12]
		Phase Ⅲ, NCT02906202	24	TI occurred in 20 patients with non-β⁰/β⁰ genotype while the average Hb level was 117 g/L, and the median level of HbA^T87Qwas 87 g/L at the 12th month after infusion^[13]
		Phase Ⅲ, NCT03207009	19	One patient with β⁰/β⁰genotype had TI for ≥ 12 months, while the Hb level of 3 patients with TI for ≥ 6 months was up to 105‒136 g/L (HbA^T87Q accounting for 95‒126 g/L)^[3]
OTL-300	Orchard Therapeutics	Phase Ⅰ/Ⅱ, NCT02453477	10	TI occurred in 3 pediatric patients, and red-cell transfusions were reduced in 4 patients^[11]
HGI-001	Hemu Gene Co., Ltd.	IIT, NCT05745532	10	The average Hb level of 5 patients was > 90 g/L during TI ≥ 12 months, with the median Hb level of 105 g/L at the most recent follow-up^[14]
BD211	BDgene Co., Ltd.	IIT, NCT05015920	10	Two patients with β⁰/β⁰genotype had TI for 25.5 months in average, with red blood cell lifespan being extended to more than 42 d^[15]
KL003	Kanglin Biotechnology	IIT, ChiCTR2200055565	11	The average neutrophil and platelet engraftment times were both 14 d. TI occurred in all patients, with the longest duration lasting 18 months^[16]
GMCN508B	Genmedicn Biopharma	IIT, NCT05762510	5	Two patients with TDT had TI, including a 10-year-old pediatric patient with β⁰/β⁺ genotype
Gene editing to re-activate the expression of HbF
ST-400	Sangamo Therapeutics	Phase Ⅰ/Ⅱ, NCT03432364	6	The low transduction efficiency of HSCs resulted in no long-term therapeutic effect^[17]
CTX001	Vertex Pharmaceuticals	Phase Ⅲ, NCT03655678	59	The median duration of TI among 48 patients was 22.5 months, with a total Hb level of 131 g/L and HbF level of 119 g/L in average^[4]
EDIT-301	Editas Medicine	Phase Ⅰ/Ⅱ, NCT05444894	9	TI occurred in 7 patients, including 6 with follow-up ≥ 6 months, whose total Hb and HbF levels were 121 g/L and 109 g/L, respectively^[18]
ET-01	EdiGene Inc.	IIT, NCT04390971	3	One patient (β⁰/β⁺) had TI for>15 months, with a total Hb level of 110 g/L at the 18th month^[19]
BRL-101	BRL Medicine	Phase Ⅰ, NCT05577312	10	TI > 22 months occurred in all patients, including 5 with β⁰/β⁰ genotype. The highest HbF level reached 140 g/L, with HbF-cells accounting for 98%‒99%^[20]
RM-001	Reforgene Medicine	Phase Ⅰ, ChiCTR2300069244	12	Twelve patients in Phase Ⅰ and 7 patients in IIT study had TI for> 6 months (including 13 with β⁰/β⁰ genotype). Thirteen patients with ≥12 months of follow-up had an average HbF level of 117 g/L^[21]
CS-101	CorrectSequence Therapeutics	IIT, NCT06291961	8	The first patient (β⁰/β⁺) had TI with HbF > 95 g/L at the 8th week

Drug product	Sponsor	Status and clinical trial identifier	Participant/n	Clinical trial result
Lentivirus-mediated β-globin gene addition
Zynteglo	Bluebird Bio	Phase Ⅰ/Ⅱ, NCT01745120	22	Transfusion independence (TI) occurred in 12 patients with non-β⁰/β⁰ genotype and 3 patients with β⁰/β⁰ genotype or IVS1-110 homozygous mutation^[12]
		Phase Ⅲ, NCT02906202	24	TI occurred in 20 patients with non-β⁰/β⁰ genotype while the average Hb level was 117 g/L, and the median level of HbA^T87Qwas 87 g/L at the 12th month after infusion^[13]
		Phase Ⅲ, NCT03207009	19	One patient with β⁰/β⁰genotype had TI for ≥ 12 months, while the Hb level of 3 patients with TI for ≥ 6 months was up to 105‒136 g/L (HbA^T87Q accounting for 95‒126 g/L)^[3]
OTL-300	Orchard Therapeutics	Phase Ⅰ/Ⅱ, NCT02453477	10	TI occurred in 3 pediatric patients, and red-cell transfusions were reduced in 4 patients^[11]
HGI-001	Hemu Gene Co., Ltd.	IIT, NCT05745532	10	The average Hb level of 5 patients was > 90 g/L during TI ≥ 12 months, with the median Hb level of 105 g/L at the most recent follow-up^[14]
BD211	BDgene Co., Ltd.	IIT, NCT05015920	10	Two patients with β⁰/β⁰genotype had TI for 25.5 months in average, with red blood cell lifespan being extended to more than 42 d^[15]
KL003	Kanglin Biotechnology	IIT, ChiCTR2200055565	11	The average neutrophil and platelet engraftment times were both 14 d. TI occurred in all patients, with the longest duration lasting 18 months^[16]
GMCN508B	Genmedicn Biopharma	IIT, NCT05762510	5	Two patients with TDT had TI, including a 10-year-old pediatric patient with β⁰/β⁺ genotype
Gene editing to re-activate the expression of HbF
ST-400	Sangamo Therapeutics	Phase Ⅰ/Ⅱ, NCT03432364	6	The low transduction efficiency of HSCs resulted in no long-term therapeutic effect^[17]
CTX001	Vertex Pharmaceuticals	Phase Ⅲ, NCT03655678	59	The median duration of TI among 48 patients was 22.5 months, with a total Hb level of 131 g/L and HbF level of 119 g/L in average^[4]
EDIT-301	Editas Medicine	Phase Ⅰ/Ⅱ, NCT05444894	9	TI occurred in 7 patients, including 6 with follow-up ≥ 6 months, whose total Hb and HbF levels were 121 g/L and 109 g/L, respectively^[18]
ET-01	EdiGene Inc.	IIT, NCT04390971	3	One patient (β⁰/β⁺) had TI for>15 months, with a total Hb level of 110 g/L at the 18th month^[19]
BRL-101	BRL Medicine	Phase Ⅰ, NCT05577312	10	TI > 22 months occurred in all patients, including 5 with β⁰/β⁰ genotype. The highest HbF level reached 140 g/L, with HbF-cells accounting for 98%‒99%^[20]
RM-001	Reforgene Medicine	Phase Ⅰ, ChiCTR2300069244	12	Twelve patients in Phase Ⅰ and 7 patients in IIT study had TI for> 6 months (including 13 with β⁰/β⁰ genotype). Thirteen patients with ≥12 months of follow-up had an average HbF level of 117 g/L^[21]
CS-101	CorrectSequence Therapeutics	IIT, NCT06291961	8	The first patient (β⁰/β⁺) had TI with HbF > 95 g/L at the 8th week

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地中海贫血基因治疗研究进展及思考

Research progress and considerations for thalassemia gene therapy

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