Research progress and considerations for thalassemia gene therapy

doi:10.3969/j.issn.1674-8115.2025.05.002

Abstract

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

CLC Number:

R556.7

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.

Figures/Tables 2

TrendMD

References 60

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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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