上海交通大学学报（医学版）

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2025 , Vol. 45 >Issue 5: 540 - 548

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.05.002

前沿述评

地中海贫血基因治疗研究进展及思考

  • 高欣洁 ,
  • 刘艳 ,
  • 王大威
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  • 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
高欣洁（2001—），女，硕士生；电子信箱：gxj0701@sjtu.edu.cn。
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。

收稿日期: 2024-12-26

  录用日期: 2025-04-23

  网络出版日期: 2025-05-22

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)

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Research progress and considerations for thalassemia gene therapy

  • GAO Xinjie ,
  • LIU Yan ,
  • WANG Dawei
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  • 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
LIU Yan, E-mail: ly30689@rjh.com.cn
WANG Dawei, E-mail: wangdawei@shsmu.edu.cn.

Received date: 2024-12-26

  Accepted date: 2025-04-23

  Online published: 2025-05-22

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)

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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

本文引用格式

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 . DOI: 10.3969/j.issn.1674-8115.2025.05.002

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

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