Research progress and considerations for thalassemia gene therapy

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.