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Introduction of β-Thalassemia

β-thalassemia is an inherited blood disorder caused by mutations in the β-globin subunit that leads to a reduction in normal hemoglobin and red blood cells in the blood. This results in insufficient oxygen delivery to the body, which can cause various health issues such as dizziness, weakness, fatigue, and bone abnormalities. β-thalassemia is a global health problem, with a high prevalence in regions such as the Mediterranean, Middle East, and Southeast Asia.

Transfusion-dependent β-thalassemia (TDT) is the most severe form of the disorder and usually requires lifelong transfusions of red blood cells as a standard course of treatment. However, regular transfusions may lead to complications such as excessive iron build-up in the body, which can cause problems with the liver, heart, and other organs.

Gene Therapy of β-Thalassemia

In recent years, there has been a significant focus on developing one-time curative therapies for β-thalassemia that eliminate the need for ongoing treatment. Gene therapy approaches have emerged as a promising option for achieving sustainable and stable expression of functional globin genes in TDT patients. These gene therapy approaches have the potential to offer a long-lasting cure for β-thalassemia with minimal risk of mortality or severe immunological complications such as graft rejection and clonal dominance.

Gene therapy aims to correct defective genes by administering functional genetic material to cells to produce lasting therapeutic effects. Scientists have developed several verified and feasible gene therapy options. Lentiviral mediated β-globin gene transfer or genome editing approaches for repairing β-globin mutations through the homology direct repair (HDR) pathway can provide a complete and healthy β-globin gene for patients' red blood cells. In addition, functional replacement of hemoglobin can also be achieved by reactivating the synthesis of gamma-globin chains to increase the expression level of fetal hemoglobin (HbF).

Fig. 1 Schematic representation of the protocols for gene therapy in β-thalassemia.Fig. 1 Schematic representation of the protocols for gene therapy in β-thalassemia. (Rattananon P, et al., 2021)

Recently, the FDA approved Zynteglo (betibeglogene autotemcel), which is the first cell-based gene therapy for the treatment of β-thalassemia in adults and children who require regular blood transfusions. The therapy restores normal adult hemoglobin production by lentivirally adding a functioning β-globin gene to hematopoietic stem cells (HSCs) derived from the patient's bone marrow. The entire process of treating a single patient can take months due to the multiple steps involved. The safety and efficacy of Zynteglo were demonstrated in two multicenter clinical studies.

Current Gene Therapy Clinical Trials in β-Thalassemia

Several companies have developed gene therapy approaches for β-thalassemia using lentiviral vector-based approaches. BDgene has developed BD211, a lentiviral vector-based gene therapy for the transduction of autologous CD34+ hematopoietic stem cells. Its lentiviral vector delivery technology improves the viral yield and infection efficiency of hematopoietic stem cells while reducing the risk of gene integration mutations. The drug is currently in a Phase 1 safety and efficacy study in subjects with non-β0/β0 TDT β-thalassemia.

An example in the treatment of β-thalassemia by boosting HbF levels is the CPRSPR gene editing therapy (exa-cel (CTX001)) developed by Vertex in collaboration with CRISPR Therapeutics. The therapy uses ex vivo CPRSPR-Cas9-mediated editing of BCL11A to produce high HbF levels in red blood cells. Exa-cel is currently being studied in five different clinical trials and could be the first CRISPR gene editing therapy to receive regulatory approval worldwide. In addition, ST-400 (BIVV003) developed by Sangamo Therapeutics/Sangamo, EDIT-301 by Editas Medicine, BRL-101 by BRL Medicine, and BEAM-101 by Beam Therapeutics are all in multiple clinical trials.

Overall, recent advancements in genome sequencing, vector biology, and gene-editing nucleases have led to promising clinical trials for β-thalassemia patients. Gene therapy has the potential to address the global health burden of β-thalassemia, with continued analysis of durability and safety and continued refinement of manufacturing and costs.


  • Rattananon, P.; et al. The future of gene therapy for transfusion-dependent beta-thalassemia: the power of the lentiviral vector for genetically modified hematopoietic stem cells. Frontiers in Pharmacology, 2021, 12: 730873.

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