The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells.

Suradej Hongeng,Parin Rattananon,Usanarat Anurathapan,Kanit Bhukhai

doi:10.3389/fphar.2021.730873

Suradej Hongeng, Parin Rattananon + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2021.730873

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Abstract

β-thalassemia, a disease that results from defects in β-globin synthesis, leads to an imbalance of β- and α-globin chains and an excess of α chains. Defective erythroid maturation, ineffective erythropoiesis, and shortened red blood cell survival are commonly observed in most β-thalassemia patients. In severe cases, blood transfusion is considered as a mainstay therapy; however, regular blood transfusions result in chronic iron overload with life-threatening complications, e.g., endocrine dysfunction, cardiomyopathy, liver disease, and ultimately premature death. Therefore, transplantation of healthy hematopoietic stem cells (HSCs) is considered an alternative treatment. Patients with a compatible human leukocyte antigen (HLA) matched donor can be cured by allogeneic HSC transplantation. However, some recipients faced a high risk of morbidity/mortality due to graft versus host disease or graft failure, while a majority of patients do not have such HLA match-related donors. Currently, the infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin gene into the erythroid progenitors of the patient is a promising approach to completely cure β-thalassemia. Here, we discuss a history of β-thalassemia treatments and limitations, in particular the development of β-globin lentiviral vectors, with emphasis on clinical applications and future perspectives in a new era of medicine.

Highlights

Reviewed by: Zijie Long, Third Affiliated Hospital of Sun Yat-sen University, China Sadiq Umar, University of Illinois at Chicago, United States
Unbound α-globin chains precipitate in red blood cell precursors and their progeny causing cellular damage, a process that leads to defective erythroid maturation, ineffective erythropoiesis, and shortened red blood cell (RBC) survival (Weatherall, 1998)
The available treatments for β-thalassemia consist of several therapeutic modalities ranging from conventional treatments such as blood transfusion combined with iron chelation therapy, splenectomy, and hematopoietic stem cell (HSC) transplantation (Figure 1) to recently approved novel treatments such as luspatercept, an activin receptor fusion protein that improves erythropoiesis, and cell and gene therapy (Taher et al, 2018; Motta et al, 2020)

Summary

Introduction

Reviewed by: Zijie Long, Third Affiliated Hospital of Sun Yat-sen University, China Sadiq Umar, University of Illinois at Chicago, United States. Future of Gene Therapy for Transfusion-Dependent BetaThalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells. The infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin gene into the erythroid progenitors of the patient is a promising approach to completely cure β-thalassemia.

Results

Conclusion