Abstract
β-thalassemia is characterized by reduced or absence of β-globin production, resulting in anemia. Current therapies include blood transfusion combined with iron chelation. BM transplantation, although curative, is restricted by the matched donor limitation. Gene therapy, on the other hand, is promising, and its success lies primarily on designing efficient globin vectors that can effectively and stably transduce HSCs. The major breakthrough in β-thalassemia gene therapy occurred a decade ago with the development of globin LVs. Since then, researchers focused on designing efficient and safe vectors, which can successfully deliver the therapeutic transgene, demonstrating no insertional mutagenesis. Furthermore, as human HSCs have intrinsic barriers to HIV-1 infection, attention is drawn towards their ex vivo manipulation, aiming to achieve higher yield of genetically modified HSCs. This paper presents the current status of gene therapy for β-thalassemia, its success and limitations, and the novel promising strategies available involving the therapeutic role of HSCs.
Highlights
The β-thalassemias represent inherited, monogenic anemias, arising from autosomal recessive mutations, affecting the synthesis of the β-chain of hemoglobin [1]
This paper presents the current status of gene therapy for β-thalassemia, its success and limitations, and the novel promising strategies available involving the therapeutic role of hematopoietic stem cell (HSC)
The efficient gene delivery of therapeutic transgenes using lentiviral vectors (LVs) has become a milestone in the field of gene therapy for hemoglobinopathies
Summary
The β-thalassemias represent inherited, monogenic anemias, arising from autosomal recessive mutations, affecting the synthesis of the β-chain of hemoglobin [1]. Current therapies for β-thalassemia include blood transfusions together with life-long iron chelation and hydroxyurea treatment for fetal hemoglobin (HbF) induction These strategies have improved patients’ mortality and have significantly delayed the onset of iron-related organ failure, treatment noncompliance is common, leading to cardiac, hepatic, or endocrine failure [4]. Allogeneic hematopoietic stem cell (HSC) transplantation of human leukocyte antigen- (HLA-) matched sibling donors can be curative, reaching cure rates up to 90% in patients younger than 17 years of age [5] It is associated with a number of drawbacks, such as the limited matched related donors and the need for long-term immunosuppression to prevent, treat or delay graft-versus-host disease (GVHD), often associated. An alternative molecular strategy based on gene therapy is undoubtedly a radical approach that overcomes all the above limitations
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