Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells

TL;DR

Researchers developed a gene therapy using lentiviral vectors to restore alpha-globin expression in red blood cells of patients with alpha thalassemia major, offering a potential cure without needing a donor.

Contribution

A novel gene therapy approach using optimized β-globin regulatory elements to restore α-globin expression in hematopoietic stem cells for alpha thalassemia.

Findings

Lentiviral vectors achieved up to 100% transduction efficiency in hematopoietic stem and progenitor cells.

Treatment restored α/β-globin mRNA ratios and increased hemoglobin levels by 50%–100% in patient-derived cells.

Vector integration was safe and within optimal copy numbers for clinical application.

Abstract

Alpha thalassemia major (ATM) is an inherited blood disorder caused by the absence of all four α-globin genes (HBA2/1), resulting in severe anemia and lifelong transfusion dependence. While allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure, donor availability remains limited. We present a gene therapy approach for autologous HSCT using lentiviral vectors (LVs) to deliver HBA2 under the regulation of optimized β-globin locus control region (LCR) enhancers, restoring α-globin expression in red blood cells. The best-performing LVs, erythroid vector-alpha (EV-α) and EV-α-UV, achieved up to 100% transduction efficiency in human hematopoietic stem and progenitor cells (HSPCs), optimal vector copy numbers, and safe integration profiles. ATM-derived HSPCs from three donors treated with these LVs yielded α/β-globin mRNA and chain ratios within the therapeutic range (∼0.5+), and restored hemoglobin levels by 50%–100%. These findings establish the safety and clinical potential of EV-α and EV-α-UV as a promising autologous stem cell gene therapy for ATM.

•β-globin regulatory elements drive the α-globin gene•Vector restores α-globin expression in alpha thalassemia patient red blood cells•Rebalance of α/β-globin ratio and functional hemoglobin production

β-globin regulatory elements drive the α-globin gene

Vector restores α-globin expression in alpha thalassemia patient red blood cells

Rebalance of α/β-globin ratio and functional hemoglobin production

Segura et al. show that vectors encoding HBA2 under β-globin regulatory elements restore α-globin expression in red blood cells derived from hematopoietic stem and progenitor cells of alpha thalassemia major (ATM) patients. Correction of the α/β-globin ratio enables hemoglobin production, supporting gene addition as a promising therapy for ATM.

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