# 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.

## Key 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.