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

Eva E R Segura1, Kevyn Hart2, Beatriz Campo Fernandez3

  • 1Molecular Biology Interdepartmental Doctoral Program, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.

Cell Reports. Medicine
|September 18, 2025
PubMed

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.

Keywords:
alpha globinalpha thalassemia majoranemiaautologousbeta-globin LCRgene therapyhematopoietic stem cellhemoglobin levellentiviral vectorsred blood cells

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