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

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Publication Year:
2025
Authors:
Eva E R Segura, Kevyn Hart, Beatriz Campo Fernandez, Devin Brown, Kevin Tam, Andrea Gutierrez Garcia, Eva Seigneurbieux, Karen Li, Carol Mulumba, Emma Blakely, Katelyn Masiuk, Roshani Sinha, Devesh Sharma, John Everett, Matthew Hogenauer, M Kyle Cromer, Frederic Bushman, Tippi C MacKenzie, Donald B Kohn
PubMed ID:
40967220
Funding Grants:
Public Summary:
Alpha-thalassemia is an inherited severe anemia due to defects in the genes encoding the alpha-globin component of hemoglobin, the major carrier of oxygen. To develop a gene therapy for alpha-thalassemia using a patient's own (autologous) blood forming stem cells, we developed and tested multiple lentiviral vector constructs, each carrying an normal human alpha-globin gene. The vectors produced alpha-globin protein and restored hemoglobin protein in a cell line model capable of making red blood cells and in primary blood-forming stem cells from three different alpha-thalassemia patients. Safety studies did not detect any risks from the vector in cell culture modles and from human cells treated with the vector and grown in immune-deficient mice. These studies led to identification of a therapeutic candidate lentiviral vector to be used for gene therapy of alpha-thalassmia and further studies to advance to a clinical trial are underway, funded by CIRM TRAN1-16919.
Scientific Abstract:
Alpha thalassemia major (ATM) is an inherited blood disorder caused by the absence of all four alpha-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 beta-globin locus control region (LCR) enhancers, restoring alpha-globin expression in red blood cells. The best-performing LVs, erythroid vector-alpha (EV-alpha) and EV-alpha-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 alpha/beta-globin mRNA and chain ratios within the therapeutic range ( approximately 0.5+), and restored hemoglobin levels by 50%-100%. These findings establish the safety and clinical potential of EV-alpha and EV-alpha-UV as a promising autologous stem cell gene therapy for ATM.