SRT at ASGCT | Abstract 3507

INTRODUCTION
Sickle cell disease (SCD) and β-thalassemia are caused by defect or deficiency in adult β-globin. Currently, FDA-approved lentiviral vector (LVV) therapies are available to insert a functional β-globin gene into autologous hematopoietic stem cells (HSC). These LVV contain sophisticated expression cassettes consisting of β-globin enhancers and elements of the locus control region (LCR) in reverse orientation. While clinical outcomes are generally positive, therapeutic efficacy is costly and limited by low viral titers, suboptimal HSC transduction efficiency and β-globin gene expression due to the complexity of large β-globin expression systems. To improve vector performance, modification in the β-globin gene orientation or size reductions of the vector by removing LCR elements has addressed some but not all of these limitations. In this study, our research group engineered SRT8-T87Q (also called MiNiRoLu), which is based on a wild-type β-globin LVV (TNS9.3.55) previously validated in a Phase 1 clinical trial for transfusion-dependent β-thalassemia, and evaluated performance in human K562 erythroleukemia cells and human CD34+ HSC from healthy donors and a SCD patient.

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