Clinical outcomes of lentiviral vector gene therapy for sickle cell disease.

abstractSickle cell disease (SCD) is a monogenic disorder in which autologous gene therapy may offer a safer curative alternative to allogeneic transplantation. We report outcomes from a phase 1/2 study using the Lenti/G-βAS3-FB lentiviral vector, which encodes an antisickling β-globin. This single-site study treated 4 adults with severe SCD. The first patient was treated using the original Lenti/βAS3-FB and initial protocol, which resulted in suboptimal clinical response. Subsequent protocol refinements included improved hematopoietic stem and progenitor cell (HSPC) collection, using plerixafor-mobilized peripheral blood apheresis with precollection erythrocytapheresis, and the use of an optimized lentiviral vector with a transduction enhancer. All patients received myeloablative busulfan conditioning followed by infusion of gene-modified autologous HSPCs. Primary end points were safety and feasibility; secondary end points included gene marking, therapeutic hemoglobin expression, and clinical outcomes. All patients achieved hematopoietic recovery without rescue transplantation. The first patient demonstrated low gene marking (peak vector copy number [VCN], 0.035) and undetectable HbAS3 expression, with minimal clinical benefit. In contrast, the 3 patients treated with the optimized protocol achieved higher and sustained gene marking (peak granulocyte VCNs, ∼0.5-2.0) and persistent HbAS3 expression. These patients experienced some reductions in vaso-occlusive crises and transfusion requirements, with 2 becoming transfusion independent. No insertional oncogenesis was observed. This trial highlights the necessity of optimized vector design and transduction protocols to achieve durable gene expression. Although this specific vector will not be pursued further, the study provides crucial insights into gene therapy protocol development. This trial was registered at www.clinicaltrials.gov as #NCT02247843.