Clinical Outcomes of Lentiviral Vector Gene Therapy for Sickle Cell Disease.
Publication Year:
2026
PubMed ID:
42008008
Funding Grants:
Public Summary:
A Phase I clinical trial of gene therapy for Sickle cell Disease is reported. 4 adult patients with severe sickle cell disease were enrolled and treated. Their blood-forming stem cells were collected and a lentiviral vector was used to add a modified beta-globin gene that impedes red blood cell sickling. The patients received high dose chemotherapy before their gene-modified stem cells were reinfused to make space for the stem cells to engraft in the bone marrow. A first patient only developed a very low number of gene-modified blood cells, so the protocol was modified to improve gene transfer to stem cells. Three patients were treated under this modified protocol. One patient had good levels of engraftment of gene corrected stem cells and has had no further sickle cell disease complications since that time.A second patient had a low level of gene corrected stem cells and symptoms of sickle cell disease returned. A third patient had persistence of blood cells containing the anti-sickling gene, but the anti-sickling protein stopped being detected after 6 months, suggesting expression was silenced. There were no safety problems from the vector. although each patient had typical side-effects from the high dose chemotherapy lasting 2-3 weeks. With the FDA approval of two commercial gene therapies for sickle cell disease, this trial was terminated early.
Scientific Abstract:
Sickle cell disease (SCD) is a monogenic disorder where autologous gene therapy may offer a safer curative alternative to allogeneic transplantation. We report outcomes from a Phase I/II study using the Lenti/G-betaAS3-FB lentiviral vector, encoding an anti-sickling beta-globin. This trial was registered at ClinicalTrials.gov (NCT02247843). This single-site study treated four adults with severe SCD. The first patient was treated using the original Lenti/betaAS3-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 pre-collection erythrocytapheresis, and 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 endpoints were safety and feasibility; secondary endpoints 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 three 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 two 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. While this specific vector will not be pursued further, the study provides crucial insights into gene therapy protocol development.