Gene therapy using optimized LentiHBBT87Q vector in two patients with transfusion dependent β-thalassemia

BackgroundGene therapy is gradually becoming recognized as a possibly curative therapeutic strategy for transfusion-dependent {beta}-thalassemia (TDT). Gene therapy addresses the problem of donor scarcity through the application of autologous hematopoietic stem cells (HSCs), which also can reduce the risks that accompany allogeneic HSC transplantation. When using gene addition strategy, lentiviral vector is critical for the efficacy and safety of {beta}-thalassemia gene therapy. In our preclinical studies, LentiHBBT87Q vector with optimized backbone was developed to efficiently restore {beta}-globin expression in HSCs-derived erythroblasts of TDT patients with minimal risk of tumorigenesis. Here, we presented the clinical trial results of gene therapy using LentiHBBT87Q vector in two TDT patients. MethodIn an ongoing phase 1/2 trial (NCT05745532), auto-HSCs were mobilized from two TDT patients, and then transduced with LentiHBBT87Q vector. The gene-modified auto-HSCs is called HGI-001 injection. After four-day consecutive myeloablative conditioning, these two patients were administrated with HGI-001 injection via intravenous infusion. Medical examinations were performed in the transplantation unit to monitor patients status till the patients were clinically stable. Then, 24-month following-up visits are conducted to assess the safety and efficacy of HGI-001 injection. The safety endpoints of this clinical study include the incident and severity of adverse events (AEs); transplant-related mortality or disability events within 100 days post drug product infusion; vector-related replication competent lentivirus (RCL) and clonal variations containing specific viral integration sites; overall survival during this clinical trial. The major efficacy endpoint is the percentage of subjects with average vector copy number (VCN) in peripheral blood mononuclear cells (PBMCs) >0.1, and average expression of exogenous HbAT87Q >2.0g/dL at the 24th month after reinfusion of HGI-001 injection ResultsThe rapid neutrophil and platelet engraftment successfully happened after reinfusion of HGI-001 injection. The two patients with non-{beta}0/{beta}0 genotype have been transfusion-independent for 24 months and 21 months post-treatment. At the last visit, the levels of HbAT87Q are 7.3 and 6.9g/dL, and the levels of total hemoglobin are 9.8 and 10.1 g/dL. After the two subjects stopped transfusions, the iron overload has been alleviated without iron chelation treatment. Most AEs are myeloablative conditioning related, and can be controlled through clinically standard therapeutic managements. No clone dominance related to vector integration nor RCL has been observed. ConclusionGene therapy with optimized LentiHBBT87Q vector (HGI-001 injection) assist two TDT patients become transfusion-independent without serious adverse events related to the product.