Successful gene therapy for transfusion-dependent α-thalassemia: a case report.

abstractα-Thalassemia is a severe inherited hemoglobin (Hb) disorder with limited curative options for patients with transfusion dependency, lacking suitable donors. We report, to our knowledge, the first-in-human application of lentiviral vector-mediated α-globin gene therapy in a girl aged 14 years with transfusion-dependent HbH disease (--SEA/αCSα). Autologous CD34+ hematopoietic stem and progenitor cells were mobilized, collected, and genetically modified ex vivo using the lentiviral vector (Lenti-HBA) to restore α-globin expression, then reinfused after busulfan conditioning. The patient achieved engraftment within 3 weeks and started to be free of transfusions from the fourth week onward. In the last year of follow-up (months 12-24), the average Hb level remained at ∼90 g/L without transfusion support, with HbA accounting for >85% of total Hb. Vector copy numbers were stable, and no evidence of clonal dominance, insertional mutagenesis, or replication-competent lentivirus was detected. Adverse events (AEs) were limited to expected busulfan-related toxicities, including grade 2 menstrual irregularity and ovarian failure (serious AE). Despite cessation of chelation therapy, iron overload progressed minimally, and no cardiac iron deposition occurred. Immune recovery, growth, and development were preserved. This case demonstrates the feasibility, safety, and durable efficacy of lentiviral α-globin gene therapy as a potential curative treatment for transfusion-dependent α-thalassemia. This trial was registered at www.clinicaltrials.gov as NCT05851105.