Beta thalassemia Gene therapy

Beta thalassemia, a hereditary blood disorder marked by defective ẞ-globin synthesis, has long imposed a heavy burden of chronic transfusion dependence, iron overload, and diminished quality of life. Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only definitive cure, its applicability is severely limited by donor availability and associated risks such as graft-versus-host disease and long-term immunosuppression In recent years, autologous gene therapy using either gene addition or genome editing has emerged as a transformative alternative. Betibeglogene autotemcel (Zynteglo®) is a lentiviral vector-based gene addition therapy encoding a ẞ-globin variant (BA-T۸۷Q). Following successful trials, it achieved regulatory approval in the EU (۲۰۱۹) and the US (۲۰۲۲), demonstrating durable transfusion independence in a significant proportion of treated individuals Despite encouraging outcomes, challenges persist including high therapy costs, access limitations, and concerns over insertional oncogenesis Parallel to gene addition efforts, genome editing techniques particularly CRISPR/Cas۹-mediated disruption of the BCL۱۱A erythroid enhancer have shown remarkable potential in reactivating fetal hemoglobin (HbF) expression. The CTX۰۰۱/"Casgevy" platform, developed by CRISPR Therapeutics and Vertex, has achieved sustained HbF upregulation and transfusion independence in early-phase clinical studies, culminating in historic regulatory approvals. Other genome editing approaches including zinc finger nucleases (ZFNS), TALENS, and CRISPR-mediated direct repair of pathogenic point mutations are under active investigation. Preclinical results in patient-derived iPSC and HSPC models have demonstrated high targeting efficiency and minimal off-target effects, heralding a shift toward precision medicine in ẞ-thalassemia gene therapy Despite transformative progress, key hurdles remain including enhancing delivery efficiency to hematopoietic stem cells, ensuring long-term safety (e.g. minimizing oncogenic risk), reducing conditioning-related toxicity, and overcoming economic and logistical barriers. As gene therapy matures into clinical reality, continued innovation in vector engineering, genome editing modalities, and equitable access frameworks will be paramount in realizing a universal cure for ẞ-thalassemia

کلیدواژه ها:

Hematology ، Oncology ، Beta thalassemia ، Gene therapy