Alternative conditioning regimens for hemoglobinopathy gene therapy: balancing efficacy, toxicity, and the next frontier

Abstract

Abstract Gene therapy for sickle cell disease and transfusion-dependent thalassemia is now widely available, yet its broader application is constrained by the need for effective and tolerable conditioning. This review examines the central role of conditioning in enabling durable engraftment of gene-modified hematopoietic stem cells, emphasizing the narrow therapeutic window between insufficient niche clearance and excessive toxicity. Busulfan remains the standard conditioning agent, supported by consistent engraftment and clinical efficacy, but its use is limited by acute and long-term toxicities, including infertility and potential genotoxicity. Emerging strategies aim to mitigate these risks. Reduced-intensity melphalan shows early promise but raises concerns regarding the durability of engraftment, whereas treosulfan offers a potentially safer profile, although data in the autologous setting are lacking. Antibody-based, nongenotoxic approaches represent a transformative direction but remain investigational. Refining conditioning through comparative trials and long-term follow-up will be critical to fully realize the curative potential of gene therapy.