Sharma Akshay, John Tami
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
Division of Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Stanford University, Palo Alto, CA.
Blood Adv. 2025 Aug 12;9(15):3845-3852. doi: 10.1182/bloodadvances.2024015413.
Two autologous hematopoietic stem cell (HSC)-based gene therapies (GTs) are now commercially available for severe sickle cell disease and transfusion-dependent β-thalassemia. However, the safety and efficacy of a subsequent autologous HSC-based GT after graft failure with a previous allogeneic hematopoietic cell transplant (HCT) remains unclear. Some individuals who have experienced a failed first attempt at a potentially curative therapy might seek a second opportunity for cure via GT. In this article, we discuss various factors related to patient and HSC health that may influence feasibility, and shared decision-making regarding whether an individual who has previously received an allogeneic HCT and experienced graft failure could consider an autologous GT. Exposure to chronic inflammatory stress and conditioning chemotherapy may compromise HSC fitness, reduce hematopoietic reserve, accelerate HSC aging, and promote the accumulation of deleterious genetic mutations, all of which may adversely affect the safety and efficacy of the GT.
目前，两种基于自体造血干细胞（HSC）的基因疗法（GT）已在商业上用于治疗严重镰状细胞病和输血依赖型β地中海贫血。然而，在先前的异基因造血细胞移植（HCT）出现移植失败后，后续基于自体HSC的GT的安全性和有效性仍不明确。一些经历了首次潜在治愈性治疗失败的个体可能会寻求通过GT获得第二次治愈机会。在本文中，我们讨论了与患者和HSC健康相关的各种因素，这些因素可能会影响可行性，以及对于先前接受过异基因HCT并经历移植失败的个体是否可以考虑自体GT的共同决策。接触慢性炎症应激和预处理化疗可能会损害HSC的健康状况，减少造血储备，加速HSC衰老，并促进有害基因突变的积累，所有这些都可能对GT的安全性和有效性产生不利影响。
