Hematopoietic cell transplantation and gene therapy for Diamond-Blackfan anemia: state of the art and science

Frontiers in Oncology

Oncology

Akshay Sharma¹  Marcin W. Wlodarski²  Senthil Velan Bhoopalan³  Shruthi Suryaprakash⁴ 

[1] Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, United States;Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States;Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, United States;Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States;

关键词: Diamond-Blackfan anemia;    DBA;    anemia;    HCT;    HSCT;    gene therapy;    RPS19;    ribosomopathy;   

DOI  :  10.3389/fonc.2023.1236038

 received in 2023-06-07, accepted in 2023-08-25,  发布年份 2023

来源: Frontiers

【 摘 要 】

Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with RPS19 being involved in 25% of patients. Corticosteroids are the only effective initial pharmacotherapy offered to transfusion-dependent patients aged 1 year or older. However, despite good initial response, only ~20-30% remain steroid-responsive while the majority of the remaining patients will require life-long red blood cell transfusions. Despite continuous chelation, iron overload and related toxicities pose a significant morbidity problem. Allogeneic hematopoietic cell transplantation (HCT) performed to completely replace the dysfunctional hematopoietic stem and progenitor cells is a curative option associated with potentially uncontrollable risks. Advances in HLA-typing, conditioning regimens, infection management, and graft-versus-host-disease prophylaxis have led to improved transplant outcomes in DBA patients, though survival is suboptimal for adolescents and adults with long transfusion-history and patients lacking well-matched donors. Additionally, many patients lack a suitable donor. To address this gap and to mitigate the risk of graft-versus-host disease, several groups are working towards developing autologous genetic therapies to provide another curative option for DBA patients across the whole age spectrum. In this review, we summarize the results of HCT studies and review advances and potential future directions in hematopoietic stem cell-based therapies for DBA.

【 授权许可】

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Copyright © 2023 Bhoopalan, Suryaprakash, Sharma and Wlodarski