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

Abstract

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.

Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy

“…Initially, approximately 80% of patients show a positive response to steroid therapy. However, approximately half of these individuals discontinue treatment due to either a loss of response or severe side effects [ 1 , 19 ]. These adverse effects may include growth retardation, increased risk of heart disease, osteoporosis, and severe infections [ 1 ].…”

“…Despite the efficacy of this approach, the availability of HLA-matched donors is not always guaranteed. HSCT carries several drawbacks, including the risk of graft-versus-host disease (GvHD), adverse effects stemming from preconditioning, the possibility of undetected mutations in silent carriers, and the necessity for immunosuppressive therapy post-transplantation [ 1 , 5 , 19 ].…”