Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia

Abstract

AbstactDiamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused by heterozygous allelic variations in ribosomal protein (RP) genes. Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA. P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production. The main therapeutic option for DBA patients is corticosteroids. However, half of these patients become non-responsive to corticosteroid therapy over prolonged treatment and have to be given blood transfusions. Hematopoietic stem cell transplantation is currently the sole curative option, however, the treatment is limited by the availability of suitable donors and the potential for serious immunological complications. Recent advances in gene therapy using lentiviral vectors have shown promise in treating RPS19-deficient DBA by promoting normal hematopoiesis. With deepening insights into the molecular framework of DBA, emerging therapies like gene therapy hold promise for providing curative solutions and advancing comprehension of the underlying disease mechanisms.

Understanding Rare Anemias: Emerging Frontiers for Diagnosis and Treatment

“…The pathophysiology of DBA involves ribosomal stress, p53 activation, translational dysfunction, and abnormal inflammatory signaling pathways. Public health strategies include awareness campaigns and research into steroid therapy and bone marrow transplantation [ 8 ].…”

“…The correction of ribosomal protein gene mutations has been facilitated by the advances in genetic engineering and gene therapy and offers promising prospects for correcting ribosomal protein gene mutations associated with disorders like Diamond–Blackfan anemia (DBA). Techniques such as CRISPR/Cas9 genome editing enable targeted interventions at the genetic level, holding potential for repairing or replacing faulty genes and improving treatment outcomes [ 8 , 47 ]. The precise approach depends on the specific mutation and the disorder being treated, with ongoing research focusing on improving the efficacy and safety of these interventions.…”

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

“…Diamond–Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by erythroid hypoplasia, primarily affecting infants [ 1 ]. This condition, estimated to occur in 5–7 cases per million live births [ 1 ], is considered one of the emerging group of disorders known as ribosomopathies [ 2 ], which arise from defects in ribosome biogenesis and function. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes [ 1 ].…”

“…This condition, estimated to occur in 5–7 cases per million live births [ 1 ], is considered one of the emerging group of disorders known as ribosomopathies [ 2 ], which arise from defects in ribosome biogenesis and function. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes [ 1 ]. In fact, the initial discovery of genetic mutations in DBA was attributed to mutations in the RPS19 gene, which encodes one of the proteins in the 40S small ribosomal subunit [ 3 ].…”

“…These therapies aim to correct the genetic defects causing DBA by introducing functional copies of the mutated genes into the patient’s cells. As research in this field progresses, there is growing potential for gene therapy to correct the underlying genetic mutations associated with DBA, using techniques such as the CRISPR/Cas9 editing tool [ 1 , 3 ].…”