RAP-011 Efficiently Rescues Erythropoiesis In Zebrafish Models Of Diamond Blackfan Anemia

Diamond Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count but normal levels of platelets and white blood cells. Ribosomal mutations in RPS19, RPS26, RPL5, and RPL11 have been identified in approximately 50% of all DBA cases. Corticosteriod therapy and bone marrow transplantion are the most common treatment options for DBA patients. However, corticosteroids have severe side effects and bone marrow transplantation is risky; thus, novel therapeutics for DBA are needed. Sotatercept (ACE-011), an activin receptor IIA ligand trap which rapidly increased hemoglobin and hematocrit in both pharmacologic models and in healthy volunteers, is currently being evaluated in diseases of ineffective erythropoiesis such as ß-thalassemia and MDS. Non-clinical studies in mice have demonstrated that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through stimulating expansion of late-stage erythroblasts through a mechanism distinct from EPO. Here, we evaluated the effect of RAP-011 in zebrafish models of ribosome insufficiency in RPS19 and RPL11 that recapitulate the anemic phenotype seen in DBA patients. Treatment with RAP-011 treatment dramatically restored hemoglobin levels compromised by ribosome stress. Furthermore, the beneficial effect of RAP-011 is synergistic with corticosteriod treatment. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by altering the microenvironment of erythroid cells, reducing p21 levels through a p53-independent manner. These findings uncover a novel signaling pathway in the pathogenesis of DBA and support the potential use of Sotatercept for the treatment of DBA patients with ribosomal disorders. Our studies also demonstrate, for the first time, that protein drugs can be effectively evaluated in zebrafish human disease models, which offer a unique opportunity to identify the targets and study their mechanisms of action.