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Rapid in vivo Drug Response Prediction Using Leukemia Cell Grafts in Zebrafish Embryos
Published on: May 23, 2025
RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1
Jason Ear1, Haigen Huang1, Tianna Wilson1
1Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
Abstract:
Diamond-Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count. Mutations in ribosomal protein genes have been identified in approximately half of all DBA cases. Corticosteriod therapy and bone marrow transplantation are common treatment options for patients; however, significant risks and complications are associated with these treatment options. Therefore, novel therapeutic approaches are needed for treating DBA. Sotatercept (ACE-011, and its murine ortholog RAP-011) acts as an activin receptor type IIA ligand trap, increasing hemoglobin and hematocrit in pharmacologic models, in healthy volunteers, and in patients with β-thalassemia, by expanding late-stage erythroblasts through a mechanism distinct from erythropoietin. Here, we evaluated the effects of RAP-011 in zebrafish models of RPL11 ribosome deficiency. Treatment with RAP-011 dramatically restored hemoglobin levels caused by ribosome stress. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by sequestering lefty1 from erythroid cells. These findings identify lefty1 as a signaling component in the development of erythroid cells and rationalize the use of sotatercept in DBA patients.
Insights
Diamond-Blackfan Anemia (DBA) is a rare blood disorder. Sotatercept (RAP-011) effectively restored red blood cell production in zebrafish models, offering a potential new therapy for DBA patients.
Area of Science:
- Hematology
- Genetics
- Pharmacology
Background:
- Diamond-Blackfan Anemia (DBA) is a bone marrow failure disorder causing low red blood cell counts.
- Mutations in ribosomal protein genes are implicated in about 50% of DBA cases.
- Current treatments like corticosteroids and bone marrow transplantation have significant risks.
Purpose of the Study:
- To evaluate the therapeutic potential of sotatercept (murine ortholog RAP-011) in zebrafish models of Diamond-Blackfan Anemia.
- To investigate the mechanism by which sotatercept influences erythropoiesis.
Main Methods:
- Utilized zebrafish models with RPL11 ribosome deficiency to mimic DBA.
- Administered RAP-011 to assess its effects on hemoglobin levels and erythropoietic activity.
- Analyzed the interaction of RAP-011 with signaling pathways, specifically lefty1.
Main Results:
- RAP-011 treatment significantly restored hemoglobin levels in zebrafish with ribosome deficiency.
- The drug appears to stimulate erythropoiesis by sequestering lefty1 from erythroid cells.
- This mechanism is distinct from erythropoietin and expands late-stage erythroblasts.
Conclusions:
- Sotatercept (RAP-011) demonstrates efficacy in restoring hemoglobin levels in a DBA model.
- Lefty1 is identified as a key signaling component in erythroid cell development.
- These findings support the potential of sotatercept as a novel therapeutic agent for Diamond-Blackfan Anemia.
