PUBLICATION
RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1
- Authors
- Ear, J., Huang, H., Wilson, T., Tehrani, Z., Lindgren, A., Sung, V., Laadem, A., Daniel, T.O., Chopra, R., Lin, S.
- ID
- ZDB-PUB-150626-6
- Date
- 2015
- Source
- Blood 126(7): 880-90 (Journal)
- Registered Authors
- Huang, Haigen, Lin, Shuo, Tehrani, Zahra
- Keywords
- none
- MeSH Terms
-
- beta-Thalassemia/blood
- beta-Thalassemia/drug therapy
- Signal Transduction/drug effects
- Left-Right Determination Factors/antagonists & inhibitors*
- Left-Right Determination Factors/blood
- Left-Right Determination Factors/genetics
- Ribosomal Proteins/blood
- Ribosomal Proteins/deficiency
- Ribosomal Proteins/genetics
- Disease Models, Animal
- Activin Receptors, Type II/antagonists & inhibitors
- Activin Receptors, Type II/blood
- Animals
- Erythropoiesis/drug effects*
- Erythropoiesis/genetics
- Gene Knockdown Techniques
- Anemia, Diamond-Blackfan/blood
- Anemia, Diamond-Blackfan/drug therapy*
- Anemia, Diamond-Blackfan/genetics
- Genes, p53
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/blood
- Zebrafish Proteins/genetics
- Humans
- Zebrafish
- Recombinant Fusion Proteins/therapeutic use*
- Ligands
- PubMed
- 26109203 Full text @ Blood
Citation
Ear, J., Huang, H., Wilson, T., Tehrani, Z., Lindgren, A., Sung, V., Laadem, A., Daniel, T.O., Chopra, R., Lin, S. (2015) RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1. Blood. 126(7):880-90.
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, a.k.a 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-thalasemia, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping