title: RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1.
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.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Jason
authors.initials: J
authors.lastname: Ear
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Haigen
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Tianna
authors.initials: T
authors.lastname: Wilson
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Zahra
authors.initials: Z
authors.lastname: Tehrani
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Anne
authors.initials: A
authors.lastname: Lindgren
authors.affiliation: Celgene Corporation, San Francisco, CA; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.affiliation: Celgene Corporation, Summit, NJ.
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Laadem
authors.affiliation: Celgene Corporation, Summit, NJ.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene Corporation, Summit, NJ.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA;
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors / Q000097:blood; D029503:Anemia, Diamond-Blackfan / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000187:drug effects* / Q000235:genetics; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006801:Humans; D055458:Left-Right Determination Factors / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D008024:Ligands; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012269:Ribosomal Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D017086:beta-Thalassemia / Q000097:blood / Q000188:drug therapy
chemical_list: D030301:Activin Receptors, Type II; D055458:Left-Right Determination Factors; D008024:Ligands; D011993:Recombinant Fusion Proteins; D012269:Ribosomal Proteins; D029961:Zebrafish Proteins; C542017:sotatercept; C000595663:ActRIIA-mIgG2aFc fusion protein; C117508:lft1 protein, zebrafish; C027624:ribosomal protein L11; C505424:acvr2aa protein, zebrafish