# Activin signaling in normal and disordered erythropoiesis

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $378,000

## Abstract

Activin signaling in normal and disordered erythropoiesis
ABSTRACT
Disorders associated with anemia such as β-thalassemia (BT) and myelodysplastic syndrome (MDS) are a
major clinical challenge in the United States, as many of these patients require chronic, expensive treatment
for survival. Two novel, very similar drugs, Sotatercept (ACE-011) and Luspatercept (ACE-536), are presently
being tested in clinical trials, and they have shown success in improving anemia and bone mass in BT, and
delay of disease onset in MDS. Importantly, Sotatercept and Luspatercept contain the extracellular domain of
activin receptor 2A (ACVR2A) and 2B (ACVR2B), respectively, and they use a non-erythropoietin (EPO)-
dependent pathway to enhance red blood cell (RBC) production. Their proposed mechanism of action is to trap
transforming growth factor (TGF) β-like ligands, thereby modulating activin signaling via altered modification of
the intracellular SMAD complex. Studies in BT mice suggest that the target of these drugs is the TGFβ-like
ligand growth differentiation factor 11 (GDF11). Moreover, it has been proposed that GDF11 is upregulated in
erythroid cells of BT and MDS mice, inhibiting late-stage erythroid differentiation via SMAD complex
phosphorylation. However, these results are not consistent with our preliminary data showing that Gdf11
deletion failed to recapitulate the phenotype observed in animals treated with RAP-536 (the mouse counterpart
of Luspatercept). In addition, Gdf11-deleted mice continued to respond to RAP-536. Thus, we hypothesize that
GDF11 is not the sole target responsible for the improvements observed in RAP-536-treated BT mice or that
lack of GDF11 is required, but not sufficient, for increased RBC production. Of note, these drugs also increase
erythropoiesis in normal individuals and mice. Here, we propose to investigate the pathways involved in normal
and ineffective erythropoiesis using wild-type (WT) and BT mice, respectively, with the following specific aims
(SA): 1. Characterize the mechanisms by which RAP-536 increases erythropoiesis in WT mice and
improves anemia in BT mice. We will characterize erythropoiesis in RAP-536 treated, WT and BT mice, and
if this drug promotes macrophage-erythroblast interaction. 2. Investigate the consequences of
simultaneous inhibition of the candidate ligands responsible for the increased erythropoiesis mediated
by RAP-536. We will inhibit GDF11, GDF8, which is highly homologous to GDF11, and Activin-B, individually
and in combination in WT and BT mice, to determine whether their inactivation is necessary for enhanced
erythropoiesis. 3. Identify which cell types respond to RAP-536 administration by targeting the
candidate Acvr2A/B receptors in erythroid and myeloid cells. We will use transgenic, SMAD-responsive,
reporter mice to identify which cells show altered pathway activity following RAP-536 treatment. To further
identify the cells that are responsible for the erythroid phenotype in RAP-536-trea...

## Key facts

- **NIH application ID:** 9889103
- **Project number:** 5R01DK090554-09
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** STEFANO RIVELLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,000
- **Award type:** 5
- **Project period:** 2010-09-30 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889103

## Citation

> US National Institutes of Health, RePORTER application 9889103, Activin signaling in normal and disordered erythropoiesis (5R01DK090554-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889103. Licensed CC0.

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