Research ArticlePulmonary Hypertension

ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eaaz5660
DOI: 10.1126/scitranslmed.aaz5660

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  • RE: ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension
    • Nicholas W Morrell, Professor, University of Cambridge
    • Other Contributors:
      • Wei Li, Senior Research Associate, University of Cambridge
      • Paul D Upton, Senior Research Associate, University of Cambridge

    We congratulate the authors on providing preclinical support for sotatercept in PAH, especially given the recent announcement of positive data from the Phase 2 (PULSAR) trial in PAH patients. Overall, the authors demonstrate compelling evidence for an inhibitory effect of ACTRIIA-Fc on the Activin/GDF-Smad2/3 axis in preclinical models of PAH and patient-derived cells. However, the functional impact of ACTRIIA-Fc on the BMP pathway remains unclear. The in vitro experiments suggest inhibition of BMP9-dependent BRE-responses by Activin A, GDF8 and GDF11 in telomerase-immortalised endothelial (TIME) cells (Fig 2D), although only GDF11 inhibited the response in cultured primary microvascular endothelial cells (Fig. S4B). The GDF11 concentration used here is 50-100 fold higher than the GDF11 concentrations the authors measured in the group 1 PAH patients (Figure S2C). It would be of interest to know whether this effect is observed at more physiological GDF11 concentrations. Furthermore, the authors show enhancement of BMP9-dependent BRE-luc signalling in TIME cells (Fig.2B) and phospho-Smad1/5 activity in PMVEC (Fig 2C) in the presence of ACTRIIA-Fc, whereas the BMP9-dependent ID1 transcriptional response in PAECs is inhibited by ACTRIIA-Fc (Fig. S4C). This indicates cell type-dependent differences in the responses, or reflects the different readouts under different experimental conditions (e.g. the exposure times) used for the individual assays.

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    Competing Interests: NWM, WL and PDU are co-founders of Morphogen-IX, developing BMP9-based therapies for PAH and other indications.

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