An emerging class of new therapeutics targeting TGF, Activin, and BMP ligands in pulmonary arterial hypertension

FIGURE 1. Schematic depicting the multiple levels of regulation of bone morphogenetic protein (BMP), growth and differentiation factor (GDF), activin and transforming growth factor‐β (TGFβ) signaling pathways. The activity of the ligands is regulated via secretion and processing. The prodomains are cleaved from the active growth factor domain (GFD) by furin‐type prohormone convertases. In the case of BMP9 and BMP10, the non‐covalent complex of the prodomain and GFD are biologically active. The availability of the GFDs for receptor binding is also regulated by local concentrations of soluble inhibitory ligand traps (eg, Gremlin, Noggin, Follistatin). Ligand selectivity is regulated and refined by the cell surface composition of complexes comprising Type‐I receptors (ALK1‐7), Type‐II receptors (BMPR‐II, ACTR‐IIA, ACTR‐IIB, TGFβR‐II) and co‐receptors (endoglin, betaglycan). Each receptor complex has selectivity for specific ligands ranging from high affinity, through lower affinities to no detectable interaction. The cytoplasmic serine/threonine kinase domains of the activated receptor complexes phosphorylate and activate canonical Smad complexes and non‐canonical kinases. Smad1/5/8 typically…

FIGURE 2. Rationale of BMP9‐based therapies in PAH. Left panel: Circulating BMP9 and BMP10 signal via high‐affinity endothelial cell surface receptor complexes comprising ALK1 and BMPR‐II with the co‐receptor, endoglin. This continuous signaling mediates normal Smad1/5/8 activity to maintain endothelial cell homeostasis. Centre panel: Genetic reduction of functional ALK1, BMP9, BMP10, BMPR‐II, endoglin, Smad4 or Smad8, exacerbated by one or more “second hits,” critically reduces endothelial BMP9/BMP10 signaling and results in the pathological changes underlying the development of PAH. Right panel: Proposed mode of action of supplementation with exogenous recombinant BMP9 (rBMP9), leading to restored endothelial cell signaling via enhancement of BMPR‐II protein levels and normalisation of endothelial cell functions. Created with BioRender.com

FIGURE 3. Overlapping genetic architecture of mutations underlying PAH and HHT may explain the paradoxical observations of alleviation of PAH in preclinical models by BMP9 agonist therapy and BMP9 blockade. BMPR2 mutations underly PAH in man, whereas GDF2 (BMP9) mutations are associated with PAH or syndromes with an HHT‐like phenotype. Mutations in ACVRL1 (ALK1) and ENG most commonly cause HHT and less frequently cause PAH. In preclinical models, recombinant BMP9 (rBMP9) agonist therapy dramatically reduces the PAH phenotype and is predicted to exert beneficial effects in preclinical HHT models. Inhibition of BMP9 with anti‐BMP9 or inhibiting BMP9 and BMP10 with ALK1‐Fc in preclinical rodent models of PAH may cause vasodilation and lead to a paradoxical protection from PAH due to the induction of an HHT‐like phenotype. Created with BioRender.com

FIGURE 4. Possible rationale for sotatercept therapy in PAH. Left panel: Signaling by activin and BMP9/BMP10 via their respective endothelial cell surface receptor complexes maintains endothelial cell homeostasis. Centre panel: Genetic reduction of functional ALK1, BMP9, BMP10, BMPR‐II, endoglin, Smad4, or Smad8 lead to reduced BMP signaling. The reduction of BMP signaling may be exacerbated by one or more “second hits” that may also cause an elevation of activin A production. The excessive activin A signals and Smad2/3 signaling may promote the pathological changes underlying the development of PAH. Right panel: Sotatercept acts as a ligand trap to neutralize activin and reduce aberrant Smad2/3 signaling. Created with BioRender.com

FIGURE 5. Multiple signalling inputs influence the net levels of cell surface BMPR‐II protein in endothelial cells. BMP9 promotes BMPR‐II transcription and increases cell surface BMPR‐II, whereas TNFα represses BMPR‐II transcription. Activin A may promote BMPR‐II protein degradation with possible enhancement of this effect by growth factors and inhibition by BMP9. Although circulating activin A levels are elevated in PAH patients, levels of the activin ligand trap, follistatin, are also elevated and, therefore, it is not known if plasma activin activity is increased. Created with BioRender.com