Circulating Biomarkers Associated With Hereditary Hemorrhagic Telangiectasia Sensitive to ALK1 Modulation

Hereditary hemorrhagic telangiectasia (HHT), the second-most-common inherited bleeding disorder worldwide, is an autosomal dominant vasculopathy characterized by telangiectasias and arteriovenous malformations causing numerous serious bleeding and nonbleeding manifestations. The disease is caused by loss-of-function mutations in components of the endothelial BMP9:ENG:ALK1:BMPRII canonical signaling pathway, triggering a concomitant reduction in vascular quiescence, symbolized by a decrease in the transcription of the inhibitor of differentiation-1 and an overactivation of VEGFR2 signaling. The sum of these defective pathways leads to the formation of fragile blood vessels prone to spontaneous rupture. In this study, we sought to identify circulating biomarkers that reflect the full disease state and to determine whether such biomarkers respond to corrective therapies. We confirmed the presence of broad HHT inflammatory dysregulation and identified soluble VEGFR1, soluble endoglin, and soluble LYVE-1 as plasma biomarkers of the ALK1 dysfunction in HHT. Importantly, in studies performed ex vivo in nonhuman primates and in vitro using human microvascular endothelial cells, we demonstrated that these endothelium-derived biomarkers are sensitive to ALK1 stimulation, by either BMP9 (the endogenous ligand) or DIAG723, a tetravalent bispecific clustering antibody that activates the ALK1:BMPRII receptor complex on the endothelial cell surface. In addition, we found that similar concentrations of DIAG723 restore both endothelial-derived biomarkers and promote ID-1 transcription in endothelial cells, thereby correcting the entire defective signaling machinery. Therefore, these circulating biomarkers could potentially be used for early diagnosis and as pharmacodynamic endpoints in HHT clinical trials and clinical practice.