An angiopoietin-2 vaccine improves arteriovenous malformation pathology in hereditary hemorrhagic telangiectasia mice

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder that causes systemic arteriovenous malformations (AVMs) associated with severe complications. Angiopoietin (ANG)-2 has been identified as a consistently upregulated secreted protein across various HHT models, and neutralizing ANG2 reduces AVMs in mice. ANG2 has thus emerged as a potential target for HHT treatment. Here, we report the development of a peptide vaccine (ANG2-P3:CRM197) that selectively targets ANG2 over ANG1 and tested its effectiveness in decreasing retinal AVMs in neonatal mice injected with BMP9/10 blocking antibodies, a model of HHT. Litter groups from female C57BL/6 mice immunized with ANG2-P3:CRM197 received injections of anti-BMP9/10 antibodies, and their retinas were examined for vascular pathology. The potential toxicity of the vaccine was evaluated in females 12 months post-immunization through echocardiography, basic metabolic panels, and lipid profiles. Circulating anti-ANG2 antibodies were detected in nursing neonates of vaccinated females, with antibody levels comparable between litters and their dams, indicating effective antibody transfer from the dams. A significant decrease in AVM number and size was observed in the retinas of pups exposed to ANG2-P3:CRM197 antibodies compared to unexposed pups. Arterial and venous diameters were normalized in the vaccinated pups retinas. The vaccinated females showed no abnormalities in cardiac, liver, or kidney functions. A vaccine strategy targeting ANG2 appears safe and improves AVM pathology in HHT mice. These findings further support the potential of inhibiting ANG2 as a viable approach for treating AVMs in HHT. KEY POINTSO_LIA peptide vaccine that targets ANG2 reduced AVM number and size, and normalized arterial and venous diameters in a mouse model of HHT. C_LIO_LIThe vaccine did not cause any abnormalities in cardiac, liver, or kidney functions, and thus appeared safe. C_LI