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

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder that causes systemic arteriovenous malformations (AVMs) associated with severe complications. Angiopoietin-2 (ANG2) has been identified as a consistently upregulated secreted protein across various HHT models, and neutralizing ANG2 reduces AVMs in mice. Therefore, ANG2 has emerged as a potential target for HHT treatment. Here, we report the development of a peptide vaccine (ANG2-P3:cross-reacting material 197 [CRM197]) that selectively targets ANG2 over ANG1 and tested its effectiveness in decreasing retinal AVMs in neonatal mice injected with bone morphogenetic protein (BMP)9/10 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 after 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 with 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.