Introduction: Brain arteriovenous malformations (bAVMs) are rare cerebrovascular lesions characterized by abnormal arterial-to-venous shunting and their rupture leads to severe morbidity and mortality. Activating KRAS mutations are common in sporadic bAVMs, but their translational relevance remains unclear. This study aims to characterize a preclinical bAVM mouse model and explore a novel therapeutic approach for bAVMs.
Methods: We delivered the KRASG12V-GFP transgene to cerebral endothelial cells using an AAV-BR1-CAG vector targeting brain vasculature. Five-week-old C57BL/6 mice were injected with 5x107 to 5x1010 genome copies of the vector. bAVM formation, intracerebral hemorrhage, and overall survival (OS) were monitored. Additionally, the effects of MEK inhibition with trametinib, with or without VEGF inhibition, were evaluated in mice with established bAVMs starting 4-weeks after viral delivery.
Results: Selective overexpression of KRASG12V-GFP in cerebral endothelial cells led to the formation of bAVMs in a dose-dependent manner. Mice receiving the highest transgene dose developed significantly more bAVMs, exhibited a higher burden of intracerebral hemorrhage, and had worse OS compared to those receiving lower transgene doses. At the time of this abstract submission, drug treatment trials using trametinib and an anti-VEGF monoclonal antibody are underway. Preliminary results show significantly improved OS in KRASG12V-GFP mice with established bAVMs treated with trametinib alone or in combination with the anti-VEGF antibody as compared to their respective controls (60% OS trametinib alone vs. 0% OS vehicle control, p< 0.05; 100% OS trametinib plus anti-VEGF antibody vs. 20% OS vehicle control, p< 0.05). We anticipate sharing the final data from these drug treatment trials at the AANS 2025 Annual Scientific Meeting.
Conclusion : Our findings suggest that, in addition to promoting bAVM formation, KRAS mutations in cerebral endothelial cells may be causally implicated in bAVM rupture. Additionally, concomitant inhibition of the MAPK and VEGF pathways may be a promising novel therapeutic strategy for KRAS-mutated bAVMs.
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