Abstract W P413: Intravenous Delivery of the AAV9-sFLT Vector Reverses the Phenotype of Spontaneously Developed Brain Arteriovenous Malformation in Mice

Abstract

Background and Purpose: Current therapies for brain arteriovenous malformation (bAVM) are invasive and have potential treatment-related morbidity. Excessive vascular endothelial growth factor (VEGF) expression is one of the key players in bAVM pathophysiology. The soluble VEGF receptor 1 (sFLT) possesses an anti-angiogenic effect. We hypothesize that intravenous delivery of adeno-associated viral vector serotype 9 (AAV9) expressing sFLT reverses the bAVM phenotype. Methods: SM22α-Cre transgenic mice were crossed with endoglin (Eng)-floxed mice to delete Eng. More than 95% of SM22 α-Cre;Eng-floxed mice spontaneously developed bAVM at age of 5 weeks. AAV9-sFLT (1x1011 viral genomes) was injected into the jugular vein of 5-week-old mice. AAV9-GFP was used as vector control. Brain vascular structure was analyzed using latex vascular casting 4 weeks after vector injection. The success of gene delivery, lymphocyte infiltration and neuronal loss was analyzed in the brain sections. Results: Due to the severity of the AVM lesion in this model, 3 of 9 AAV9-GFP-treated mice and 2 of 8 AAV9-sFLT-treated mice died during the 4-week treatment period. One paralyzed mouse in the AAV9-GFP group was euthanized before the treatment period ended. Only 1 of the 6 surviving mice in the AAV9-sFLT group had detectable bAVM, whereas all 5 mice in the AAV9-GFP group had it. GFP expression was detected in the bAVM lesion of AAV9-GFP-treated mice. Neither lymphocyte infiltration nor neuronal loss was observed. Conclusion: Because intravenous delivery of AAV9-sFLT reverses the bAVM phenotype without inducing intra-brain lymphocyte filtration and neuronal loss, AAV-mediated sFLT delivery could thus be developed into a specific, non-invasive therapy for patients with bAVM.