Background & Purpose: Brain arteriovenous malformation (bAVM) is a risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. We tested a minimally invasive gene therapy using an adeno-associated viral vector (AAV9) to intravenously (IV) deliver an anti-angiogenic agent, soluble FLT1 (sFLT1), to two bAVM mouse models.
Method: Model 1 consists of SM22αCre;Endoglin (Eng, a bAVM causative gene)-floxed mice, which have a 90% occurrence of spontaneous bAVM after 5 weeks and 50% mortality after 6 weeks. In Model 2, bAVM is induced in RosaCreER;Eng-floxed mice through tamoxifen-mediated Eng-deletion and AAV1-VEGF-induced brain angiogenesis. AAV9-sFLT1 or AAV9-GFP was IV injected to 4-week-old Model 1 mice, or Model 2 mice 8 weeks after model induction. Brain vasculature was analyzed 4 weeks later through vessel-casting and brain section staining with CD31 antibody. Potential toxicities were assessed by analyzing brain and liver histology, and measuring serum alkaline phosphatase (ALP) and alanine transaminase (ALT) activities as well as creatinine (CR) levels.
Results: sFLT1-treatment increased Model 1 mice survival. BAVMs were detected in all GFP-treated, but only in 25% of sFLT1-treated mice. In Model 2, sFLT1 treatment reduced abnormal vessels. No neuronal death or lymphocyte was detected in the brain of sFLT1-treated mice. AAV9 treatment did not cause weight loss, or alter CR levels or ALP and ALT activities. Small clusters of inflammatory cells were detected in the liver of 58% of GFP- and 56% of sFLT1-treated mice.
Conclusion: Systemic sFLT1 gene therapy reduces bAVM severity with minimal adverse effect. Future studies should consider restricting sFLT1 expression in the brain to reduce liver inflammation.