An Innovative Gene Therapy by Selective and Regulative Neutralizing VEGF in HHT-Associated Brain Arteriovenous Malformations



Wan Zhu, PhD, is a Post Doctoral Research Fellow at the University of California, San Francisco working under the direction of Dr. Hua Su. In 2015, Dr. Zhu was awarded a $30,000 Young Investigator Grant by Cure HHT.



Proposed Research Summary

Brain AVMs (bAVMs) have the most devastating outcomes due to the possibility of vessel rupture in the brain. Most current therapies are invasive and have high risks, therefore, there is a need for new treatment strategies. Previous studies have shown that an increased level of an angiogenic factor, vascular endothelial growth factor (VEGF), plays an important role in AVM formation. Inhibition of VEGF by an antibody drug such as bevacizumab (Avastin) reduces lesion sizes. However, antibody-treatment is very costly and has significant side effects. Dr. Zhu’s project proposes an innovative and noninvasive strategy injecting a viral vector into the localized site to bind VEGF and inhibit VEGF pathogenic effects in AVMs. It is believed that this strategy can be used to treat bAVMs in HHT patients and with minor modifications this strategy can be used to treat HHT patients who have AVMs in other organs.

Dr. Zhu’s research was published in Stroke in May 2017. 


Published Abstract

Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity

Background and Purpose: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. Excessive vascular endothelial growth factor has been implicated in bAVM pathophysiology. Because soluble FLT1 binds to vascular endothelial growth factor with high affinity, we tested intravenous delivery of an adeno-associated viral vector serotype-9 expressing soluble FLT1 (AAV9-sFLT1) to alleviate the bAVM phenotype.

Methods: Two mouse models were used. In model 1, bAVM was induced in R26CreER;Eng2f/2f mice through global Eng gene deletion and brain focal angiogenic stimulation; AAV2-sFLT02 (an AAV expressing a shorter form of sFLT1) was injected into the brain at the time of model induction, and AAV9-sFLT1, intravenously injected 8 weeks after. In model 2, SM22αCre;Eng2f/2f mice had a 90% occurrence of spontaneous bAVM at 5 weeks of age and 50% mortality at 6 weeks; AAV9-sFLT1 was intravenously delivered into 4- to 5-week-old mice. Tissue samples were collected 4 weeks after AAV9-sFLT1 delivery.

Results: AAV2-sFLT02 inhibited bAVM formation, and AAV9-sFLT1 reduced abnormal vessels in model 1 (GFP versus sFLT1: 3.66±1.58/200 vessels versus 1.98±1.29, P<0.05). AAV9-sFLT1 reduced the occurrence of bAVM (GFP versus sFLT1: 100% versus 36%) and mortality (GFP versus sFLT1: 57% [12/22 mice] versus 24% [4/19 mice], P<0.05) in model 2. Kidney and liver function did not change significantly. Minor liver inflammation was found in 56% of AAV9-sFLT1-treated model 1 mice.

Conclusions: By applying a regulated mechanism to restrict sFLT1 expression to bAVM, AAV9-sFLT1 can potentially be developed into a safer therapy to reduce the bAVM severity.


Publication – Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity. Stroke.