Abstract
The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.
Highlights
AGE-RELATED MACULAR DEGENERATION (AMD) is the leading cause of blindness in the elderly
As for safety, we found that high titers of rAAV2.7m8 and rAAV2 expressing KH902 resulted in a vascular sheathing pathology that is associated with immune cell infiltration
A similar pathology has been reported in patients receiving antiVEGF treatment who experienced a worsening in vision[3,19,20] (NCT04418427). We show that this phenotype is associated with increased expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1), two proteins that are essential for extravasation of immune cells by increasing vessel wall interaction with immune cells
Summary
AGE-RELATED MACULAR DEGENERATION (AMD) is the leading cause of blindness in the elderly. It currently affects 196 million people worldwide and is expected to affect 288 million by 2040.1,2 The wet form of AMD is a severe advanced form of the disease, characterized by retinal and/ or choroidal neovascularization (CNV) that result in retinal edemas, causing rapid vision loss if untreated. Vascular endothelial growth factor (VEGF) is a growth factor that promotes neovascularization and abnormal angiogenesis in multiple vascular-related diseases. Inhibition of VEGF function has been shown to reduce neovascular pathologies and edemas in the eye.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
