AIBP, apoA-I, and aflibercept combination gene therapy overcomes anti-VEGF resistance in experimental neovascular AMD

Abstract

Purpose : Anti-VEGF resistance is a major unmet clinical need in managing choroidal neovascularization (CNV) or nAMD. We have reported that laser-induced CNV in young mice, which shows a high responsiveness to anti-VEGF treatment, and in old mice, which displays resistance to anti-VEGF therapy, exhibits cardinal characteristics of capillary and arteriolar CNV, respectively. Importantly, a combination of AIBP, apoA-I, and aflibercept overcomes anti-VEGF resistance in laser-induced CNV in old mice by inhibiting arteriolar CNV. The objective is to develop an AIBP/apoA-I/anti-VEGF combination gene therapy with long-term efficacy for nAMD.

Methods : AAV vectors were packaged into AAV2.7m8 capsid. We intravitreally injected three groups of AAVs: 1) control; 2) AAV-AIBP + AAV-apoA-I + AAV-aflibercept; and 3) AAV-aflibercept into C57BL6J mice, followed by CNV induction 4 weeks later. CNV leakage and area were quantified by fluorescein angiography (FA) and choroid flatmount, respectively, 7 days after laser injury (Fig. 1A). To perform a treatment experiment (i.e., induce gene expression after laser injury), we generated inducible AAV gene expression vectors using the Tet-One Systems. We intravitreally injected three groups of AAVs: 1) AAV-TetOne-mGreenLatern; 2) AAV-TetOne-AIBP + AAV-TetOne-apoA-I + AAV-TetOne-aflibercept-T2A-mGreenLatern; and 3) AAV-TetOne-aflibercept into mice. Laser photocoagulation was performed 4 weeks later. Injected mice were fed with Dox drinking water 2 days after laser injury. CNV leakage and area were quantified 7 days after laser injury (Fig. 2A).

Results : Combination gene therapy and AAV-aflibercept monotherapy are equally effective in reducing leakage and CNV area in young mice with capillary CNV (Fig. 1B). In old mice, inducible expression of AIBP, apoA-I, and aflibercept was effective in treating anti-VEGF resistance by inhibiting arteriolar CNV while AAV-aflibercept monotherapy was ineffective (Fig. 2B).

Conclusions : It is feasible to develop a long-term AIBP/apoA-I/aflibercept combination gene therapy in ameliorating anti-VEGF resistance in the treament of nAMD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Combination gene therapy and AAV-aflibercept monotherapy are equally effective in the treatment of capillary CNV in young mice.

 

AAV mediated inducible expression of AIBP, apoA-I, and aflibercept overcomes anti-VEGF resistance in old mice.