Anti-Scg3 Gene Therapy to Treat Choroidal Neovascularization in Mice

Authors

Chengchi Huang
Liyang Ji
Avinash Kaur
Hong Tian
Prabuddha Waduge
Keith A Webster
Wei Li

Publication Date

7-6-2023

Journal

Biomedicines

DOI

10.3390/biomedicines11071910

PMID

37509549

PMCID

PMC10377229

PubMedCentral® Posted Date

7-6-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

age-related macular degeneration, choroidal neovascularization, gene therapy, secretogranin III (Scg3), anti-Scg3 gene therapy, disease-targeted gene therapy, vascular endothelial growth factor (VEGF), anti-VEGF gene therapy

Abstract

Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries. The disease is currently treated with anti-angiogenic biologics, including aflibercept, against vascular endothelial growth factor (VEGF) but with limited efficacy, treatment resistance and requirement for frequent intravitreal injections. Although anti-VEGF gene therapy may provide sustained therapy that obviates multiple injections, the efficacy and side effects related to VEGF pathway targeting remain, and alternative strategies to block angiogenesis independently of VEGF are needed. We recently reported that secretogranin III (Scg3) induces only pathological angiogenesis through VEGF-independent pathways, and Scg3-neutralizing antibodies selectively inhibit pathological but not physiological angiogenesis in mouse proliferative retinopathy models. Anti-Scg3 antibodies synergize dose-dependently with VEGF inhibitors in a CNV model. Here, we report that an adeno-associated virus-8 (AAV8) vector expressing anti-Scg3 Fab ameliorated CNV with an efficacy similar to that of AAV-aflibercept in a mouse model. This study is the first to test an anti-angiogenic gene therapy protocol that selectively targets pathological angiogenesis via a VEGF-independent mechanism. The findings support further safety/efficacy studies of anti-Scg3 gene therapy as monotherapy or combined with anti-VEGF to treat nAMD.