Anti-Scg3 Gene Therapy to Treat Choroidal Neovascularization in Mice

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)...

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Published in:Biomedicines 2023-07, Vol.11 (7), p.1910
Main Authors: Huang, Chengchi, Ji, Liyang, Kaur, Avinash, Tian, Hong, Waduge, Prabuddha, Webster, Keith A, Li, Wei
Format: Article
Language:English
Subjects:
Age
age-related macular degeneration
Angiogenesis
Animal models
anti-Scg3 gene therapy
Antibodies
Blindness
Cell growth
choroidal neovascularization
Clinical trials
Cloning
disease-targeted gene therapy
Gene therapy
Genes
Lasers
Macular degeneration
Medical imaging
Neovascularization
Patient compliance
Peptides
Plasmids
Proteins
Retinopathy
Scientific equipment and supplies industry
secretogranin III (Scg3)
Synergism
Vascular endothelial growth factor
Vascularization
Viral antibodies
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Summary: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.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11071910