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Updated: Oct 9, 2025
Author Spotlight: Insights and Innovations in Gene Expression Manipulation Techniques for Choroid Plexus Research
Published on: June 16, 2023
Selectively targeting disease-restricted secretogranin III to alleviate choroidal neovascularization
Liyang Ji1,2,3, Prabuddha Waduge1,2, Lili Hao2,4
1Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
Abstract:
Choroidal neovascularization (CNV), a leading cause of blindness in the elderly, is routinely treated with vascular endothelial growth factor (VEGF) inhibitors that have limited efficacy and potentially adverse side effects. An unmet clinical need is to develop novel therapies against other angiogenic factors for alternative or combination treatment to improve efficacy and safety. We recently described secretogranin III (Scg3) as a disease-selective angiogenic factor, causally linked to diabetic retinopathy and acting independently of the VEGF pathway. An important question is whether such a disease-selective Scg3 pathway contributes to other states of pathological angiogenesis beyond diabetic retinopathy. By applying a novel in vivo endothelial ligand binding assay, we found that the binding of Scg3 to CNV vessels in live mice was markedly increased over background binding to healthy choriocapillaris and blocked by an Scg3-neutralizing antibody, whereas VEGF showed no such differential binding. Intravitreal injection of anti-Scg3 humanized antibody Fab (hFab) inhibited Matrigel-induced CNV with similar efficacy to the anti-VEGF drug aflibercept. Importantly, a combination of anti-Scg3 hFab and aflibercept synergistically alleviated CNV. Homozygous deletion of the Scg3 gene markedly reduced CNV severity and abolished the therapeutic activity of anti-Scg3 hFab, but not aflibercept, suggesting a role for Scg3 in VEGF-independent CNV pathogenesis and therapy. Our work demonstrates the stringent disease selectivity of Scg3 binding and positions anti-Scg3 hFab as a next-generation disease-targeted anti-angiogenic therapy for CNV.
Insights
Secretogranin III (Scg3) is a novel angiogenic factor contributing to choroidal neovascularization (CNV). Targeting Scg3 offers a new therapeutic strategy for CNV, potentially improving upon existing vascular endothelial growth factor (VEGF) inhibitors.
Area of Science:
- Ophthalmology
- Angiogenesis Research
- Molecular Biology
Background:
- Choroidal neovascularization (CNV) causes blindness in the elderly, with current vascular endothelial growth factor (VEGF) inhibitors having limitations.
- There is a clinical need for alternative or combination therapies targeting novel angiogenic factors to enhance efficacy and safety.
- Secretogranin III (Scg3) was previously identified as a disease-selective angiogenic factor, independent of the VEGF pathway, in diabetic retinopathy.
Purpose of the Study:
- To investigate the role of Scg3 in pathological angiogenesis in choroidal neovascularization (CNV).
- To evaluate the therapeutic potential of targeting Scg3 for CNV treatment, alone and in combination with anti-VEGF therapy.
Main Methods:
- Utilized a novel in vivo endothelial ligand binding assay to assess Scg3 binding to CNV vessels in mice.
- Administered intravitreal injections of anti-Scg3 humanized antibody Fab (hFab) and aflibercept (anti-VEGF) in a Matrigel-induced CNV model.
- Assessed CNV severity in Scg3 gene-deleted mice and evaluated the efficacy of anti-Scg3 hFab and aflibercept.
Main Results:
- Scg3 demonstrated disease-selective binding to CNV vessels, unlike VEGF.
- Intravitreal anti-Scg3 hFab inhibited CNV with efficacy comparable to aflibercept.
- Combination therapy with anti-Scg3 hFab and aflibercept showed synergistic inhibition of CNV.
- Scg3 gene deletion reduced CNV severity and abrogated anti-Scg3 hFab efficacy, confirming Scg3's role in VEGF-independent CNV.
Conclusions:
- Scg3 is a key pathogenic factor in VEGF-independent choroidal neovascularization (CNV).
- Anti-Scg3 hFab represents a promising next-generation, disease-targeted anti-angiogenic therapy for CNV.
- Combination therapy targeting both Scg3 and VEGF may offer superior treatment outcomes for CNV.
