Duration 5min, Q&A 3min
Inhibition of Choroidal Neovascularization by Subconjunctival Gene Delivery of Calreticulin-Derived Peptide, Vasostatin 112
The majority of diseases that cause catastrophic vision loss, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of prematurity (ROP) and ocular tumours, do so as a result of pathologic ocular neovascularization. Thus, development of cost effective and less-invasive treatments for targeting retinal and choroidal angiogenesis are a priority in ophthalmology. Vasostatin, the N-terminal domain (amino acids 1-180) of calreticulin, is a potent inhibitor of angiogenesis isolated from culture supernatants of an EBV-immortalized B cell line. We have recently identified the functional domain of vasostatin into a peptide fragment of 112 residues, vasostatin-like peptide 112 (VS112). VS112 which could be superior to current therapeutic approaches for it specifically targets endothelial cells and it also has anti-inflammatory properties. This study aimed to investigate the effects of VS112 gene delivery on experimental choroidal neovascularization (CNV).
Recombinant VS112 protein and human umbilical vein endothelial cells (HUVECs) were used for angiogenesis assay in vitro. Adenoviral vector-mediate VS112 and Laser-induced CNV models in Brown Norway rats were used for in vivo study.
The anti-angiogenic effects of VS112 were validated by migration and tube formation assays performed on cultured endothelial cells, and by rat aorta ring assays. CNV lesions were induced in the rats by fundus argon laser photocoagulation. The extent of CNV was examined by fundus fluorescein angiography (FAG) and histological analysis.
Results and Conclusion
In this study, we first showed that VS112 inhibits angiogenic activity in several assays of angiogenesis including human endothelial cell migration and tube formation, and vessel sprouting from rat aortic ring explants. We then investigated the therapeutic potential of VS112 in laser-induced CNV models through subconjunctival gene delivery by an adenoviral vector which releases peptide slowly over 4 weeks. Serial FAG analysis indicated that subconjunctival VS112 gene delivery significantly reduced CNV lesions on all subsequent days. Histological analysis revealed attenuated CNV lesions and choroidal vascularity in the VS112-treated eyes. The present study provides evidence supporting that sustained delivery of a vasostatin-like anti-angiogenic peptide (VS112) using a minimally invasive procedure promises to revolutionise the management of ocular neovascularisation.
[ Keyword ]
Choroidal Neovascularization, Vasostatin 112
[ Conflict of Interest ]