Interventions against VEGF overexpression, available strategies and future developments
Abstract
Purpose
Neovascular diabetic retinopathy (DR) and age-related macular degeneration (AMD) are characterized by increased VEGF signaling. VEGF can be targeted using monoclonal antibody-based drugs (e.g. ranibizumab, aflibercept) or by modified oligonucleotides (e.g. pegaptanib). The main difference between the two classes is that antibodies recognize all VEGF isoforms while oligonucleotides may be more specific for certain isoform such as VEGF165. New ways of intervention stem out from the observation that VEGF expression can be post-transcriptionally regulated by the RNA-binding HuR/Elav-like1 protein. We evaluated if targeting HuR is a potential tool to hinder VEGF overexpression.
Methods
2.5 µM HuR siRNA (naked or delivered by nanocarriers) was intravitreally administered in a DR model. Rats were sacrificed 48 h after siRNA injection and retinal tissues collected for Western blot, ELISA, histological examination.
Results
HuR siRNA treatment blunts both HuR and VEGF increase, restating normal VEGF content in DR retina. HuR siRNA exerts its protective effect when included in liposomal nanocarriers, since the naked molecule does not prevent diabetic retinal damage.
Conclusions
An HuR-based strategy may be a target in the chain of events controlling VEGF expression synergizing with oligonucleotide-based interventions having the potential to modulate the expression of VEGF without fully blocking it.
