Abstract
Purpose :
The aim of this work is to confirm the Efficacy and assess the Safety of the SYL1801, a siRNA targeting NRARP (NOTCH Regulated Ankyrin Repeat Protein), which is administered in eye drops for the treatment of corneal neovascularization (CNV), a common hallmark of retinal diseases such as age-related macular degeneration (AMD). Several in vivo and in vitro models and technics were used
Methods :
SYL1801, was topically administered to 1) a laser-induced CNV rat model to evaluate the efficacy, 2) to NZW rabbits to assess the biodistribution and 3) ophthalmically and intravenously to BN rats for toxicology studies. mRNA quantification was performed by Q-(RT)-PCR. HUVEC and Human Peripheral blood mononuclear cells (PBMC) were transfected with SYL1801 to assess its anti-angiogenic and immunogenic potential, respectively
Results :
Previously, SYL1801 showed that NRARP silencing in endothelial cells reduces VEGF-induced proliferation and migration and that its topical instillation quickly reaches rat retina, decreasing NRARP mRNA levels and lesion area in CNV model. In addition to efficacy, this drug also has showed high safety profile. After ophthalmic administration to rabbits, SYL1801 biodistribution showed that it enters into target cells and the amount of compound detected in some off-target tissues is very low and decreases quickly. Regarding the toxicology profile, administration of elevated doses of SYL1801 (topically or intravenously) for 7 consecutive days, or 14 days of daily intravenous injection in rats, does not produce any adverse effects. Consistently with these in vivo results, in vitro results confirmed that single SYL1801 application has a long-lasting retrievable effect, specifically interfering NRARP, but does not affect other receptors genes with high homology of sequence. Moreover, transfection of SYL1801 into PBMCs does not induce the release of pro-inflammatory cytokines
Conclusions :
SYL1801 repeated ophthalmic instillation efficiently reaches retina-choroids and specifically down-regulates NRARP, reducing the vascular lessons in a CNV model. In addition, its specificity, localized action, long-lasting retrievable effect with rapid clearance and good safety profile, with immunosafety and no related adverse events, place SYL1801 as a promising drug for topical treatment of retinal diseases
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.