Abstract
Purpose :
Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in children. There is currently no approved drug therapy for ROP. Secretogranin III (Scg3) was recently discovered as a highly disease-restricted angiogenic factor, and anti-Scg3 monoclonal antibody (mAb) was demonstrated with high efficacy to treat oxygen-induced retinopathy (OIR), a surrogate model of ROP. The purpose of this study is to compare the efficacy and safety of anti-Scg3 mAb to VEGF inhibitor aflibercept to treat OIR in mice.
Methods :
The OIR animal model was established in neonatal C57BL/6 mice at postnatal day 7 (P7) with exposure to 75% oxygen for consecutive 5 days. Scg3-neutralizing mAb, aflibercept or control was administrated intravitreally or intraperitoneally at P14 in OIR mice. Retinas were isolated on P17, stained with fluorescent isolectin B4 and analyzed for retinal neovascularization (RNV) by confocal microscopy. Electroretinography (ERG) was analyzed at P42 to evaluate retinal function impairment after intravitreal injection. After intraperitoneal injection, the adverse effects of Scg3 mAb or aflibercept on retinal vasculogenesis were determined by quantifying retinal vascular area and density. Mouse body weight was monitored every other day. Kidney toxicity was analyzed by histopathological and immunohistochemical examinations.
Results :
Intravitreal or systemic Scg3 mAb alleviated OIR-induced pathological RNV with similar high efficacy to aflibercept. Scg3 mAb showed no adverse effect on ERG, whereas aflibercept significantly reduced b-wave amplitude at P42 (p<0.05). Systemic treatment of neonatal mice with aflibercept suppressed retinal vascular development with reduced vessel area and density (p<0.01), and inhibited weight gain (p<0.001). Aflibercept-treated neonatal mice also developed renal cyst formation with reduced vessels density. However, none of these adverse effects were observed for anti-Scg3 mAb at similar doses.
Conclusions :
Our results demonstrate that anti-Scg3 mAb can ameliorate OIR-induced RNV with high efficacy but undetectable adverse effects, suggesting that anti-Scg3 antibody may have the safety and efficacy profile required to treat ROP. Owing to the disease selectivity of Scg3, these findings imply that anti-Scg3 mAb has the potential for clinical therapy of ROP with minimal side effects on developing retina.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.