Anti-secretogranin III therapy of oxygen-induced retinopathy with optimal safety
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Retinopathy of prematurity (ROP) with pathological retinal neovascularization is the most common cause of blindness in children. ROP is currently treated with laser therapy or cryotherapy, both of which may adversely affect the peripheral vision with limited efficacy. Owing to the susceptibility of the developing retina and vasculatures to pharmacological intervention, there is currently no approved drug therapy for ROP in preterm infants. Secretogranin III (Scg3) was recently discovered as a highly disease-restricted angiogenic factor, and a Scg3-neutralizing monoclonal antibody (mAb) was reported with high efficacy to alleviate oxygen-induced retinopathy (OIR) in mice, a surrogate model of ROP. Herein we independently investigated the efficacy of anti-Scg3 mAb in OIR mice and characterized its safety in neonatal mice. We developed a new Scg3-neutralizing mAb recognizing a distinct epitope and independently established the therapeutic activity of anti-Scg3 therapy to alleviate OIR-induced pathological retinal neovascularization in mice. Importantly, anti-Scg3 mAb showed no detectable adverse effects on electroretinography and developing retinal vasculature. Furthermore, systemic anti-Scg3 mAb induced no renal tubular injury or abnormality in kidney vessel development and body weight gain of neonatal mice. In contrast, anti-vascular endothelial growth factor drug aflibercept showed significant side effects in neonatal mice. These results suggest that anti-Scg3 mAb may have the safety and efficacy profiles required for ROP therapy.
KeywordsSecretogranin III Scg3 Angiogenic factor Anti-angiogenic therapy Oxygen-induced retinopathy Retinopathy of prematurity
The authors thank Keith Webster and Philip Rosenfeld for scientific advice and discussion, Rong Wen for instrument support, G. Gaidosh for confocal service, Zhijie Niu for technical support.
This study was supported by NIH R01EY027749-01A1 (W.L.), R21EY027065 (W.L.), R41EY027665 (W.L. and H.T.), American Diabetes Association 1-18-IBS-172 (W.L.), Special Scholar Award from Research to Prevent Blindness (RPB) (W.L.), the Postgraduate Program of China Scholarships Council # 3100 (F.T.), American Heart Association Predoctoral Fellowship 14PRE18310014 and 16PRE27250308 (M.E.L), NIH P30-EY014801 and an institutional grant from RPB.
Compliance with ethical standards
Conflict of interest
M.E.L, H.T. and W.L. are shareholders of Everglades Biopharma, LLC and/or LigandomicsRx, LLC. M.E.L., W.W. and W.L. are inventors of pending patents.
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