VIAN-c4551 inhibits oxygen-induced retinopathy in mice

Abstract

Purpose : Retinopathy of prematurity (ROP) is a significant world-wide cause of treatable blindness in preterm infants generated by the ischemia-induced angiogenesis occurring as a complication of preterm birth. Vasoinhibin is an endogenous protein that inhibits retinal angiogenesis with significant therapeutic potential supported by VIAN-c4551, a potent, stable, orally active heptapeptide vasoinhibin analog. Here, we examined the ability of VIAN-c4551 to inhibit abnormal retinal neovascularization in the mouse model of ROP.

Methods : We used the well-established ROP model of oxygen-induced retinopathy. C57BL/6 mice at postnatal day 7 (P7) were placed with their nursing mothers under 75% oxygen for 5 days. On return to normal air, newborn mice develop retinal neovascularization that peaks 5 days (P17) after their return to normoxia. The pups were daily injected intraperitoneally with vehicle (PBS) or VIAN-c4551 from P12 to P17, when they were euthanized. The retinas were either flat-mounted and stained for blood vessels to quantify neovascularization areas or processed for the expression of angiogenesis and inflammatory markers by RT-qPCR. The electrical activity of the retina was measured at P17 in control mice.

Results : Retinal vasculature labeled by DyLight 594-conjugated LEL-lectin showed the expected hyperoxia-hypoxia-induced increase in neovascular and avascular zones of the retina characteristic of the ROP murine model. VIAN-c4551 reduced the neovascular (p=0.0289) and avascular zones (p=0.0308). Consistently, VIAN-c4551 decreased the mRNA expression of makers of endothelial cells, CD31 (p=0.0214) and vascular endothelial cadherin (p=0.0526); hypoxia, hypoxia-inducible factor 1a (HIF1a) (p=0.0033); and inflammation, glial fibrillary acidic protein, tumor necrosis factor a, and inducible nitric oxide synthase (p<0.05). VIAN-c4551 did not alter the electroretinogram and body weight of control mice.

Conclusions : The systemic administration of VIAN-c4551 inhibits neovascularization in the mouse model of oxygen-induced retinopathy. These findings support the therapeutic potential of this vasoinhibin analog in ROP and other vasoproliferative retinopathies. As the eye drop delivery of VIAN-c4551 inhibits diabetes-induced retinopathy in rodents, ongoing studies are addressing this non-invasive route of administration in the ROP mouse model.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.