VIAN-c4551 in eye drops inhibits the excessive retinal vasopermeability induced by VEGF and diabetes in rodents

Abstract

Purpose : VIAN-c4551 is a cyclic, retro-inverse heptapeptide analog of vasoinhibin, an endogenous protein that inhibits the excessive growth and permeability of blood vessels in the retina. VIAN-c4551 stands as a potent, stable, and easy to produce inhibitor of VEGF, the major angiogenic and vasopermeability factor in diabetic retinopathy and diabetic macular edema. Intravitreal inhibitors of VEGF have become first line of treatment, but suboptimal responders and the invasiveness of frequent intravitreal injections demand better treatments. Here, we tested whether intravitreal, oral, or eye drop deliveries of VIAN-c4551 inhibit the excessive vasopermeability induced by VEGF or diabetes in the retina of rats and mice.

Methods : Rats were injected intravitreally with vehicle (PBS) or VEGF (250 ng, 260 nM) alone or together with VIAN-c4551 (100 ng, 2.6 µM) or the anti-VEGF monoclonal antibody ranibizumab (6.6 µg, 2.6 µM). VIAN-c4551 was also delivered orally (5 mg/kg) or in a single eye drop (5 µg/µl, 6.6 mM) one hour before the intravitreal injection of VEGF. Diabetes was generated with streptozotocin and, 6 weeks later, diabetic rats were injected intravitreally with vehicle, VIAN-c4551, or ranibizumab. Other diabetic rats and mice received one daily eye drop containing VIAN-c4551 or vehicle (lubricant) for 5 days. The Evans blue method was performed 24 hours after the last administration of VIAN-c4551 to evaluate the extravasation of albumin as index of retinal vasopermeability.

Results : VEGF and diabetes induced a significant (p<0.005) 2 to 3-fold increase in retinal vasopermeability that was prevented or reversed, respectively, by the intravitreal, oral, and eye drop administration of VIAN-c4551. Efficacy was like that of intravitreal ranibizumab. VIAN-c4551 alone did not affect basal vasopermeability in retinas.

Conclusions : VIAN-c4551 has significant therapeutic potential for preventing and reversing abnormal vasopermeability in diabetic macular edema, diabetic retinopathy, and other vascular retinopathies. Oral and topical deliveries of VIAN-4551 reach the back of the eye allowing non-invasive and safe treatments for early interventions that favor dosing and adherence. Ongoing studies are addressing the mechanism, safety, and pharmacokynetics of VIAN-c4551 in eye drops.

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