Abstract
Purpose :
Endothelin-1 (ET-1), the most potent endogenous vasoconstrictor, is upregulated in the plasma and ocular tissues of patients with ischemic retinal diseases, including diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, and glaucoma. ET-1 binds to the endothelin receptors on vascular mural cells, resulting in reduced blood flow to retinal tissues (i.e., retinal non-perfusion (RNP)). Recent evidence suggests that the current standard of care with anti-VEGF treatment does not improve RNP, a clear unmet need in these patients. We hypothesized that in a mouse oxygen-induced retinopathy (OIR) model, a surrogate of ischemic retinal diseases, ET-1 is at least partially responsible for RNP and resultant VEGF-mediated maladaptive neovascularization (NV), which can be blocked by PER-001, an endothelin receptor antagonist.
Methods :
Mice were exposed to hyperoxia from P7 to P11, then treated topically with PER-001 twice daily (BID), matching vehicle BID, or systemic aflibercept once daily (QD) from P12 to P16. At peak NV on P17, vessel regrowth and severity of NV was quantified in the retinas. A dose response experiment was performed with 0.625, 1.563, and 3.125 µg topical PER-001 BID treatment, with topical vehicle control and systemic aflibercept treatment groups as comparators. A follow-on study investigated the effects of 2.5 and 12.5 µg topical PER-001 treatments in comparison to topical vehicle and systemic aflibercept treatment. Lastly, we investigated the potential combinatorial effect of topical PER-001 (6.25 and 12.5 µg) with systemic aflibercept (0.25 and 1.0 mg/kg), respectively, on NV.
Results :
In the mouse OIR model, topical treatment with PER-001 BID led to a dose-dependent reduction in NV to a similar degree as systemic treatment with aflibercept QD (56.5% vs 57.9%) when compared to control (****p<0.0001, Student’s t-test). PER-001 topical treatment combined with systemic aflibercept treatment provided no additive benefit in reduction of NV, suggesting a crosstalk between ET-1 and VEGF signaling, consistent with prior reports.
Conclusions :
ET-1 is a key driver of RNP and VEGF signaling in the OIR model, and treatment with PER-001 reduces retinal NV at equal efficacy as aflibercept, making it a promising therapeutic for treatment of underlying RNP in ischemic retinal diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.