Pharmacodynamic response of optic nerve head (ONH) vasculature measured by OCT-angiography (OCTA) after administration of the endothelin receptor antagonist PER-001

Abstract

Purpose : Reduction of ocular blood flow in glaucoma is thought to be related to upregulation of the endothelin system. The purpose of this study was to characterize the effect of PER-001 on the macro and microvasculature of the ONH in glaucomatous and control eyes.

Methods : OCTA (Spectralis, Heidelberg Engineering GmbH) was used to quantify the ONH vasculature in 6 anesthetized adult rhesus monkeys (Macaca mulatta, 4F/2M ages 7-12 y) with unilateral experimental glaucoma (EG, PMID: 27564522). OCTA scans were 15 x 15 deg (768 x 768 A-lines) centered on the ONH and registered to the original baseline in real time during acquisition. ONH rim was defined by Bruch’s membrane opening laterally and posteriorly and by the internal limiting membrane anteriorly; the integral of all voxels within these boundaries (scaled for lateral magnification of the rhesus eye) defined ONH rim volume, while the same voxels weighted by the OCTA signal defined the ONH rim vascular volume. Large vessels and microvascular-capillaries were also analyzed separately. OCTA scans were recorded for each eye, starting 15-30 min prior to bilateral intravitreal administration of 50 µL of PER-001 or vehicle, and thereafter every 30 min for 6 hr. Statistical analysis included repeated measures ANOVA, linear regression and t-tests.

Results : At the point PER-001 assays were conducted, ONH neuroretinal minimum rim width in EG vs fellow control (FC) eyes, respectively, was 155 ± 74 vs 291 ± 39 µm (p=0.005); peripapillary retinal nerve fiber layer thickness was 77 ± 21 vs 100 ± 8.5 µm (p=0.04); thus, representing a moderate stage of EG damage. Following administration of PER-001, ONH volume increased significantly more in EG than FC eyes, which was explained almost entirely by an increase in total vascular volume, including an increase for both large vessel and microvascular-capillary volume (Figs. 1,2). Subtle effects of vehicle alone were far exceeded by those of PER-001.

Conclusions : Administration of PER-001 elicited an increase of ONH vascular volume, including dilatory effects on both large vessels and ONH tissue microvasculature. These effects were stronger in EG compared to control eyes and consistent with the hypothesis that upregulation of the endothelin system contributes to vascular compromise in glaucoma. Further studies of PER-001 in glaucoma are warranted.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.