Neuroprotective and Anti-Inflammatory Effects of a Novel Soluble Guanylate Cyclase Activator Runcaciguat in Ischemic Retinal Disease Animal Models

Abstract

Purpose : Neuroinflammatory processes and neurodegeneration are important elements of ischemic retinopathies including diabetic retinopathy (DR). There is a great need for therapies targeting earlier disease before irreversible damage. Soluble guanylate cyclase (sGC) exhibits neuroprotective effects in the central nervous system, but its expression and role in the retina remains unclear. sGC activators might be of potential benefit, especially since they can act on sGC rendered nonfunctional by oxidative stress. The purpose of this study was to evaluate the effect of a novel sGC activator, runcaciguat, in retinal ischemia-reperfusion (I/R) and DR animal models.

Methods : Expression of sGC alpha and beta subunits was evaluated in post-mortem human retina specimens by immunohistochemistry. Transient retinal ischemia-reperfusion was induced in rats by elevation of the intraocular pressure for 20-45 minutes. Streptozotocin injection was used to induce diabetes in other rats. Genome wide expression and RNA Sequencing analyses were performed following I/R. Oral runcaciguat (0.1-10 mg/kg PO QD) was evaluated in a prophylactic and/or interventional setting. Treatment effect on retinal morphology and function were evaluated by histological staining, optokinetic testing (OKT), and electroretinography (ERG).

Results : In addition to retinal blood vessels, multiple human neuronal elements expressed both sGC alpha and beta subunits, including retinal ganglion cells. I/R upregulated multiple inflammatory chemokines, including Ccl2, Cxcl10, Ccl3, Ccl4, and Timp1, at 1 hour after reperfusion and peaking by 6 hours. Runcaciguat-treated rats exhibited better visual acuity compared with vehicle (0.17±0.03 cycle/degree vs. 0.02±0.01 cycle/degree, p value<0.0001) as measured by OKT, and neuroretinal function as measured by ERG. Runcaciguat-treated rats had improved morphology including increased inner plexiform layer thickness. Runcaciguat-treated diabetic rats exhibited superior neuroretinal function by ERG (312.3±65.5 µv vs 182.3±60.4 µv) and increased inner plexiform layer thickness (31.95±11.94 µm vs 27.93±10.21 µm) and ganglion cell count, compared to vehicle treatment.

Conclusions : The anti-inflammatory and neuroprotective effects of runcaciguat support sGC as a novel early therapeutic target for diabetic and other ischemic retinopathies.

This is a 2021 ARVO Annual Meeting abstract.