Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition

Abstract

Purpose : Despite decades of research, therapeutic options for millions of patients suffering from age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP) remain limited, especially for earlier stages of pathogenesis when the opportunity to preserve retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Based on the premise that cyclic nucleotide phosphodiesterases (PDEs) function as integrative signaling nodes that could be therapeutically targeted, we set out to investigate the effects of selective PDE-inhibitor (PDEi) therapy on the hallmarks of age-related and inherited retinal diseases.

Methods : We conducted in vitro studies utilizing the human-derived ARPE-19 cell line, as well as in vivo studies employing several murine models; namely, the photosensitive Abca4^-/-Rdh8^-/- mouse, which exhibits epigenetic and pathological hallmarks of human AMD, the streptozotocin model of DR, and the rd10 model of RP. By comparing PDEi-treated groups to vehicle-treated controls, retinal phenotypes were characterized using optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), immunohistochemistry (IHC), and electroretinography (ERG). Integrative single-cell transcriptomics, proteomics, and phosphoproteomics were also performed to delineate pertinent molecular mechanisms.

Results : Across various models of retinopathy, OCT, SLO, and/or IHC analyses demonstrated structural preservation and ERG analyses revealed functional improvement with PDEi therapy. For instance, rd10 mice reared on a diet infused with Rolipram, a selective inhibitor of PDE4, exhibited an approximate two-fold improvement in retinal function relative to controls (n = 4, *P = 0.0308), consistent with a reduction in Fas-mediated apoptosis and overall improvement in photoreceptor viability as determined by IHC (Fig. 1).

Conclusions : Our results demonstrate that selective PDE inhibition stabilized the transcriptome, proteome, and phosphoproteome, thereby preserving retinal structure and function across human and animal models of retinopathy. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the most common causes of blindness.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.