Abstract
Purpose :
Despite decades of research, therapeutic options for millions of patients suffering from age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and glaucoma remain limited, especially in earlier stages of disease when the opportunity to preserve retinal structure and visual function is greatest. To address this urgent, unmet medical need, we have discovered a new class of small molecules, ‘Stress Resilience-Enhancing Drugs’ (SREDs), that effectively slowed or halted disease progression in multiple genetic and environmental animal models of AMD, DR, RP, and glaucoma.
Methods :
We previously demonstrated the efficacy of selective phosphodiesterase inhibitors (PDEi), a prototypical subclass of SREDs, in the streptozotocin mouse model of DR and the rd10 mouse model of RP. Here, we extend our study of PDEi to the treatment of glaucoma, using the elevated intraocular pressure (IOP) mouse model. Additionally, we employ the photosensitive Abca4-/-Rdh8-/- mouse that exhibits pathological hallmarks of AMD to evaluate epigenetic modulators, another subclass of SREDs consisting of selective inhibitors of histone deacetylases (HDACi) and methyltransferases (SUVi). By comparing SRED-treated groups to vehicle-treated controls, retinal phenotypes were characterized using optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), immunohistochemistry (IHC), and/or electroretinography (ERG).
Results :
In the IOP model, continuous oral administration of PDEi improved retinal ganglion cell (RGC) function by approximately 2.2-fold relative to control on pattern ERG (n ≤ 4, *P = 0.0168); concomitantly, IHC revealed a 73% improvement in RGC survival following IOP stress (Fig. 1). In the Abca4-/-Rdh8-/- model, both HDACi and SUVi treatments improved retinal function following bright-light stress by up to 2-fold on photopic ERG, consistent with improved photoreceptor survival and retinal morphology on OCT and SLO imaging.
Conclusions :
Our results demonstrate the efficacy of SREDs in preserving retinal morphology and function across both animal models of glaucoma and AMD. The conserved therapeutic effect supports the hypothesis that SREDs target universal underlying mechanisms of disease, thereby providing proof-of-concept for a new class of medications with potential clinical utility in treating the most common causes of blindness.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.