Small molecule Photoregulin3 prevents retinal degeneration in the RhoP23H mouse model of retinitis pigmentosa

Abstract

Regulation of rod gene expression has emerged as a potential therapeutic strategy to treat retinal degenerative diseases like retinitis pigmentosa (RP). We previously reported on a small molecule modulator of the rod transcription factor Nr2e3, Photoregulin1 (PR1), that regulates the expression of photoreceptor-specific genes. Although PR1 slows the progression of retinal degeneration in models of RP in vitro, in vivo analyses were not possible with PR1. We now report a structurally unrelated compound, Photoregulin3 (PR3) that also inhibits rod photoreceptor gene expression, potentially though Nr2e3 modulation. To determine the effectiveness of PR3 as a potential therapy for RP, we treated RhoP23H mice with PR3 and assessed retinal structure and function. PR3-treated RhoP23H mice showed significant structural and functional photoreceptor rescue compared with vehicle-treated littermate control mice. These results provide further support that pharmacological modulation of rod gene expression provides a potential strategy for the treatment of RP.

Knockout of Nr2e3 prevents rod photoreceptor differentiation and leads to selective L-/M-cone photoreceptor degeneration in zebrafish

“…Many RP-causing mutations occur in rod-specific genes. The rationale for such a strategy is that knocking down rod determinants such as Nrl or Nr2e3 reprograms rods to a cone fate, rendering rod-specific gene mutations irrelevant, with consequent preservation of retinal structural integrity and function [37][38][39][40].…”

Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration

“…To confirm that this treatment approach has applicability in non-PDE-dependent models of IRD, we used Rho P23H/P23H mice (41,42). As described previously (30,43), these mice experience rapid, severe rod degeneration shortly after eye opening, with the majority of rods gone by P24 ( Figure 6A). As we had observed in Rd1 mice, intravitreal injection of 4Ig coinciding with the onset of retinal degeneration improved survival of ONL photoreceptors in Rho P23H/P23H mice (Figure 6, D and G, and Supplemental Figure 6, G and H).…”

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

“…Thus, the NR2E3 antagonist PR1 provided preliminary evidence of photoreceptor neuroprotection, although the authors did not demonstrate effects on visual physiology in vivo. The same group later published their findings on a next-generation NR2E3 inhibitor, photoregulin-3 (PR3), which reduced rod-specific gene expression and increased S-opsin + cells in culture and in vivo following systemic PR3 treatment of wt mice [79]. Systemic treatment of PR3 prevented rod photoreceptor death in the Rho P23H rod degeneration mouse and also improved photopic and scotopic function on ERG [79].…”

“…The same group later published their findings on a next-generation NR2E3 inhibitor, photoregulin-3 (PR3), which reduced rod-specific gene expression and increased S-opsin + cells in culture and in vivo following systemic PR3 treatment of wt mice [79]. Systemic treatment of PR3 prevented rod photoreceptor death in the Rho P23H rod degeneration mouse and also improved photopic and scotopic function on ERG [79]. Although the authors assayed retina histology, gene expression, and ERG after only 1 week of treatment, the potential of NR2E3 inhibition to slow retinal degeneration in vivo represents an intriguing possibility for treatment of RP.…”

“…This suggests that modulation of the NR2E3 pathway (either inhibition or upregulation) in mouse models of RP may therefore slow retinal degeneration by either similar or distinct mechanisms. NR2E3 antagonism may reduce rod photoreceptor susceptibility to genetic retinal degeneration by conferring cone-like properties [79], whereas NR2E3 overexpression may reset rod gene expression networks and improve retinal homeostasis [81].…”