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.

PurposeMutations in rod photoreceptor genes can cause retinitis pigmentosa (RP). Rod gene expression is regulated by the nuclear hormone receptor, Nr2e3. Genetic deletion of Nr2e3 reprograms rods into cells that resemble cone photoreceptors, and might therefore prevent their death from some forms of RP. There are no identified ligands for Nr2e3; however, reverse agonists might mimic the genetic rescue effect and may be therapeutically useful for the treatment of RP.MethodsWe screened for small molecule modulators of Nr2e3 using primary retinal cell cultures and characterized the most potent, which we have named photoregulin1 (PR1), in vitro and in vivo. We also tested the ability of PR1 to slow the progression of photoreceptor degeneration in two common mouse models of autosomal dominant RP, the RhoP23H and the Pde6brd1 mutations.ResultsIn developing retina, PR1 causes a decrease in rod gene expression and an increase in S opsin+ cones. Photoregulin1 continues to inhibit rod gene expression in adult mice. When applied to two mouse models of RP, PR1 slows the degeneration of photoreceptors.ConclusionsChemical compounds identified as modulators of Nr2e3 activity may be useful for the treatment of RP through their effects on expression of disease-causing mutant genes.

Background Peri‐implantitis is a frequent finding but estimates of its prevalence vary widely. This may be due to the wide variety of disease definitions. In 2017 the World Workshop on Periodontal and Peri‐implant Diseases and Conditions established new criteria for disease definitions. The aim of this study is to assess the potential impact of a new definition on the future reporting of peri‐implant disease. Methods Data from a 2015 report of peri‐implant prevalence were examined using the new diagnostic criteria. This cross‐sectional study was performed on 95 patients with 220 implants who had their implants placed between 1998 and 2003. An examiner masked to the previous diagnosis examined the radiographs and patient data to make a diagnosis based on 3 mm of bone loss from the expected level of bone. This reanalysis was used to calculate the prevalence of peri‐implant disease and generate new relative risk indicators. Results The mean follow‐up time for the patients was 10.9 years. Using the 2017 criteria, peri‐implant mucositis was found in 35.3% of the implants and 52.2% of the subjects, and peri‐implantitis occurred in 8.7% of the implants and 15.2% of the subjects. This constituted a drop in peri‐implantitis at both patient and implant level of nearly 50% from the prior analysis. Smoking at time of implant placement emerged as a new risk factor in this analysis that was not identified in the prior analysis. Conclusions The new diagnostic criteria significantly reduce the reported prevalence of peri‐implantitis and bring new risk factors into focus.

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