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.
Highlights
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease with a prevalence of 1 to 3,000-5,000 births (Hartong et al, 2006; Parmeggiani, 2011; Boughman et al, 1980)
The reductions in rod gene expression from deletion of Nrl or Nr2e3, with either conditional deletion or CRISPR-Cas9 deletion, were sufficient to promote the survival of photoreceptors in multiple models of recessive and dominant RP (Montana et al, 2013; Zhu et al, 2017; Yu et al, 2017)
As a secondary screen for the initial hits we used primary retinal cell cultures and assayed Rhodopsin expression because it is a well-defined target of Nr2e3 signaling and is expressed at high levels exclusively in rod photoreceptors (Cheng et al, 2004; Peng et al, 2005; Haider et al, 2009)
Summary
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease with a prevalence of 1 to 3,000-5,000 births (Hartong et al, 2006; Parmeggiani, 2011; Boughman et al, 1980). One emerging approach to treating retinal degeneration is through targeting the factors that regulate rod gene expression. Studies of retinal development have identified several transcription factors that regulate photoreceptor gene expression. Neuroscience eLife digest There are several diseases that cause people to lose their eyesight and become blind One of these diseases, called retinitis pigmentosa, kills cells at the back of the eye known as rod cells. Nakamura et al report the discovery of a small drug-like molecule, that they name Photoregulin, which alters the activity of a transcription factor that regulates rod genes. Mice with a mutation that replicates many of the features of retinitis pigmentosa were given Photoregulin to see if it could slow the progression of the disease. With PR3 treatment, we show anatomical and functional preservation of the retina in RhoP23H mice, providing in vivo proof-of-concept of this novel therapeutic strategy for the treatment of RP
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
