Potential of Small Molecule–Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa

Nakamura, Paul A.; Tang, Shibing; Shimchuk, Andy A; Ding, Sheng; Reh, Thomas A.

doi:10.1167/iovs.16-20177

Cited by 22 publications

(22 citation statements)

References 42 publications

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“…We dissociated retina from postnatal day 5 (P5) mice and cultured them in media containing the small molecules. After treatment for 2 days, we assessed Rhodopsin expression with an immunofluorescence-based assay ( Nakamura et al, 2016 ). One compound, PR3 ( Figure 1A ), showed robust reduction in Rhodopsin compared to DMSO and PR1 treatment ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently reported that this regulatory pathway can be modulated using small molecule modulators of rod gene expression that we have named Photoregulins ( Nakamura et al, 2016 ). Treatment of developing or mature retina with Photoregulin1 (PR1) reduces rod gene expression and increases the expression of some cone genes.…”

Section: Introductionmentioning

confidence: 99%

“…Treatment of developing or mature retina with Photoregulin1 (PR1) reduces rod gene expression and increases the expression of some cone genes. In addition, treatment of two mouse models of RP (mice with the Rho P23H and the Pde6b Rd1 mutations) with PR1 slows rod degeneration in vitro ( Nakamura et al, 2016 ). However, in vivo analyses of PR1 were limited by the compound's potency, solubility, and stability in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Nakamura

Shimchuk

Tang

et al. 2017

eLife

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nakamura

Shimchuk

Tang

et al. 2017

eLife

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Xie

Han

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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M 2019, 'Knockout of Nr2e3 prevents rod photoreceptor differentiation and leads to selective L-/M-cone photoreceptor degeneration in zebrafish', AbstractMutations in the photoreceptor cell-specific nuclear receptor gene Nr2e3 increased the number of S-cone photoreceptors in human and murine retinas and led to retinal degeneration that involved photoreceptor and nonphotoreceptor cells. The mechanisms underlying these complex phenotypes remain unclear. In the hope of understanding the precise role of Nr2e3 in photoreceptor cell fate determination and differentiation, we generated a line of Nr2e3 knockout zebrafish using CRISPR technology. In these Nr2e3-null animals, rod precursors undergo terminal mitoses but fail to differentiate as rods. Rod-specific genes are not expressed and the outer segment (OS) fails to form. Formation and differentiation of cone photoreceptors is normal. Specifically, there is no increase in the number of UV-cone or S-cone photoreceptors. Laminated retinal structure is maintained. After normal development, L-/M-cones selectively degenerate, with progressive shortening of OS that starts at age 1 month. The amount of cone phototransduction proteins is concomitantly reduced, whereas UV-and S-cones have normal OS lengths even at age 10 months. In vitro studies show Nr2e3 synergizes with Crx and Nrl to enhance rhodopsin gene expression. Nr2e3 does not affect cone opsin expression. Our results extend the knowledge of Nr2e3's roles and have specific implications for the interpretation of the phenotypes observed in human and murine retinas. Furthermore, our model may offer new opportunities in finding treatments for enhanced S-cone syndrome (ESCS) and other retinal degenerative diseases.

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“…Previous studies have explored using induced pluripotent stem cells (iPSCs) and organoid cultures as stem cell-based approaches for patient-specific treatment for retinal regeneration [82][83][84][85][86] . However, the advancement of stem cell therapy was hampered by our limited knowledge on the molecular mechanisms underlying retinogenesis and disease progression in humans, too.…”

Section: Inherited Retinal Diseases Are a Group Of Retinal Disorders mentioning

confidence: 99%

Single-cell RNA-seq analysis maps the development of human fetal retina

Lü

et al. 2018

Preprint

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Vision starts with image formation at the retina, which contains diverse neuronal cell types that extract, process, and relay visual information to higher order processing centers in the brain. Though there has been steady progress in defining retinal cell types, very little is known about retinal development in humans, which starts well before birth. In this study, we performed transcriptomic profiling of developing human fetal retina from gestational weeks 12 to 27 using single-cell RNA-seq (scRNA-seq) and used pseudotime analysis to reconstruct the developmental trajectories of retinogenesis. Our analysis reveals transcriptional programs driving differentiation down four different cell types and suggests that Müller glia (MG) can serve as embryonic progenitors in early retinal development. In addition, we also show that transcriptional differences separate retinal progenitor cells (RPCs) into distinct subtypes and use this information to reconstruct RPC developmental trajectories and cell fate. Our results support a hierarchical program of differentiation governing cell-type diversity in the developing human retina. In summary, our work details comprehensive molecular classification of retinal cells, reconstructs their relationships, and paves the way for future mechanistic studies on the impact of gene regulation upon human retinogenesis.

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Potential of Small Molecule–Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa

Cited by 22 publications

References 42 publications

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

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

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

Single-cell RNA-seq analysis maps the development of human fetal retina

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