Current Therapeutic Strategies for P23H RHO-Linked RP

Nguyen, Anh Thi Hong; Campbell, Matthew; Kiang, Anna‐Sophia; Humphries, Marian M.; Humphries, Peter

doi:10.1007/978-1-4614-3209-8_60

Cited by 13 publications

(10 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently shown that reductions in rod gene expression caused by treatment with PR1 were sufficient to slow the degeneration of Rho P23H photoreceptors in vitro ( Nakamura et al, 2016 ). The Rho P23H mutation causes misfolding of Rhodopsin in rod photoreceptors, which leads to activation of the unfolded protein response and eventually results in rod and cone death ( Nguyen et al, 2014 ). In Rho P23H mice, most rod photoreceptors undergo apoptosis by the end of the third postnatal week ( Sakami et al, 2011 ).…”

Section: Resultsmentioning

confidence: 99%

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

Nakamura

Shimchuk

Tang

et al. 2017

eLife

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Nakamura

Shimchuk

Tang

et al. 2017

eLife

View full text Add to dashboard Cite

show abstract

“…However, when abnormalities exceed the homeostatic capacity of the UPR, cell death signaling molecules such as the CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) are induced to promote the transcription of pro-apoptotic molecules. Therefore, ER stress can be involved in cell death, and the pathogenesis of blindness due to retinitis pigmentosa, an inherited retinal degeneration, at least partly involves ER stress [19–21]. Light exposure-induced ER stress was previously reported in a photoreceptor cell line [22, 23] and in the retinal pigment epithelium (RPE), which maintains photoreceptors, of autophagy-deficient mice [24, 25], and in the neural retina [23].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina

et al. 2017

View full text Add to dashboard Cite

Excessive exposure to light promotes degenerative and blinding retinal diseases such as age-related macular degeneration and retinitis pigmentosa. However, the underlying mechanisms of photo-induced retinal degeneration are not fully understood, and a generalizable preventive intervention has not been proposed. Bilberry extract is an antioxidant-rich supplement that ameliorates ocular symptoms. However, its effects on photo-stressed retinas have not been clarified. In this study, we examined the neuroprotective effects of bilberry extract against photo-stress in murine retinas. Light-induced visual function impairment recorded by scotopic and phototopic electroretinograms showing respective rod and cone photoreceptor function was attenuated by oral administration of bilberry extract through a stomach tube in Balb/c mice (750 mg/kg body weight). Bilberry extract also suppressed photo-induced apoptosis in the photoreceptor cell layer and shortening of the outer segments of rod and cone photoreceptors. Levels of photo-induced reactive oxygen species (ROS), oxidative and endoplasmic reticulum (ER) stress markers, as measured by real-time reverse transcriptase polymerase chain reaction, were reduced by bilberry extract treatment. Reduction of ROS by N-acetyl-L-cysteine, a well-known antioxidant also suppressed ER stress. Immunohistochemical analysis of activating transcription factor 4 expression showed the presence of ER stress in the retina, and at least in part, in Müller glial cells. The photo-induced disruption of tight junctions in the retinal pigment epithelium was also attenuated by bilberry extract, repressing an oxidative stress marker, although ER stress markers were not repressed. Our results suggest that bilberry extract attenuates photo-induced apoptosis and visual dysfunction most likely, and at least in part, through ROS reduction, and subsequent ER stress attenuation in the retina. This study can help understand the mechanisms of photo-stress and contribute to developing a new, potentially useful therapeutic approach using bilberry extract for preventing retinal photo-damage.

show abstract

“…[ 1 – 3 ] In particular, the P23H mutation of rhodopsin is the most common cause of autosomal dominant retinitis pigmentosa (ADRP) in North America, as it is responsible for 12% of all known cases. [ 3 – 5 ] In this form of RP, the mutant rhodopsin is misfolded, which may lead to endoplasmic reticulum stress and, ultimately, rod cell death (for review see [ 6 ]). However, in P23H knock-in mice, the IRE1 pathway and not the pro-apoptotic PERK pathway is activated.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

et al. 2016

View full text Add to dashboard Cite

PurposeTo test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E) that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa.MethodsTen-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+) were injected into the quadriceps with recombinant adeno-associated virus (rAAV) carrying either enhanced green fluorescent protein (eGFP) or EpoR76E. Visual function (electroretinogram) and retina structure (optical coherence tomography, histology, and immunohistochemistry) were assessed at 7 and 12 months of age.ResultsThe outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age.ConclusionsSystemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone.

show abstract

Current Therapeutic Strategies for P23H RHO-Linked RP

Cited by 13 publications

References 32 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

Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina

Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

Contact Info

Product

Resources

About