Photoreceptor Cell Loss Research Articles

Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme.

Leber congenital amaurosis (LCA) is a group of inherited retinal diseases characterized by early-onset, rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with ultrastructure expansion microscopy, we reveal the structural and molecular defects underlying LCA type 5 (LCA5) with nanoscale resolution. We show that LCA5-encoded lebercilin, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localized at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrate that mutant mice deficient in lebercilin exhibited early axonemal defects at the bulge region and the distal OS, accompanied by reduced levels of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, adeno-associated virus-based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival. Our approach thus provides a next level of assessment of retinal (gene) therapy efficacy at the molecular level.

Modeling rod and cone photoreceptor cell survival in vivo using optical coherence tomography

Many retinal diseases involve the loss of light-sensing photoreceptor cells (rods and cones) over time. The severity and distribution of photoreceptor loss varies widely across diseases and affected individuals, so characterizing the degree and pattern of photoreceptor loss can clarify pathophysiology and prognosis. Currently, in vivo visualization of individual photoreceptors requires technology such as adaptive optics, which has numerous limitations and is not widely used. By contrast, optical coherence tomography (OCT) is nearly ubiquitous in daily clinical practice given its ease of image acquisition and detailed visualization of retinal structure. However, OCT cannot resolve individual photoreceptors, and no OCT-based method exists to distinguish between the loss of rods versus cones. Here, we present a computational model that quantitatively estimates rod versus cone photoreceptor loss from OCT. Using histologic data of human photoreceptor topography, we constructed an OCT-based reference model to simulate outer nuclear layer thinning caused by differential loss of rods and cones. The model was able to estimate rod and cone loss using in vivo OCT data from patients with Stargardt disease and healthy controls. Our model provides a powerful new tool to quantify photoreceptor loss using OCT data alone, with potentially broad applications for research and clinical care.

Definition of the transcriptional units of inherited retinal disease genes by meta-analysis of human retinal transcriptome data

BackgroundInherited retinal diseases (IRD) are genetically heterogeneous disorders that cause the dysfunction or loss of photoreceptor cells and ultimately lead to blindness. To date, next-generation sequencing procedures fail to detect pathogenic sequence variants in coding regions of known IRD disease genes in about 30–40% of patients. One of the possible explanations for this missing heritability is the presence of yet unidentified transcripts of known IRD genes. Here, we aimed to define the transcript composition of IRD genes in the human retina by a meta-analysis of publicly available RNA-seq datasets using an ad-hoc designed pipeline.ResultsWe analysed 218 IRD genes and identified 5,054 transcripts, 3,367 of which were not previously reported. We assessed their putative expression levels and focused our attention on 435 transcripts predicted to account for at least 5% of the expression of the corresponding gene. We looked at the possible impact of the newly identified transcripts at the protein level and experimentally validated a subset of them.ConclusionsThis study provides an unprecedented, detailed overview of the complexity of the human retinal transcriptome that can be instrumental in contributing to the resolution of some cases of missing heritability in IRD patients.

The Role of Oxidative Stress in the Aging Eye

Given the expanding elderly population in the United States and the world, it is important to understand the processes underlying both natural and pathological age-related changes in the eye. Both the anterior and posterior segment of the eye undergo changes in biological, chemical, and physical properties driven by oxidative stress. With advancing age, changes in the anterior segment include dermatochalasis, blepharoptosis, thickening of the sclera, loss of corneal endothelial cells, and stiffening of the lens. Changes in the posterior segment include lowered viscoelasticity of the vitreous body, photoreceptor cell loss, and drusen deposition at the macula and fovea. Age-related ocular pathologies including glaucoma, cataracts, and age-related macular degeneration are largely mediated by oxidative stress. The prevalence of these diseases is expected to increase in the coming years, highlighting the need to develop new therapies that address oxidative stress and slow the progression of age-related pathologies.

Binocular benefit following monocular subretinal AAV injection in a mouse model of autosomal dominant retinitis pigmentosa (adRP)

Autosomal dominant retinitis pigmentosa (adRP) is frequently caused by mutations in RHO, the gene for rhodopsin. In previous experiments in dogs with the T4R mutation in RHO, an AAV2/5 vector expressing an shRNA directed to human and dog RHO mRNA and an shRNA-resistant human RHO cDNA (AAV-RHO820-shRNA820) prevented retinal degeneration for more than eight months following injection. It is crucial, however, to determine if this RNA replacement vector acts in a mutation-independent and species-independent manner. We, therefore, injected mice transgenic for human P23H RHO with this vector unilaterally at postnatal day 30. We monitored their retinal structure by using spectral-domain optical coherence tomography (SD-OCT) and retinal function using electroretinography (ERG) for nine months. We compared these to P23H RHO transgenic mice injected unilaterally with a control vector. Though retinas continued to thin over time, compared to control injected eyes, treatment with AAV-RHO820-shRNA820 slowed the loss of photoreceptor cells and the decrease in ERG amplitudes during the nine-month study period. Unexpectedly, we also observed the preservation of retinal structure and function in the untreated contralateral eyes of AAV-RHO820-shRNA820 treated mice. PCR analysis and western blots showed that a low amount of vector from injected eyes was present in uninjected eyes. In addition, protective neurotrophic factors bFGF and GDNF were elevated in both eyes of treated mice. Our finding suggests that using this or similar RNA replacement vectors in human gene therapy may provide clinical benefit to both eyes of patients with adRP.

The Absence of FAIM Leads to a Delay in Dark Adaptation and Hampers Arrestin-1 Translocation upon Light Reception in the Retina.

The short and long isoforms of FAIM (FAIM-S and FAIM-L) hold important functions in the central nervous system, and their expression levels are specifically enriched in the retina. We previously described that Faim knockout (KO) mice present structural and molecular alterations in the retina compatible with a neurodegenerative phenotype. Here, we aimed to study Faim KO retinal functions and molecular mechanisms leading to its alterations. Electroretinographic recordings showed that aged Faim KO mice present functional loss of rod photoreceptor and ganglion cells. Additionally, we found a significant delay in dark adaptation from early adult ages. This functional deficit is exacerbated by luminic stress, which also caused histopathological alterations. Interestingly, Faim KO mice present abnormal Arrestin-1 redistribution upon light reception, and we show that Arrestin-1 is ubiquitinated, a process that is abrogated by either FAIM-S or FAIM-L in vitro. Our results suggest that FAIM assists Arrestin-1 light-dependent translocation by a process that likely involves ubiquitination. In the absence of FAIM, this impairment could be the cause of dark adaptation delay and increased light sensitivity. Multiple retinal diseases are linked to deficits in photoresponse termination, and hence, investigating the role of FAIM could shed light onto the underlying mechanisms of their pathophysiology.

A mouse model of cone photoreceptor function loss (cpfl9) with degeneration due to a mutation in Gucy2e.

During routine screening of mouse strains and stocks by the Eye Mutant Resource at The Jackson Laboratory for genetic mouse models of human ocular disorders, we identified cpfl9, a mouse model with cone photoreceptor function loss. The mice exhibited an early-onset phenotype that was easily recognized by the absence of a cone-mediated b-wave electroretinography response and by a reduction in rod-mediated photoresponses at four weeks of age. By genetic mapping and high-throughput sequencing of a whole exome capture library of cpfl9, a homozygous 25 bp deletion within exon 11 of the Gucy2e gene was identified, which is predicted to result in a frame shift leading to premature termination. The corresponding protein in human, retinal guanylate cyclase 1 (GUCY2D), plays an important role in rod and cone photoreceptor cell function. Loss-of-function mutations in human GUCY2D cause LCA1, one of the most common forms of Leber congenital amaurosis, which results in blindness at birth or in early childhood. The early loss of cone and reduced rod photoreceptor cell function in the cpfl9 mutant is accompanied by a later, progressive loss of cone and rod photoreceptor cells, which may be relevant to understanding disease pathology in a subset of LCA1 patients and in individuals with cone-rod dystrophy caused by recessive GUCY2D variants. cpfl9 mice will be useful for studying the role of Gucy2e in the retina.

An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.

Subretinal gene therapy delays vision loss in a Bardet-Biedl Syndrome type 10 mouse model

Blindness in Bardet-Biedl syndrome (BBS) is caused by dysfunction and loss of photoreceptor cells in the retina. BBS10, mutations of which account for approximately 21% of all BBS cases, encodes a chaperonin protein indispensable for the assembly of the BBSome, a cargo adaptor important for ciliary trafficking. The loss of BBSome function in the eye causes a reduced light sensitivity of photoreceptor cells, photoreceptor ciliary malformation, dysfunctional ciliary trafficking, and photoreceptor cell death. Cone photoreceptors lacking BBS10 have congenitally low electrical function in electroretinography. In this study, we performed gene augmentation therapy by injecting a viral construct subretinally to deliver the coding sequence of the mouse Bbs10 gene to treat retinal degeneration in a BBS10 mouse model. Long-term efficacy was assessed by measuring the electrical functions of the retina over time, imaging of the treated regions to visualize cell survival, conducting visually guided swim assays to measure functional vision, and performing retinal histology. We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their electrical function after gene augmentation. Measurement of functional vision showed that subretinal gene therapy provided a significant benefit in delaying vision loss.

Products of the visual cycle are detected in mice lacking retinol binding protein 4, the only known vitamin A carrier in plasma

Efficient delivery of vitamin A to the retinal pigment epithelium is vital to the production of the light-sensitive visual chromophore 11-cis-retinal. Nevertheless, retinol binding protein 4 (RBP4) is the only known carrier of vitamin A in plasma. Here, we present new findings that further characterize the visual cycle in the presence of Rbp4 deficiency. In the face of impaired delivery of retinol in Rbp4-/- mice, we determined that 11-cis-retinaldehyde reached levels that were ∼60% of WT at 4months of age and all-trans-retinyl ester was 18% of normal yet photoreceptor cell loss was apparent by 8months of age. The lack of Rbp4 appeared to have a greater impact on scotopic rod-mediated responses than on cone function at early ages. Also, despite severely impaired delivery of retinol, bisretinoid lipofuscin that forms as a byproduct of the visual cycle was measurable by HPLC and by quantitative fundus autofluorescence. In mice carrying an Rpe65 amino acid variant that slows visual cycle kinetics, Rbp4 deficiency had a less pronounced effect on 11-cis-retinal levels. Finally, we found that ocular retinoids were not altered in mice expressing elevated adipose-derived total Rbp4 protein (hRBP4+/+AdiCre+/-). In conclusion, our findings are consistent with a model in which vitamin A can be delivered to the retina by Rbp4-independent pathways.

Lessons Learned from the Development of the First FDA-Approved Gene Therapy Drug, Voretigene Neparvovec-rzyl.

In the 5 years following U.S. Food and Drug Administration (FDA) approval of the first gene therapy reagent approved to treat a genetic disease, voretigene neparvovec-rzyl (Luxturna), retinal disease clinics, hospital pharmacies, operating rooms, and even health insurance entities around the world have incorporated gene therapy as a standard procedure. The success of Luxturna has helped pave the way to establish a template for developing other gene therapy reagents that promise to restore sight or halt the progression of photoreceptor cell loss in both inherited and acquired retinal diseases. Here we review lessons learned from development of a gene therapy drug for RPE65 disease and how these lessons may expedite the development of additional treatments for previously untreatable blinding conditions.

No evidence for age-related alterations in the marmoset retina.

The physiological aging process of the retina is accompanied by various and sometimes extensive changes: Macular degeneration, retinopathies and glaucoma are the most common findings in the elderly and can potentially lead to irreversible visual disablements up to blindness. To study the aging process and to identify possible therapeutic targets to counteract these diseases, the use of appropriate animal models is mandatory. Besides the most commonly used rodent species, a non-human primate, the common marmoset (Callithrix jacchus) emerged as a promising animal model of human aging over the last years. However, the visual aging process in this species is only partially characterized, especially with regard to retinal aberrations. Therefore, we assessed here for the first time potential changes in retinal morphology of the common marmoset of different age groups. By cell type specific immunolabeling, we analyzed different cell types and distributions, potential photoreceptor and ganglion cell loss, and structural reorganization. We detected no signs of age-related differences in staining patterns or densities of various cell populations. For example, there were no signs of photoreceptor degeneration, and there was only minimal sprouting of rod bipolar cells in aged retinas. Altogether, we describe here the maintenance of a stable neuronal architecture, distribution and number of different cell populations with only mild aberrations during the aging process in the common marmoset retina. These findings are in stark contrast to previously reported findings in rodent species and humans and deserve further investigations to identify the underlying mechanisms and possible therapeutic targets.

Protective effects of CRTH2 suppression in dry age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. Oxidative stress-induced retinal pigment epithelium (RPE) cell apoptosis is a crucial pathogenic hallmark in AMD. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a prostaglandin (PG) D2 receptor, has been implicated in various pathophysiological events, especially inflammation and stress-induced cell apoptosis. However, its specific role in AMD is not fully understood. Here we studied the effect of CRTH2 on AMD. Our results showed that when stimulated by H2O2, CRTH2 mRNA expression in cells tended to increase. Flow cytometry revealed that the CRTH2 inhibitor could protect the RPE from apoptosis. After NaIO3 injection, a larger area of retinal degeneration was observed in wild-type mice than in CRTH2−/− mice. Optical coherence tomography (OCT) and Hematoxylin and Eosin (H&E) staining of retinal sections showed that sodium iodate-induced loss of photoreceptor cells was reduced in CRTH2−/− mice after treatment; TUNEL-positive cells were mostly found in the outer nuclear layer. In the control group, NaIO3 stimulation increased the number of TUNEL-positive cells, whereas the percentage of TUNEL-positive cells was significantly lower in CRTH2−/− mice. Similarly, the CRTH2 receptor inhibitor CAY10471 similarly inhibited sodium iodate-induced retinal damage. Our results suggest that targeting CRTH2 is a promising therapeutic strategy for the treatment of progressive retinal degeneration in AMD.

The connecting cilium inner scaffold provides a structural foundation that protects against retinal degeneration.

Inherited retinal degeneration due to loss of photoreceptor cells is a leading cause of human blindness. These cells possess a photosensitive outer segment linked to the cell body through the connecting cilium (CC). While structural defects of the CC have been associated with retinal degeneration, its nanoscale molecular composition, assembly, and function are barely known. Here, using expansion microscopy and electron microscopy, we reveal the molecular architecture of the CC and demonstrate that microtubules are linked together by a CC inner scaffold containing POC5, CENTRIN, and FAM161A. Dissecting CC inner scaffold assembly during photoreceptor development in mouse revealed that it acts as a structural zipper, progressively bridging microtubule doublets and straightening the CC. Furthermore, we show that Fam161a disruption in mouse leads to specific CC inner scaffold loss and triggers microtubule doublet spreading, prior to outer segment collapse and photoreceptor degeneration, suggesting a molecular mechanism for a subtype of retinitis pigmentosa.

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas‐mediated gene repair or gene therapy in vitro. AAV‐based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.

Genetics of Inherited Retinal Diseases in Understudied Populations.

Retinitis pigmentosa is one of the major forms of inherited retinal dystrophy transmitted in all Mendelian and non-Mendelian forms of inheritance. It involves the loss of retinal photoreceptor cells with severe loss of vision or blindness within the first 2 decades of life. RP occurs at a relatively high prevalence in India and is often associated with consanguinity in certain South Asian communities where this practice is customary. This review describes the studies that have been published with regard to genetics of retinitis pigmentosa in India and neighboring South Asian countries. These populations have been understudied in these aspects although to a variable degree from one country to another. Genetic studies on RP in India have been carried out with a range of methods aimed at detecting specific mutations, to screening of candidate genes or selected genomic regions, homozygosity mapping to whole genome sequencing. These efforts have led to a molecular genetic characterization of RP in Indian families. Similar studies on large extended families from Pakistan have provided insight into several novel genes underlying the pathogenesis of these diseases. The extreme degree of clinical and genetic heterogeneity of RP renders it challenging to identify the associated genes in these populations, and to translate the research output towards better management of the disease, as there are no unifying genetic features that are characteristic of any population so far.

Raloxifene, a cannabinoid type-2 receptor inverse agonist, mitigates visual deficits and pathology and modulates microglia after ocular blast

Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state. We previously found that treating mice with CB2 inverse agonists after traumatic brain injury, produced by either focal cranial air blast or dorsal cranial impact, greatly attenuated the visual deficits and pathology that otherwise resulted. Here we examined the consequences of single and repeat OBI and the benefit provided by raloxifene, an FDA-approved estrogen receptor drug that possesses noteworthy CB2 inverse agonism. After single OBI, although the amplitudes of the A- and B-waves of the electroretinogram and pupil light response appeared to be normal, the mice showed hints of deficits in contrast sensitivity and visual acuity, a trend toward optic nerve axon loss, and significantly increased light aversion, which were reversed by 2 weeks of daily treatment with raloxifene. Mice subjected to repeat OBI (5 blasts spaced 1 min apart), exhibited more severe visual deficits, including decreases in contrast sensitivity, visual acuity, the amplitudes of the A- and B-waves of the electroretinogram, light aversion, and resting pupil diameter (i.e. hyperconstriction), accompanied by the loss of photoreceptor cells and optic nerve axons, nearly all of which were mitigated by raloxifene. Interestingly, optic nerve axon abundance was strongly correlated with contrast sensitivity and visual acuity across all groups of experimental mice in the repeat OBI study, suggesting optic nerve axon loss with repeat OBI and its attenuation with raloxifene are associated with the extent of these two deficits while photoreceptor abundance was highly correlated with A-wave amplitude and resting pupil size, suggesting a prominent role for photoreceptors in these two deficits. Quantitative PCR (qPCR) showed levels of M1-type microglial markers (e.g. iNOS, IL1β, TNFα, and CD32) in retina, optic nerve, and thalamus were increased 3 days after repeat OBI. With raloxifene treatment, the overall expression of M1 markers was more similar to that in sham mice. Raloxifene treatment was also associated with the elevation of IL10 transcripts in all three tissues compared to repeat OBI alone, but the results for the three other M2 microglial markers we examined were more varied. Taken together, the qPCR results suggest that raloxifene benefit for visual function and pathology was associated with a lessening of the pro-inflammatory actions of microglia. The benefit we find for raloxifene following OBI provides a strong basis for phase-2 efficacy testing in human clinical trials for treating ocular injury.

Biocompatibility of Human Induced Pluripotent Stem Cell–Derived Retinal Progenitor Cell Grafts in Immunocompromised Rats

Loss of photoreceptor cells is a primary feature of inherited retinal degenerative disorders including age-related macular degeneration and retinitis pigmentosa. To restore vision in affected patients, photoreceptor cell replacement will be required. The ideal donor cells for this application are induced pluripotent stem cells (iPSCs) because they can be derived from and transplanted into the same patient obviating the need for long-term immunosuppression. A major limitation for retinal cell replacement therapy is donor cell loss associated with simple methods of cell delivery such as subretinal injections of bolus cell suspensions. Transplantation with supportive biomaterials can help maintain cellular integrity, increase cell survival, and encourage proper cellular alignment and improve integration with the host retina. Using a pig model of retinal degeneration, we recently demonstrated that polycaprolactone (PCL) scaffolds fabricated with two photon lithography have excellent local and systemic tolerability. In this study, we describe rapid photopolymerization-mediated production of PCL-based bioabsorbable scaffolds, a technique for loading iPSC-derived retinal progenitor cells onto the scaffold, methods of surgical transplantation in an immunocompromised rat model and tolerability of the subretinal grafts at 1, 3, and 6 months of follow-up (n = 150). We observed no local or systemic toxicity, nor did we observe any tumor formation despite extensive clinical evaluation, clinical chemistry, hematology, gross tissue examination and detailed histopathology. Demonstrating the local and systemic compatibility of biodegradable scaffolds carrying human iPSC-derived retinal progenitor cells is an important step toward clinical safety trials of this approach in humans.

Retina stem cells, hopes and obstacles.

Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.

Neuroprotective Effect of 4-Phenylbutyric Acid against Photo-Stress in the Retina

Exposure to excessive visible light causes retinal degeneration and may influence the progression of retinal blinding diseases. However, there are currently no applied treatments. Here, we focused on endoplasmic reticulum (ER) stress, which can cause cellular degeneration and apoptosis in response to stress. We analyzed functional, histological, and molecular changes in the light-exposed retina and the effects of administering an ER-stress inhibitor, 4-phenylbutyric acid (4-PBA), in mice. We found that light-induced visual function impairment related to photoreceptor cell loss and outer segment degeneration were substantially suppressed by 4-PBA administration, following attenuated photoreceptor apoptosis. Induction of retinal ER stress soon after light exposure, represented by upregulation of the immunoglobulin heavy chain binding protein (BiP) and C/EBP-Homologous Protein (CHOP), were suppressed by 4-PBA. Concurrently, light-induced oxidative stress markers, Nuclear factor erythroid 2–related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1), and mitochondrial apoptotic markers, B-cell lymphoma 2 apoptosis regulator (Bcl-2)-associated death promoter (Bad), and Bcl-2-associated X protein (Bax), were suppressed by 4-PBA administration. Increased expression of glial fibrillary acidic protein denoted retinal neuroinflammation, and inflammatory cytokines were induced after light exposure; however, 4-PBA acted as an anti-inflammatory. Suppression of ER stress by 4-PBA may be a new therapeutic approach to suppress the progression of retinal neurodegeneration and protect visual function against photo-stress.