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Graefe's Archive For Clinical and... Jun 2024This study aims to answer a key question: is MYO7A-inherited retinal dystrophy (MYO7A-IRD) a photoreceptor-first or retinal pigment epithelium-first disease? A second...
PURPOSE
This study aims to answer a key question: is MYO7A-inherited retinal dystrophy (MYO7A-IRD) a photoreceptor-first or retinal pigment epithelium-first disease? A second aim was to determine the most useful biomarkers to monitor disease progression in pediatric patients with Usher syndrome type 1B (USH1) secondary to MYO7A mutation.
METHODS
Fifty-two eyes from 26 patients with genetically-confirmed MYO7A-IRD underwent swept-source optical coherence tomography (SS-OCT). Structural abnormalities were evaluated and correlated with follow-up time and best corrected visual acuity (BCVA). All patients were evaluated at baseline and after ≥ 40 months of follow-up.
RESULTS
The mean (SD) patient age was 9.92 (± 4.1) years. Mean follow-up time was 43 (± 3.2) months. At the final evaluation, the most common qualitative abnormalities in the subfoveal area were alterations in the photoreceptor outer segments (76.9% of eyes) and in the interdigitation zone (IZ) (80.8%). The presence of cystoid macular edema at baseline was independently associated with worse BCVA at the final assessment (increase in LogMAR estimate = 0.142; t(45.00) = 2.78, p = 0.009). The mean width of the ellipsoid and interdigitation zones decreased significantly (by 668 μm and 278 μm, respectively; both p < 0.001).
CONCLUSION
This study shows that disruption of the photoreceptor outer segments and the IZ are the first alterations detected by SS-OCT in the early phases of MYO7A-IRD. These data highlight the potential value of measuring the width of the ellipsoid and IZ to evaluate disease progression. These findings also demonstrate the utility of monitoring for the emergence of cystic lesions as biomarkers of worse visual prognosis in patients with MYO7A-IRD.
PubMed: 38871877
DOI: 10.1007/s00417-024-06545-3 -
Scientific Reports Jun 2024This study aims to correlate adaptive optics-transscleral flood illumination (AO-TFI) images of the retinal pigment epithelium (RPE) in central serous chorioretinopathy...
This study aims to correlate adaptive optics-transscleral flood illumination (AO-TFI) images of the retinal pigment epithelium (RPE) in central serous chorioretinopathy (CSCR) with standard clinical images and compare cell morphological features with those of healthy eyes. After stitching 125 AO-TFI images acquired in CSCR eyes (including 6 active CSCR, 15 resolved CSCR, and 3 from healthy contralateral), 24 montages were correlated with blue-autofluorescence, infrared and optical coherence tomography images. All 68 AO-TFI images acquired in pathological areas exhibited significant RPE contrast changes. Among the 52 healthy areas in clinical images, AO-TFI revealed a normal RPE mosaic in 62% of the images and an altered RPE pattern in 38% of the images. Morphological features of the RPE cells were quantified in 54 AO-TFI images depicting clinically normal areas (from 12 CSCR eyes). Comparison with data from 149 AO-TFI images acquired in 33 healthy eyes revealed significantly increased morphological heterogeneity. In CSCR, AO-TFI not only enabled high-resolution imaging of outer retinal alterations, but also revealed RPE abnormalities undetectable by all other imaging modalities. Further studies are required to estimate the prognosis value of these abnormalities. Imaging of the RPE using AO-TFI holds great promise for improving our understanding of the CSCR pathogenesis.
Topics: Humans; Retinal Pigment Epithelium; Central Serous Chorioretinopathy; Male; Female; Middle Aged; Tomography, Optical Coherence; Adult; Fluorescein Angiography; Optical Imaging; Sclera
PubMed: 38871803
DOI: 10.1038/s41598-024-64524-4 -
Anatomia, Histologia, Embryologia Jul 2024The pecten is a fold-structured projection at the ocular fundus in bird eyes, showing morphological diversity between the diurnal and nocturnal species. However, its...
The pecten is a fold-structured projection at the ocular fundus in bird eyes, showing morphological diversity between the diurnal and nocturnal species. However, its biological functions remain unclear. This study investigated the morphological and histological characteristics of pectens in wild birds. Additionally, the expression of non-visual opsin genes was studied in chicken pectens. These genes, identified in the chicken retina and brain, perceive light periodicity regardless of visual communication. Similar pleat numbers have been detected among bird taxa; however, pecten size ratios in the ocular fundus showed noticeable differences between diurnal and nocturnal birds. The pectens in nocturnal brown hawk owl show extremely poor vessel distribution and diameters compared with that of diurnal species. RT-PCR analysis confirmed the expression of Opn5L3, Opn4x, Rrh and Rgr genes. In situ hybridization analysis revealed the distribution of Rgr-positive reactions in non-melanotic cells around the pecten vessels. This study suggests a novel hypothesis that pectens develop dominantly in diurnal birds as light acceptors and contribute to continuous visual function or the onset of periodic behaviour.
Topics: Animals; Opsins; Retina; In Situ Hybridization; Chickens; Birds; Circadian Rhythm; Brain
PubMed: 38868938
DOI: 10.1111/ahe.13071 -
Effective intravitreal gene delivery to retinal pigment epithelium with hyaluronic acid nanospheres.Molecular Therapy. Nucleic Acids Jun 2024Inherited retinal degeneration (IRD) can cause a wide range of different forms of vision loss and blindness, and in spite of extensive advancements in gene therapy...
Inherited retinal degeneration (IRD) can cause a wide range of different forms of vision loss and blindness, and in spite of extensive advancements in gene therapy research, therapeutic approaches for targeting IRDs are still lacking. We have recently developed an approach for the intravitreal co-delivery of hyaluronic-acid nanospheres (HA-NSs) with sulfotyrosine (ST), effectively reaching the outer retina from the vitreal cavity. Here, our goal was to understand whether DNA-filled HA-NSs could generate gene expression in the outer retina. TxRed-labeled HA-NSs were compacted with plasmid DNA carrying a GFP reporter gene and intravitreally injected into the mouse retina. Follow-up at 4 weeks showed widespread gene expression in the outer retina and reduced, albeit present, expression at 8 weeks post-injection. Further analysis revealed this expression to be largely localized to the retinal pigment epithelium (RPE). These data show that intravitreal delivery of HA-NSs is a promising non-viral platform for the delivery of therapeutic genes and can generate pan-tissue, persistent gene expression in the RPE.
PubMed: 38868364
DOI: 10.1016/j.omtn.2024.102222 -
Cureus May 2024Objective In this study, we aimed to evaluate the choroidal thickness in patients with unilateral strabismic amblyopia by using spectral domain-enhanced depth...
Objective In this study, we aimed to evaluate the choroidal thickness in patients with unilateral strabismic amblyopia by using spectral domain-enhanced depth imaging-optical coherence tomography (SD-EDI-OCT) (Heidelberg Engineering GmbH, Heidelberg, Germany). Methods Twenty-five children with strabismic amblyopia and 20 age- and sex-matched healthy controls were included in this study. Seven sections were obtained, each comprising 25 repetitive images from each section at 200-micron intervals, and measurements were taken from nine different points at vertical and horizontal lines (1 and 3 mm from the subfoveal, superior, inferior, temporal, and nasal regions), centered on the fovea, using SD-EDI-OCT. Choroidal thickness values were obtained by measuring the distance between the basal border of the retinal pigment epithelium and the choroidoscleral border. The Mann-Whitney U test was used to compare choroidal thickness between the amblyopic and the control groups. Results The mean age of children with amblyopia and that of controls were 8.4 ±2.7 and 9.9 ±3.3 years, respectively (p=0.120). The mean subfoveal choroidal thickness was 372.8 ±78.9 μm in amblyopic eyes and 372.4 ±79.3 μm in the fellow eyes, both of which were thicker than the control eyes (310.9 ±76.3 μm; p<0.05 for each). Similarly, the mean values for the choroidal thickness of the amblyopic children at 1 mm nasal (320 ±86 μm), 1 mm superior (363 ±70 μm), and 3 mm superior (336 ±62 μm) were also significantly thicker than those of the corresponding control eyes (p<0.05 for each). There was a negative correlation between the subfoveal choroidal thickness and axial length (r=-0.332, p=0.005). There were no correlations between the choroidal thickness, age, and visual acuity. Conclusions The choroidal thicknesses of strabismic and fellow eyes were similar in patients with strabismic amblyopia. However, the choroidal thickness of both eyes in strabismic children was significantly thicker than those of the healthy controls. Emmetropization may be defective in both eyes of strabismic amblyopic patients.
PubMed: 38868277
DOI: 10.7759/cureus.60219 -
Proceedings of the National Academy of... Jun 2024Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive...
Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive photoreceptor degeneration, and has been implicated in the pathogenesis of age-related macular degeneration. Xenogenic expression of alternative oxidases in mammalian cells and tissues mitigates phenotypes arising from some mitochondrial electron transport defects, but can exacerbate others. We expressed an alternative oxidase from (AOX) in ETC-deficient murine RPE in vivo to assess the retinal consequences of stimulating coenzyme Q oxidation and respiration without ATP generation. RPE-restricted expression of AOX in this context is surprisingly beneficial. This focused intervention mitigates RPE mTORC1 activation, dedifferentiation, hypertrophy, stress marker expression, pseudohypoxia, and aerobic glycolysis. These RPE cell autonomous changes are accompanied by increased glucose delivery to photoreceptors with attendant improvements in photoreceptor structure and function. RPE-restricted AOX expression normalizes accumulated levels of succinate and 2-hydroxyglutarate in ETC-deficient RPE, and counteracts deficiencies in numerous neural retinal metabolites. These features can be attributed to the activation of mitochondrial inner membrane flavoproteins such as succinate dehydrogenase and proline dehydrogenase, and alleviation of inhibition of 2-oxyglutarate-dependent dioxygenases such as prolyl hydroxylases and epigenetic modifiers. Our work underscores the importance to outer retinal health of coenzyme Q oxidation in the RPE and identifies a metabolic network critical for photoreceptor survival in the context of RPE mitochondrial dysfunction.
Topics: Animals; Mitochondria; Mice; Oxidoreductases; Retinal Pigment Epithelium; Plant Proteins; Mitochondrial Proteins; Ciona intestinalis; Ubiquinone; Retinal Degeneration; Photoreceptor Cells, Vertebrate
PubMed: 38865272
DOI: 10.1073/pnas.2402384121 -
Investigative Ophthalmology & Visual... Jun 2024N6-methyladenosine (m6A) methylation is a chemical modification that occurs on RNA molecules, where the hydrogen atom of adenine (A) nucleotides is replaced by a methyl...
PURPOSE
N6-methyladenosine (m6A) methylation is a chemical modification that occurs on RNA molecules, where the hydrogen atom of adenine (A) nucleotides is replaced by a methyl group, forming N6-methyladenosine. This modification is a dynamic and reversible process that plays a crucial role in regulating various biological processes, including RNA stability, transport, translation, and degradation. Currently, there is a lack of research on the role of m6A modifications in maintaining the characteristics of RPE cells. m6A readers play a crucial role in executing the functions of m6A modifications, which prompted our investigation into their regulatory roles in the RPE.
METHODS
Phagocytosis assays, immunofluorescence staining, flow cytometry experiments, β-galactosidase staining, and RNA sequencing (RNA-seq) were conducted to assess the functional and cellular characteristics changes in retinal pigment epithelium (RPE) cells following short-hairpin RNA-mediated knockdown of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). RNA-seq and ultraviolet crosslinking immunoprecipitation with high-throughput sequencing (HITS-CLIP) were employed to identify the target genes regulated by IGF2BP2. adeno-associated virus (AAV) subretinal injection was performed in 6- to 8-week-old C57 mice to reduce IGF2BP2 expression in the RPE, and the impact of IGF2BP2 knockdown on mouse visual function was assessed using immunofluorescence, quantitative real-time PCR, optical coherence tomography, and electroretinography.
RESULTS
IGF2BP2 was found to have a pronounced effect on RPE phagocytosis. Subsequent in-depth exploration revealed that IGF2BP2 modulates the mRNA stability of PAX6 and OTX2, and the loss of IGF2BP2 induces inflammatory and aging phenotypes in RPE cells. IGF2BP2 knockdown impaired RPE function, leading to retinal dysfunction in vivo.
CONCLUSIONS
Our data suggest a crucial role of IGF2BP2 as an m6A reader in maintaining RPE homeostasis by regulating the stability of PAX6 and OTX2, making it a potential target for preventing the occurrence of retinal diseases related to RPE malfunction.
Topics: Retinal Pigment Epithelium; Animals; Mice; PAX6 Transcription Factor; Homeostasis; Mice, Inbred C57BL; Otx Transcription Factors; RNA-Binding Proteins; Phagocytosis; Flow Cytometry; Gene Expression Regulation; Tomography, Optical Coherence; Electroretinography; Cells, Cultured
PubMed: 38861275
DOI: 10.1167/iovs.65.6.17 -
Acta Ophthalmologica Jun 2024Central serous chorioretinopathy (CSC) is a frequently occurring chorioretinal disease, that is commonly associated with subretinal fluid accumulation in a generally...
Central serous chorioretinopathy (CSC) is a frequently occurring chorioretinal disease, that is commonly associated with subretinal fluid accumulation in a generally young population. Even though choroidal abnormalities have been found to be of importance, the exact pathogenesis of CSC is still being learned. The origin of pigment epithelial detachments, seen in many CSC patients, is also unclear. Based on the follow-up of a CSC patient for more than 5 years, we hypothesize that intraocular pressure and, by extension, the pressure gradient across the Bruch's membrane, may be one factor in the pathogenesis of pigment epithelial detachments in CSC, which might very well have implications for the occurrence of and possible ways to prevent subretinal fluid in CSC.
PubMed: 38860298
DOI: 10.1111/aos.16730 -
Oxford Medical Case Reports Jun 2024Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment...
Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment epithelium (RPE), which can progress to pigmentary retinopathy (PR). We present a case of PRD in a female pediatric patient who has pathogenic variants in the PRPH2 and PEX1 genes. The patient has associated macular edema and secondary visual impairment. Treatment has included serial dexamethasone intravitreal implant injections and topical dorzolamide. The PEX1 gene mutation is associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum (PBD-ZSS) and resulting retinal dystrophies. The PRPH2 mutation may play a role in macular edema and PRD, as it is implicated in macular degeneration, choroid defects, and photoreceptor dysfunction. In this case, we review multiple gene mutations playing potential etiologic roles for PRD and discuss care management.
PubMed: 38860019
DOI: 10.1093/omcr/omae067 -
Experimental Eye Research Jun 2024The retinal pigment epithelium (RPE) is omnivorous and can utilize a wide range of substrates for oxidative phosphorylation. Certain tissues with high mitochondrial...
The retinal pigment epithelium (RPE) is omnivorous and can utilize a wide range of substrates for oxidative phosphorylation. Certain tissues with high mitochondrial metabolic load are capable of ketogenesis, a biochemical pathway that consolidates acetyl-CoA into ketone bodies. Earlier work demonstrated that the RPE expresses the rate-limiting enzyme for ketogenesis, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and that the RPE indeed produces ketone bodies, including beta-hydroxybutyrate (β-HB). Prior work, based on detecting β-HB via enzymatic assays, suggested that differentiated cultures of primary RPE preferentially export β-HB across the apical membrane. Here, we compare the accuracy of measuring β-HB by enzymatic assay kits to mass spectrometry analysis. We found that commercial kits lack the sensitivity to accurately measure the levels of β-HB in RPE cultures and are prone to artifact. Using mass spectrometry, we found that while RPE cultures secrete β-HB, they do so equally to both apical and basal sides. We also find RPE is capable of consuming β-HB as levels rise. Using isotopically labeled glucose, amino acid, and fatty acid tracers, we found that carbons from both fatty acids and ketogenic amino acids, but not from glucose, produce β-HB. Altogether, we substantiate β-HB secretion in RPE but find that the secretion is equal apically and basally, RPE β-HB can derive from ketogenic amino acids or fatty acids, and accurate β-HB assessment requires mass spectrometric analysis.
PubMed: 38857822
DOI: 10.1016/j.exer.2024.109966