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Choroidal thickness in healthy eyes using enhanced depth imaging optical coherence tomography and comparison with cases of retinitis pigmentosa
摘要： Introduction. — The goal of this study was to measure by spectral domain optical coherence tomography (SD-OCT) with EDI the choroidal thickness in healthy subjects and to compare these parameters with those of patients with retinitis pigmentosa (RP). Methods. — Data were obtained from 60 healthy patients without history or family history of retinal or choroidal disease or glaucoma. A case-control study was also conducted on 40 eyes of 20 patients with RP and 40 eyes of 20 healthy refraction- and age-matched controls, selected from among the 60 healthy patients. OCT was used with the EDI protocol. The primary outcome measure was choroidal thickness. Results. — Among healthy patients, the overall choroidal thickness was 287.7 μm. Mean choroidal thickness was lower on the nasal side (236.6 μm from the fovea) compared with the temporal side (262.3 μm, P = 0.002). It also varied according to age, being highest among 20—29-year-old patients and decreasing thereafter with increasing age. Choroidal thickness was significantly higher in healthy patients than in RP patients, regardless of the location (P < 0.001). Conclusion. — This observational study confirms that choroidal thickness varies with age and location. It decreases in subjects with RP and is related to worsening of retinal damage, independently of age-related thinning. Further studies are needed to understand whether choroidal vascular alteration is a cause or a consequence of the degenerative pathology.
关键词： Photoreceptor degeneration,Choroidal thickness,Case-control study,Retinitis pigmentosa,Enhanced depth imaging optical coherence tomography
更新于2025-09-23 15:23:52
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Early Alteration of Retinal Neurons in <i>Aipl1</i> <sup>?/?</sup> Animals
摘要： PURPOSE. Mutations in the photoreceptor cell-specific gene encoding aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) lead to Leber congenital amaurosis (LCA4), retinitis pigmentosa, and cone–rod dystrophy. Gene therapy appears to be promising in the treatment for AIPL1-mediated vision loss in humans. Prior to initiating these treatments, however, it is crucial to understand how the retinal neurons remodel themselves in response to photoreceptor cell degeneration. In this study, using an animal model for AIPL1-LCA, Aipl1(cid:2)/(cid:2) mice, we investigate the changes in postreceptoral retinal neurons during the course of photoreceptor cell loss. METHODS. Morphology of the Aipl1(cid:2)/(cid:2) retina from postnatal day 8 to 150 was compared to that of age-matched, wild-type C57Bl6/J retina (WT) by immunocytochemistry using cell-specific markers. RESULTS. Expression of postsynaptic proteins in bipolar cells is reduced prior to photoreceptor cell degeneration at postnatal day 8. Bipolar and horizontal cells retract their dendrites. Cell bodies and axons of bipolar and horizontal cells are disorganized during the course of degeneration. M¨uller cell processes become hypertrophic and form a dense fibrotic layer outside the inner nuclear layer. CONCLUSIONS. An early defect in photoreceptor cells in the AIPL1-LCA mouse model affects the expression of postsynaptic markers, suggesting abnormal development of bipolar synapses. Once degeneration of photoreceptor cells is initiated, remodeling of retinal neurons in the Aipl1(cid:2)/(cid:2) animal is rapid.
关键词： childhood blindness,photoreceptor degeneration,retina,LCA,remodeling
更新于2025-09-23 15:22:29
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<i>ATF6</i> Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement
摘要： PURPOSE. Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identi?ed, their genetic basis remains unknown in a signi?cant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. METHODS. Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-?ltering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was con?rmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. RESULTS. The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identi?cation of biallelic loss-of-function mutations in the ATF6 gene. The ?rst variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533t1G>C). Sanger sequencing con?rmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. CONCLUSIONS. Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.
关键词： unfolded protein response,next-generation sequencing,ATF6,photoreceptor degeneration
更新于2025-09-11 14:15:04
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Concepts and Strategies in Retinal Gene Therapy
摘要： Genetic defects of the retina or retinal pigment epithelium (RPE) cause a substantial number of sight-impairing or blinding disorders, many of which eventually cause the degeneration and death of the visual cells. Previously considered incurable, some of these retinal diseases can now be treated, at least experimentally, by gene therapy. This new era of retinal therapeutics followed the successful restoration of retinal function in a canine model of RPE65 Leber congenital amaurosis (LCA) through adeno-associated virus 2 (AAV2) vector-mediated gene augmentation targeting the RPE layer of the eye. Restoring isomerohydrolase activity in the RPE corrected the retinoid visual cycle and vision defect. When treated at the predegenerate disease stage, treatment was both effective and permanent, and photoreceptor structure was preserved. Validation studies by other groups in both large and small animal models, along with preclinical safety studies in nonhuman primates (NPHs) and dogs, confirmed that the treatment was safe and effective. A further series of detailed studies in patients and animal models established the dependence of human cone photoreceptors on RPE65 isomerase, determined that the remaining photoreceptors in blind eyes were amenable to treatment, showed that the visual cortex in man and dog was intact and responsive in spite of early blindness, and developed outcome measures that could be used readily to assess treatment outcomes. These studies were followed by three independent clinical trials showing the treatment to be safe. Since then, additional RPE65-LCA clinical trials have been initiated both in academic settings and through commercial entities in the United States and elsewhere. To date, LCA remains the only blinding genetic disease to be successfully treated in humans.
关键词： RPE65,AAV vectors,photoreceptor degeneration,Leber congenital amaurosis,retinal gene therapy
更新于2025-09-04 15:30:14
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Neuronal Expression of Junctional Adhesion Molecule-C is Essential for Retinal Thickness and Photoreceptor Survival
摘要： Background: Photoreceptor cell death is a key pathology of retinal degeneration diseases. To date, the molecular mechanisms for this pathological process remain largely unclear. Junctional adhesion molecule-c (Jam-c) has been shown to play important roles in different biological events. However, its effect on retinal neuronal cells is unknown. Objective: To determine the effect of Jam-c on adult mouse eyes, particularly, on retinal structure, vasculature and photoreceptor cells, in order to explore potential important target molecules for ocular diseases. Methods: Jam-c global knockout mice, endothelial-specific and neuronal-specific Jam-c conditional knockout mice using Tie2-Cre and Nestin-Cre mice respectively were used in this study. Mouse eyes were harvested from the different groups and eye size examined. Cryosections of the eyes were made and stained with Hematoxylin and Eosin (H&E) and the thicknesses of retinal layers measured. Retinal blood vessels and cone and rod photoreceptors were analyzed using isolectin B4, peanut agglutinin and rhodopsin as markers respectively. In vivo Jam-c knockdown in mouse eyes was performed by intravitreal injection of Jam-c shRNA. Jam-c expression in the retinae was quantified by real-time PCR. Results: Global Jam-c gene deletion in mice resulted in smaller eyes and decreased the diameters of lens and iris. Jam-c-/- mice display marked thinning of the outer nuclear layer (ONL), less numbers of photoreceptor cells, and abnormal retinal vasculature. Importantly, neuronal-specific Jam-c deletion led to similar phenotype, whereas no obvious defect was observed in endothelial-specific Jam-c knockout mice. Moreover, Jam-c knockdown by shRNA also decreased ONL thickness and photoreceptor numbers. Conclusion: We found that Jam-c is critically required for the normal size and retinal structure. Particularly, Jam-c plays important roles in maintaining the normal retinal thickness, vasculature and photoreceptor numbers. Jam-c thus may therefore have important roles in various ocular diseases.
关键词： retina,photoreceptor degeneration,neuroprotection.,vasculature,Junctional adhesion molecule-c
更新于2025-09-04 15:30:14