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Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect
摘要： Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3?months. The visual acuity of one exceptional responder improved from light perception to 20/400.
关键词： antisense oligonucleotide,CEP290,photoreceptor ciliopathies,Leber congenital amaurosis,vision improvement
更新于2025-09-09 09:28:46
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Granular lesions of short-wavelength and near-infrared autofluorescence in diabetic macular oedema
摘要： Objectives To document and characterise hyper- and hypo-re?ective lesions, which we describe as ‘granular’ on short-wavelength auto?uorescence (SW-AF) and near-infrared (NIR)-AF images in diabetic macular oedema (DMO). Methods Consecutive 103 eyes of 78 patients suffering from centre-involving DMO were reviewed retrospectively. Mosaics of hyper- and hypo-?uorescent dots on both SW-AF and NIR-AF signals were delineated and de?ned as granular lesions in the macula. We evaluated the association of such lesions with the logarithm of the minimum angle of resolution visual acuity (logMAR VA) and spectral-domain optical coherence tomography (SD-OCT) images. Results Diffuse mosaics of hyper- and hypo-?uorescent dots were delineated in 36 and 45 eyes on SW-AF and NIR-AF images, respectively, and both AF images de?ned granular lesions in 33 eyes. These lesions were delineated in both the fovea and extrafoveal areas on NIR-AF images but were limited to the parafoveal and perifoveal sub?elds on SW-AF images. There was a signi?cant difference in logMAR VA between eyes with and without granular lesions (0.358 ± 0.269 vs. 0.185 ± 0.234; P = 0.001). Granular lesions were associated with the mosaic pattern on NIR-AF images (P < 0.001) but not with other parameters on SW-AF and NIR-AF images. The retinal thickness in the central sub?eld was greater in eyes with granular lesions (538.0 ± 163.6 μm vs. 448.8 ± 120.2 μm; P = 0.003). Granular lesions were associated with ELM disruption and hyper-re?ective foci in the outer retinal layers (P = 0.004 and P = 0.037, respectively). Conclusions Granular lesions de?ned on both SW-AF and NIR-AF images were related to retinal oedema with photoreceptor damage and concomitant VA reduction in DMO.
关键词： diabetic macular oedema,photoreceptor damage,near-infrared auto?uorescence,granular lesions,short-wavelength auto?uorescence
更新于2025-09-09 09:28:46
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Signal transmission at invaginating cone photoreceptor synaptic contacts following deletion of the presynaptic cytomatrix protein Bassoon in mouse retina
摘要： A key feature of the mammalian retina is the segregation of visual information in parallel pathways, starting at the photoreceptor terminals. Cone photoreceptors establish synaptic contacts with On bipolar and horizontal cells at invaginating, ribbon-containing synaptic sites, whereas Off bipolar cells form flat, non-ribbon-containing contacts. The cytomatrix protein Bassoon anchors ribbons at the active zone, and its absence induces detachment of ribbons from the active zone. In this study we investigate the impact of a missing Bassoon on synaptic transmission at the first synapse of the visual system. Release properties of cone photoreceptors were studied in wild-type and mutant mouse retinae with a genetic disruption of the presynaptic cytomatrix protein Bassoon using whole-cell voltage-clamp recordings. Light and electron microscopy revealed the distribution of Ca2+ channels and synaptic vesicles, respectively, in both mouse lines. Whole-cell recordings from postsynaptic horizontal cells of the two mouse lines showed that the presence of Bassoon (and a ribbon) enhanced the rate of exocytosis during tonic and evoked release by increasing synaptic vesicle pool size and replenishment rate, while at the same time slowing synaptic vesicle release. Furthermore, the number of Cav1.4 channels and synaptic vesicles was significantly higher at wild-type than at Bassoon mutant synaptic sites. The results of our study demonstrate that glutamate release from cone photoreceptor terminals can occur independent of a synaptic ribbon, but seems restricted to active zones, and they show the importance of a the synaptic ribbon in sustained and spatially and temporally synchronized neurotransmitter release.
关键词： signal transmission,retina,cone photoreceptor,horizontal cell,ribbon synapse,Bassoon
更新于2025-09-09 09:28:46
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Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration
摘要： Background: We have previously reported that xeno-transplanted human ESC-derived retinas are able to mature in the immunodeficient retinal degeneration rodent models, similar to allo-transplantations using mouse iPSC-derived retina. The photoreceptors in the latter developed outer segments and formed synapses with host bipolar cells, driving light responses of host retinal ganglion cells. In view of clinical application, here we further confirmed the competency of human iPSC-derived retina (hiPSC-retina) to mature in the degenerated retinas of rat and monkey models. Methods: Human iPSC-retinas were transplanted in rhodopsin mutant SD-Foxn1 Tg(S334ter)3LavRrrc nude rats and two monkeys with laser-induced photoreceptor degeneration. Graft maturation was studied by immunohistochemistry and its function was examined by multi-electrode array (MEA) recording in rat retinas and visually-guided saccade (VGS) in a monkey. Findings: A substantial amount of mature photoreceptors in hiPSC-retina graft survived well in the host retinas for at least 5 months (rat) to over 2 years (monkey). In 4 of 7 transplanted rat retinas, RGC light responses were detected at the grafted area. A mild recovery of light perception was also suggested by the VGS performance 1.5 years after transplantation in that monkey. Interpretation: Our results support the competency of hiPSC-derived retinas to be clinically applied for transplantation therapy in retinal degeneration, although the light responses observed in the present models were not conclusively distinguishable from residual functions of degenerating host retinas. The functional analysis may be further elaborated using other models with more advanced retinal degeneration.
关键词： Human iPSC,Retinal degeneration,Photoreceptor transplantation,Visually-guided saccades,Multi-electrode array
更新于2025-09-04 15:30:14
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Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids
摘要： The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. De?ciencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt’s disease, and Leber’s congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina.
关键词： metabolism,photoreceptor,visual chromophores,retinylamine,RPE65,retinal pigment epithelium,retinoid visual cycle,gene therapy,retinoids
更新于2025-09-04 15:30:14
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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
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How light traverses the inverted vertebrate retina
摘要： In our eyes, as in the eyes of all vertebrates, images of the environment are projected onto an inverted retina, where photons must pass through most of the retinal layers before being captured by the light-sensitive cells. Light scattering in these retinal layers must decrease the signal-to-noise ratio of the images and thus interfere with clear vision. Surprisingly however, our eyes display splendid visual abilities. This apparent contradiction could be resolved if intraretinal light scattering were to be minimized by built-in optical elements that facilitate light transmission through the tissue. Indeed, we were able to show that one function of radial glial (Müller) cells is to act as effective optical fibers in the living retina, bypassing the light-scattering structures in front of the light-sensitive cells. Each Müller cell serves as a ‘private’ light cable, providing one individual cone photoreceptor cell with its appropriate pixel of the environmental image, thus optimizing special resolution and visual acuity.
关键词： Photoreceptor cells,Glial cells,Visual acuity,Scattering,Vision
更新于2025-09-04 15:30:14