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The prospective, comparative evaluation of combined navigated laser photocoagulation and intravitreal ranibizumab in the treatment of diabetic macular edema has shown advantage of a combination therapy compared to ranibizumab monotherapy at year 1 with significantly reduced injections. The purpose of this retrospective study was to determine the long-term visual gains and need of injections in a 3 year-follow-up period. Retrospective analysis of patients of the original study in the long-term follow-up from month 12 to 36. BCVA measurements following the original 1 year study were taken using logMAR charts. Injections were provided with standard of care using PRN, based on change in BCVA and CRT using SD-OCT scans. Main outcome measures were change in BCVA and mean number of injections from 12 to 36 months. BCVA was stable in both groups from 12 through 36 months, showing a change of 0.16 ± 0.1 log MAR. Following the initial reduction in required injections at month 12, combination therapy patients continued to require 1.3 times fewer injections over the next 24 months (2.91 ± 2.3 vs 3.85±3.7 injections for monotherapy). Combination of navigated laser and ranibizumab achieved BCVA gains equivalent to anti-VEGF monotherapy. These results could be maintained through month 36. Required injections were 2.0 injections lower in year 1 and further 1.3 times fewer in year 2 and 3 in the combination group compared to monotherapy. Adding navigated laser photocoagulation to intravitreal anti-VEGF therapy may still represent a superior therapeutic approach to DME patients.

Optical Coherence Tomography Angiography (OCTA) has become an essential non-invasive imaging technique for high-resolution visualization of retinal microvasculature. This study evaluates the performance of a novel Swept-Source OCTA device, Intalight DREAM, compared to established systems: Heidelberg Spectralis, Topcon Triton, and Zeiss Cirrus. We assessed acquisition time and microvascular parameters in the superficial (SCP) and deep (DCP) capillary plexuses using the OCTA Vascular Analyser algorithm for standardized image analysis across devices on 30 eyes from 15 healthy participants. In the SCP, DREAM demonstrated a higher median vessel length (47 μm) and greater fractal dimension (mean: 1.999) than the other devices, indicating enhanced continuity and network complexity. In the DCP, DREAM showed a smaller foveal avascular zone (median: 0.339 mm 2 ) compared to Spectralis (0.51 mm 2 ), Triton (0.5935 mm 2 ), and Cirrus (0.9145 mm 2 ), along with a smaller vessel diameter (median: 23 μm) compared to Triton and Cirrus. With a median imaging time of 9.1 s, DREAM was significantly faster than the Spectralis system (23.3 s) while providing largely comparable image quality, enhancing patient comfort, and potentially minimizing motion artifacts. These findings suggest that DREAM OCT is a promising tool for deep retinal imaging, with strong potential for clinical application and research.

To evaluate surgical indications and causative underlying diseases in patients undergoing enucleation in a tertiary eye unit. Retrospective analysis of all enucleations performed at the University Eye Hospital of LMU Munich from January 2007 to December 2022. 491 eyes of 491 patients were enucleated in this period; 237 right and 254 left eyes. 59.3% (291) of patients were male, while 40.7% (200) were female. The median patient age at enucleation was 59 years (range 2–99, IQR 43–72). The four most common surgical indications were painful blind eye (318, 64.8%), malignancy (139, 28.3%), disfiguring blind eye (14, 2.9%) and treatment-refractory perforated corneal ulcer (13, 2.6%). There was only one indication for enucleation due to acute trauma (1, 0.2%). Information on causative diagnosis was available from 2013 to 2022 (257). The most common causative diagnoses leading to enucleation were choroidal melanoma (107, 41.6%), status post (s/p) trauma (65, 25.3%), and s/p retinal detachment (17, 6.6%). The annual enucleation count showed a decline from 2007 to 2022. Regarding indications for enucleation there is a negative trend for “painful blind eye” and “malignant tumor”. Our study demonstrates a decrease in the annual number of enucleations between 2007 and 2022. While the causative diagnoses remained unchanged over the last ten years, there was a negative trend in surgical indications due to malignant tumors and painful blind eyes. Only one enucleation was performed due to acute trauma.

Gene therapy using recombinant adeno‐associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2‐based peptide‐display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high‐level retinal transduction after intravitreal injection in mice, dogs and non‐human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof‐of‐concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone‐specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3 −/− mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies. Synopsis Ocular gene therapy aims to improve or preserve vision in patients with inherited blinding disorders. The current technology still relies on subretinal administration of therapeutic vectors, which harbours risks of collateral damage and only treats a small portion of the affected retina. This study presents two novel engineered viral vectors capable of widespread targeting of retinal cells through a less invasive delivery route. Novel vectors AAV2.GL and AAV2.NN achieve widespread photoreceptor transduction in mouse, dog and non‐human primate after single intravitreal delivery. AAV2.GL and AAV2.NN have cone and rod photoreceptor tropism. AAV2.NN outperforms existing vectors in targeting rod photoreceptors in mice. Gene supplementation using AAV2.GL rescues cone function and CNGA3 protein expression in the Cnga3 −/− mouse model of achromatopsia. Graphical Abstract Ocular gene therapy aims to improve or preserve vision in patients with inherited blinding disorders. The current technology still relies on subretinal administration of therapeutic vectors, which harbours risks of collateral damage and only treats a small portion of the affected retina. This study presents two novel engineered viral vectors capable of widespread targeting of retinal cells through a less invasive delivery route.

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3 , which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3 - and CNGB3 -linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.

To characterize the diagnostic yield of the spot sign in the diagnostic workup of acute arterial occlusions of the eye in elderly patients. Clinical characteristics of consecutive patients aged ≥ 50 years with acute central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO) or anterior ischemic optic neuropathy (AION) were recorded. Videos of transocular sonography were assessed for the presence of the spot sign by two blinded readers. Group comparisons were made between CRAO-patients with and without the spot sign. Two experienced cardiovascular physicians allocated CRAO-cases to a presumed aetiology, without and with knowledge on the presence/absence of the spot sign. One-hundred-twenty-three patients were included, 46 of whom suffered from CRAO. A spot sign was seen in 32 of 46 of patients with CRAO and in 7 of 23 patients with BRAO. Interobserver agreement was excellent (Cohen`s kappa 0.98). CRAO-patients with the spot sign significantly more frequently had a medical history of cardiovascular disease (62.8 vs. 21.4%, p = 0.03) and left heart valve pathologies (51.9 vs. 10%, p = 0.03). The spot sign was not found in any of the three patients with CRAO secondary to cranial giant cell arteritis. The assumed CRAO aetiology differed in 37% of cases between two cardiovascular physicians, regardless whether transocular sonography findings were known or not. The spot sign is a simple sonographic finding with excellent interobserver agreement, which proofs the embolic nature of CRAO, but does not allow exact attribution of the underlying aetiology.

Glioblastoma is the most common human brain cancer entity and is maintained by a glioblastoma stem cell (GSC) subpopulation. In this issue of the JCI, El-Sehemy and colleagues explored the effects that Norrin, a well-characterized activator of Wnt/β-catenin signaling, had on tumor growth. Norrin inhibited cell growth via β-catenin signaling in GSCs that had low expression levels of the transcription factor ASCL1. However, Norrin had the opposite effect in GSCs with high ASCL1 expression levels. The modulation of Norrin expression, with respect to high or low ASCL1 levels in GSCs, significantly reduced tumor growth in vivo, and subsequently increased the survival rate of mice. Notably, Norrin mediates enhanced tumor growth of glioblastomas by activating the Notch pathway. This study clarifies the opposing effects of Norrin on glioblastoma tumor growth and provides potential therapeutic targets for glioblastoma treatment.

Epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial cells is a crucial event in the onset of proliferative vitreoretinopathy (PVR), the most common reason for treatment failure in retinal detachment surgery. We studied alterations in the cell surface glycan expression profile upon EMT of RPE cells and focused on its relevance for the interaction with galectin-3 (Gal-3), a carbohydrate binding protein, which can inhibit attachment and spreading of human RPE cells in a dose- and carbohydrate-dependent manner, and thus bares the potential to counteract PVR-associated cellular events. Lectin blot analysis revealed that EMT of RPE cells in vitro confers a glycomic shift towards an abundance of Thomsen-Friedenreich antigen, poly-N-acetyllactosamine chains, and complex-type branched N-glycans. Using inhibitors of glycosylation we found that both, binding of Gal-3 to the RPE cell surface and Gal-3-mediated inhibition of RPE attachment and spreading, strongly depend on the interaction of Gal-3 with tri- or tetra-antennary complex type N-glycans and sialylation of glycans but not on complex-type O-glycans. Importantly, we found that β1,6 N-acetylglucosaminyltransferase V (Mgat5), the key enzyme catalyzing the synthesis of tetra- or tri-antennary complex type N-glycans, is increased upon EMT of RPE cells. Silencing of Mgat5 by siRNA and CRISPR-Cas9 genome editing resulted in reduced Gal-3 binding. We conclude from these data that binding of recombinant Gal-3 to the RPE cell surface and inhibitory effects on RPE attachment and spreading largely dependent on interaction with Mgat5 modified N-glycans, which are more abundant on dedifferentiated than on the healthy, native RPE cells. Based on these findings we hypothesize that EMT of RPE cells in vitro confers glycomic changes, which account for high affinity binding of recombinant Gal-3, particularly to the cell surface of myofibroblastic RPE. From a future perspective recombinant Gal-3 may disclose a therapeutic option allowing for selectively targeting RPE cells with pathogenic relevance for development of PVR.

Glioblastoma is the most common human brain cancer entity and is maintained by a glioblastoma stem cell (GSC) subpopulation. In this issue of the JCI, El-Sehemy and colleagues explored the effects that Norrin, a well- characterized activator of Wnt/[beta]-catenin signaling, had on tumor growth. Norrin inhibited cell growth via [beta]-catenin signaling in GSCs that had low expression levels of the transcription factor ASCL1. However, Norrin had the opposite effect in GSCs with high ASCL1 expression levels. The modulation of Norrin expression, with respect to high or low ASCL1 levels in GSCs, significantly reduced tumor growth in vivo, and subsequently increased the survival rate of mice. Notably, Norrin mediates enhanced tumor growth of glioblastomas by activating the Notch pathway. This study clarifies the opposing effects of Norrin on glioblastoma tumor growth and provides potential therapeutic targets for glioblastoma treatment.