Search Results (33)

The early history of retinal laser therapy began with the observation of solar blindness, leading to the development of various laser technologies for treating retinal diseases. The first retinal photocoagulation machine was developed in 1956, and subsequent advancements introduced ruby and argon lasers. While conventional theories posited that retinal damage was an indispensable prerequisite for therapeutic effects, emergent insights highlight the non-damaging mechanisms, such as photostimulation- and self-repair-related mechanisms. Novel therapies, such as subthreshold micropulse laser (SMPL) and selective retina therapy (SRT), are now being employed alongside innovative delivery systems to improve treatment efficiency and safety. Clinical studies are underway to evaluate the efficacy of these therapies for conditions like diabetic retinopathy and central serous chorioretinopathy. Despite the challenges in standardization and long-term evaluation, these innovations represent significant progress towards safer and more effective laser treatment for retinal diseases. Full article

We developed ligandomics for the in vivo profiling of vascular ligands in mice, discovering secretogranin III (Scg3) as a novel angiogenic factor that selectively binds to retinal vessels of diabetic but not healthy mice. This discovery led to the development of anti-Scg3 therapy for ocular vasculopathies. However, in vivo ligandomics requires intracardial perfusion to remove unbound phage clones, limiting its use to vascular endothelial cells (ECs). To extend ligandomics to non-vascular cells, we investigated ex vivo ligandomics. We isolated ECs and retinal ganglion cells (RGCs) from diabetic and healthy mouse retinas by immunopanning. We quantified the binding of clonal phages displaying Scg3 and vascular endothelial growth factor (VEGF), confirming that their binding patterns to isolated diabetic versus healthy ECs matched in vivo patterns. Additionally, Scg3 and VEGF binding to isolated RGCs reflected their in vivo activity. These results support the feasibility of ex vivo ligandomics. We further mapped ligands binding to immunopanned diabetic and healthy ECs and RGCs by ligandomics, confirming that Scg3 was enriched with selective binding to diabetic ECs but not healthy ECs or diabetic/healthy RGCs. These findings demonstrate the feasibility of ex vivo ligandomics, which can be broadly applied to various cell types, tissues, diseases, and species. Full article

Background/Objectives: Uveal melanoma is the most common primary intraocular malignancy in adults. Treatment options for localized, early-stage disease include enucleation, brachytherapy, and proton beam therapy. This review aims to evaluate the role of proton therapy in the definitive management of uveal melanoma, focusing on its physics, radiobiology, treatment techniques, and associated outcomes. Methods: This narrative review synthesizes current literature on proton therapy for uveal melanoma, emphasizing case selection, treatment efficacy, and side effects. Results: Proton therapy offers significant advantages for thicker uveal melanomas (over 8 mm) due to its unique physical properties, including a rapid dose fall-off that protects critical structures like the retina and optic nerve. Proton therapy may have benefits in tumor control for ocular melanomas given its increased relative biological effectiveness relative to photon therapy for these typically more radioresistant melanomas. Proton therapy may also hold special value for uveal melanomas in close proximity to the optic nerve, as patients are at high risk of visual toxicities with brachytherapy. The review discusses the efficacy of proton therapy across small, medium, and large tumors, along with strategies for improving patient survival through combined systemic therapy. Additionally, the potential of ocular reirradiation with proton therapy is addressed. Conclusions: Proton therapy is an effective treatment for uveal melanoma. It offers advantages over brachytherapy for large tumors, tumors that are close to the optic nerve or insertion of extra-ocular muscles. Full article

Subthreshold lasers operate below the threshold of visible tissue damage, thereby preventing ophthalmoscopically visible thermal damage to the chorio-retinal layers. They could represent a safe and effective alternative and/or adjunctive procedure to conventional lasers in treating diabetic macula edema (DME), central serous chorioretinopathy (CSCR), and branch retina vein occlusion (BRVO). This review focuses on the use of subthreshold micropulse laser (SMPL), its settings, and clinical applications. Despite their widespread use, a standardized protocol for sub-threshold laser settings has not been established yet, and thus, there is uncertainty in selecting effective and safe parameters for any specific situation. We conducted a comprehensive overview of the existing indications for subthreshold laser therapy and their settings for different retinal diseases. The debate revolves around which parameters could guarantee the safety of the procedure for each case, depending on the duty cycle, the laser wavelength, the spot duration, and the power, with laser power titration on one side or choosing a fixed lowered power value on the other side. SMPL therapy for DME, CSCR, and BRVO-associated macular edema has shown significant effectiveness in reducing the macular thickness, facilitating subretinal fluid absorptions, increasing the best corrected visual acuity (BCVA) and reducing the number of intravitreal injections (IVI) required annually. We presented a broad list of the laser parameters reported in the literature, organized into different tables divided based on the specific pathology, with the aim of providing a useful tool for future studies. Full article

Background/Objectives: This study evaluated the clinical outcomes of selective retina therapy (SRT) for treating central serous chorioretinopathy. A fundus image-based titration method was used for laser irradiation. Methods: This retrospective cohort study included 29 eyes (29 patients) that underwent SRT for CSC. Both the pulse energy and number of micropulses were adjusted according to the fundus image. Mean best-corrected visual acuity (BCVA), central foveal thickness (CFT), and subretinal fluid (SRF) height were measured 1, 2, 3, 4, and 6 months after SRT. Mean deviation (MD) was measured using microperimetry at 3 and 6 months post-treatment. Results: At 6 months after SRT treatment, SRF was completely resolved in 89.7% of cases (26/29 eyes). The mean Snellen BCVA significantly improved from 0.34 ± 0.31 logMAR (logarithm of the minimum angle of resolution) (20/40) at baseline to 0.24 ± 0.24 logMAR (20/32) at 6 months (p = 0.009). The 0.1 improvement in mean BCVA is equivalent to a 5-letter gain on the ETDRS chart. The mean CFT decreased significantly from 309.31 ± 81.6 μm at baseline to 211.07 ± 50.21 μm at 6 months (p < 0.001). The mean SRF height also decreased significantly from 138.36 ± 56.78 μm at baseline to 23.75 ± 61.19 μm at 6 months (p < 0.001). The mean MD was improved from −1.56 ± 1.47 dB at baseline to −1.03 ± 2.43 dB at 6 months (p = 0.07) after treatment. Conclusions: SRT using fundus image-based titration can yield favorable functional and anatomical outcomes in the treatment of CSC. Full article

Retinopathy of prematurity (ROP) is a primary cause of visual impairment and blindness in premature newborns, characterized by vascular abnormalities in the developing retina, with microvascular alteration, neovascularization, and in the most severe cases retinal detachment. To elucidate the pathophysiology and develop therapeutics for ROP, several pre-clinical experimental models of ROP were developed in different species. Among them, the oxygen-induced retinopathy (OIR) mouse model has gained the most popularity and critically contributed to our current understanding of pathological retinal angiogenesis and the discovery of potential anti-angiogenic therapies. A deeper comprehension of molecular regulators of OIR such as hypoxia-inducible growth factors including vascular endothelial growth factors as primary perpetrators and other new metabolic modulators such as lipids and amino acids influencing pathological retinal angiogenesis is also emerging, indicating possible targets for treatment strategies. This review delves into the historical progressions that gave rise to the modern OIR models with a focus on the mouse model. It also reviews the fundamental principles of OIR, recent advances in its automated assessment, and a selected summary of metabolic investigation enabled by OIR models including amino acid transport and metabolism. Full article

Purpose: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. Methods: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. Results: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. Conclusions: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids. Full article

Background: With the clinical advances in the field of gene therapy, the development of objective measures of visual function of patients with inherited retinal dystrophies (IRDs) is of utmost importance. Here, we propose one such measure. Methods: We retrospectively analyzed data from a cohort of 194 eyes of 97 genetically diagnosed patients with retinitis pigmentosa (RP), the most common IRD, followed at the UPMC Vision Institute. The analyzed data included the reflectivity ratio (RR) of the retinal nerve fiber layer (RNFL) to that of the entire retina, visual acuity (VA) and the thickness of the retinal outer nuclear layer (ONL) and the RNFL. Results: There was a strong positive correlation between the RR and VA. Both VA and the RR were negatively correlated with disease duration; VA, but not the RR, was negatively correlated with age. The RR correlated with the ONL but not with the RNFL thickness or the intraocular pressure. Age, RR, disease duration and ONL thickness were found to be independent predictors of VA by multivariate analysis. Conclusion: The OCT RR could serve as an independent predictor of visual acuity, and by extension of retinal function, in genetically diagnosed RP patients. Such objective measures can be of great value in patient selection for therapeutic trials. Full article

Purpose: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy’s current state of the art. Material and Methods: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results. Full article

A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to partially restore vision in patients with retinal diseases that have resulted in the loss of photoreceptors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been major breakthroughs in retinal prosthesis technology, with the creation of numerous types of implants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate the remaining cells in the retina with electric signals to create a visual sensation. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying electronic retinal prostheses. Engineering aspects are explored, including electrode–retina alignment, electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events, visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing debate over whether implantable retinal devices still offer a promising approach for the treatment of retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as optogenetics. This review compares retinal prostheses with these alternative therapies, providing a balanced perspective on their advantages and limitations. The recent advancements in retinal prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of retinal prostheses. While acknowledging the challenges and complexities of the technology, this article highlights the significant potential of retinal prostheses for vision restoration in individuals with retinal diseases and calls for continued research and development to refine and enhance their performance, ultimately improving patient outcomes and quality of life. Full article

Retinitis pigmentosa (RP) is a frequent cause of blindness among the working population in industrial countries due to the inheritable death of photoreceptors. Though gene therapy was recently approved for mutations in the RPE65 gene, there is in general no effective treatment presently. Previously, abnormally high levels of cGMP and overactivation of its dependent protein kinase (PKG) have been suggested as causative for the fatal effects on photoreceptors, making it meaningful to explore the cGMP-PKG downstream signaling for more pathological insights and novel therapeutic target development purposes. Here, we manipulated the cGMP-PKG system in degenerating retinas from the rd1 mouse model pharmacologically via adding a PKG inhibitory cGMP-analogue to organotypic retinal explant cultures. A combination of phosphorylated peptide enrichment and mass spectrometry was then applied to study the cGMP-PKG-dependent phosphoproteome. We identified a host of novel potential cGMP-PKG downstream substrates and related kinases using this approach and selected the RAF1 protein, which may act as both a substrate and a kinase, for further validation. This showed that the RAS/RAF1/MAPK/ERK pathway may be involved in retinal degeneration in a yet unclarified mechanism, thus deserving further investigation in the future. Full article

Optical microsurgery confined to the retinal pigment epithelium (RPE) requires locally optimized laser parameters and reliable real-time feedback dosimetry (RFD) to prevent unwanted neuroretinal overexposure. This study aimed to compare pulses of different durations and application modes (single, ramp, burst). Moreover, optical coherence tomography (OCT)-based RFD was investigated in an ex vivo experiment, utilizing nine porcine eyes that were exposed to laser pulses of 8, 12, 16 and 20 µs duration (wavelength: 532 nm, exposure area: 90 × 90 µm², radiant exposure: 247 to 1975 mJ/µm²). Simultaneously, time-resolved OCT M-scans were recorded (central wavelength: 870 nm, scan rate: 85 kHz) for RFD. Post irradiation, retinal changes were assessed with color fundus photography (CFP) and cross-sectional OCT B-scans. RPE cell damage was quantified via fluorescence-based cell viability assay and compared to the OCT dosimetry feedback. Our experiments indicate cumulative RPE damage for pulse bursts of 16 µs and 20 µs, whereas no cumulative effects were found for pulse durations of 8 µs and 12 µs applied in ramp mode. According to statistical analysis, OCT-RFD correctly detected RPE cell damage with 96% sensitivity and 97% specificity using pulses of 8 µs duration in ramp mode. Full article

This study evaluates the long-term effects of selective retina therapy (SRT) on the retinal pigment epithelium (RPE) and neuroretina in patients with central serous chorioretinopathy. SRT was performed on 36 patients using a Nd:YLF-Laser at 527 nm (R:GEN^®, Lutronic, Goyang-Si, Republic of Korea). A total of 994 titration spots were examined using up to three years’ multimodal imaging. Leakage in fluorescein angiography (FA) was observed after SRT in 523 lesions and resolved after one month. SRT lesions were not visible clinically, but appeared as brightly reflective areas in infrared and multicolor images. Normal morphology was observed in optical coherence tomography (OCT) immediately after SRT. After one month, thickening of the RPE and interdigitation zone changes were seen and disappeared after 539 ± 308 days. No RPE atrophies occurred during the observation period. Decreased fundus autofluorescence (FAF) was mostly observed directly after SRT followed by increased FAF at one month, which faded over time. A significant decrease in the number of visible lesions in the FA and FAF was observed within the three-year follow-up. OCT findings are consistent with animal studies showing SRT-related defect closure by hypertrophy and migration of neighboring cells without RPE atrophy or photoreceptor damage. This suggests that SRT is a safe treatment option for macular diseases and does not lead to retinal atrophy. Full article

The purpose of this study was to compare the safety and efficacy of selective retina therapy (SRT) combined with the intravitreal injection of ranibizumab (IVR) in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). This trial was a 12-month single-center, randomized, single-masked prospective study. Eligible patients were randomized (1:1) to IVR and SRT (IVR + SRT group), or IVR and sham SRT (IVR + sham group). After the initial IVR, all participants received ME resolution criteria-driven pro re nata treatment. SRT or sham SRT was always applied one day after IVR. The primary outcome measure of this study was the mean change in central macular thickness (CMT) from baseline, and the secondary outcome measures were the mean change in visual acuity from baseline and the number of IVR treatments at a 52-week follow-up. Thirteen patients were in the IVR + SRT group, and 11 were in the IVR + sham group. Compared to the baseline, mean CMT and BCVA improved significantly after 52 weeks in both groups, with no significant difference between the two groups. The mean number of IVR was 2.85 ± 1.52 in the IVR + SRT group and 4.73 ± 2.33 in the IVR + sham group at the 52-week follow-up, with a significant difference between the two groups (p < 0.05). IVR combined with SRT may significantly decrease the number of IVR treatments while maintaining the visual and anatomical improvement effect of IVR monotherapy. Full article

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments. Full article