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BACKGROUND AND OBJECTIVE: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of risuteganib. PATIENTS AND METHODS: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal risuteganib (1.0 mg) or sham injection. The risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. RESULTS: Thirty-nine patients (risuteganib, n = 25; sham, n = 14) completed the study. There was a significant ( P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance ( P = .056) in the risuteganib group. All color vision metrics demonstrated a trend toward improvement in risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the risuteganib and control group ( P = .0493) and between responders and nonresponders ( P = .0478). MP showed that risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. CONCLUSION: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:430–438.]

The aim of this study is to investigate the therapeutic potential of higher doses of PU-91, quercetin, or in combination on transmitochondrial cybrid cell lines with various mtDNA haplogroups derived from patients with age-related macular degeneration (AMD), glaucoma (Glc), keratoconus (KC), and normal (NL) individuals. Cybrids were treated with PU-91 (P) (200 µM) alone, quercetin (Q) (20 µM) alone, or a combination of PU-91 and quercetin (P+Q) for 48 h. Cellular metabolism and the intracellular levels of reactive oxygen species (ROS) were measured by MTT and H2DCFDA assays, respectively. Quantitative real-time PCR was performed to measure the expression levels of genes associated with mitochondrial biogenesis, antioxidant enzymes, inflammation, apoptosis, and senescence pathways. PU-91(P) (i) improves cellular metabolism in AMD cybrids, (ii) decreases ROS production in AMD cybrids, and (iii) downregulates the expression of LMNB1 in AMD cybrids. Combination treatment of PU-91 plus quercetin (P+Q) (i) improves cellular metabolism in AMD, (ii) induces higher expression levels of TFAM, SOD2, IL6, and BAX in AMD cybrids, and (iii) upregulates CDKN1A genes expression in all disease cybrids. Our study demonstrated that the P+Q combination improves cellular metabolism and mitochondrial biogenesis in AMD cybrids, but senescence is greatly exacerbated in all cybrids regardless of disease type by the P+Q combined treatment.

BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of SARS-CoV-2 infections has decreased significantly; the long-term outlook of COVID-19 remains a serious cause of high death worldwide; with the mortality rate still surpassing even the worst mortality rates recorded for the influenza viruses. The continuous emergence of SARS-CoV-2 variants of concern (VOCs), including multiple heavily mutated Omicron sub-variants, have prolonged the COVID-19 pandemic and outlines the urgent need for a next-generation vaccine that will protect from multiple SARS-CoV-2 VOCs.MethodsIn the present study, we designed a multi-epitope-based Coronavirus vaccine that incorporated B, CD4+, and CD8+T cell epitopes conserved among all known SARS-CoV-2 VOCs and selectively recognized by CD8+and CD4+T-cells from asymptomatic COVID-19 patients irrespective of VOC infection. The safety, immunogenicity, and cross-protective immunity of this pan-Coronavirus vaccine were studied against six VOCs using an innovative triple transgenic h-ACE-2-HLA-A2/DR mouse model.ResultsThe Pan-Coronavirus vaccine: (i) is safe; (ii) induces high frequencies of lung-resident functional CD8+and CD4+TEMand TRMcells; and (iii) provides robust protection against virus replication and COVID-19-related lung pathology and death caused by six SARS-CoV-2 VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma or P1 (B.1.1.28.1), Delta (lineage B.1.617.2) and Omicron (B.1.1.529).Conclusions: A multi-epitope pan-Coronavirus vaccine bearing conserved human B and T cell epitopes from structural and non-structural SARS-CoV-2 antigens induced cross-protective immunity that cleared the virus, and reduced COVID-19-related lung pathology and death caused by multiple SARS-CoV-2 VOCs.

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4+ and CD8+ T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4+ and CD8+ T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4+ and CD8+ T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 ( P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:327–335.]

Purpose To review the biosimilars of anti–vascular endothelial growth factor agents for retinal diseases and provide an update about their development. Design Literature review. Methods A comprehensive literature review was performed for scientific articles, clinical trials, and press releases for the development of biosimilars in ophthalmology. Results To date, Razumab (Intas Pharmaceuticals Ltd, Ahmedabad, GJ, India) is the only approved biosimilar for ophthalmic use, but the landscape will rapidly change in the future with multiple biosimilar candidates, which are currently in phase 3 trials, showing promising early results. Conclusion Biosimilars hold the potential to reduce the financial burden of the highly efficacious biologic therapy in retinal pathologies. However, the off-label bevacizumab may differentiate the success of biosimilars in different geographic regions.

The last decade in the treatment of vascular pathologies of the retina has largely been limited to one cytokine: the vascular endothelial growth factor (VEGF) and its interaction with the receptor ...

Purpose: 7-ketocholesterol (7kCh), a natural byproduct of oxidation in lipoprotein deposits is implicated in the pathogenesis of diabetic retinopathy and age-related macular degeneration (AMD). This study was performed to investigate whether several clinical drugs can inhibit 7kCh-induced caspase activation and mitigate its apoptotic effects on retinal cells in vitro. Method: Two populations of retinal cells, human retinal pigment epithelial cells (ARPE-19) and rat neuroretinal cells (R28) were exposed to 7kCh in the presence of the following inhibitors: Z-VAD-FMK (pan-caspase inhibitor), simvastatin, memantine, epicatechin, and Z-IETD-FMK (caspase-8 inhibitor) or Z-ATAD-FMK (caspase-12 inhibitor). Caspase-3/7, -8, and -12 activity levels were measured by fluorochrome caspase assays to quantify cell death. IncuCyte live-cell microscopic images were obtained to quantify cell counts. Results: Exposure to 7kCh for 24 hours significantly increased caspase activities for both ARPE-19 and R28 cells (P < 0.05). In ARPE cells, pretreatment with various drugs had significantly lower caspase-3/7, -8, and -12 activities, reported in % change in mean signal intensity (msi): Z-VAD-FMK (48% decrease, P < 0.01), memantine (decreased 47.8% at 1 µM, P = 0.0039 and 81.9% at 1 mM, P < 0.001), simvastatin (decreased 85.3% at 0.01 µM, P < 0.001 and 84.8% at 0.05 µM, P < 0.001) or epicatechin (83.6% decrease, P < 0.05), Z-IETD-FMK (68.1% decrease, P < 0.01), and Z-ATAD-FMK (47.7% decrease, P = 0.0017). In contrast, R28 cells exposed to 7kCh continued to have elevated caspase-3/7, -8, and -12 activities (between 25.7% decrease and 17.5% increase in msi, P > 0.05) regardless of the pretreatment. Conclusion: Several current drugs protect ARPE-19 cells but not R28 cells from 7kCh-induced apoptosis, suggesting that a multiple-drug approach is needed to protect both cells types in various retinal diseases.

To analyze the role of intravitreal anti-vascular endothelial growth factor (anti-VEGF) or steroid injection for the management of Irvine Gass syndrome. It is an interventional, retrospective, multicenter study. One hundred and thirty-two injections were given in 79 eyes of 72 patients with Irvine Gass syndrome. Patients were treated with at least one intravitreal injection of either anti-VEGF or steroid. Outcomes were measured at 12 months (± 1 week). [Ranibizumab (Lucentis; Genentech, South San Francisco, CA) (Razumab; Intas Pharmaceutical Ltd, Ahmedabad, India) Bevacizumab (Avastin; Genentech, South San Francisco, CA) or Aflibercept (Eylea; Regeneron, Tarrytown, NY)] or steroids [Dexamethasone implant (Ozurdex, Allergan Inc, Irvine, CA) or intravitreal triamcinolone)]. Intravitreal injections were initiated in (67.6%) of eyes within 14 weeks of diagnosis. Intravitreal dexamethasone implant was used as the initial intravitreal therapy in (73.4%) of eyes. More than fifty percent (54.5%) of the patients were switched from anti-VEGF to Intravitreal dexamethasone implant. Reduction in the mean CMT was 336.7 ± 191.7 and 160.1 ± 153.1 microns in eyes treated within four weeks and more than 14 weeks from diagnosis (p = 0.005). Mean ETDRS letter gain was 16.7 ± 12.9 and 5.2 ± 9.2 in eyes treated within 4 weeks and more than 14 weeks from diagnosis (p = 0.004). Three eyes injected with intravitreal dexamethasone implant reported an intraocular pressure spike of > 25 mmHg which was controlled with topical medications. No other ocular or systemic adverse events were observed. Study results suggest that physicians tend to introduce intravitreal therapy within 14 weeks of diagnosis. The most common therapy at initiation and for the switch is intravitreal dexamethasone implant. Patients treated early (within 4 weeks) respond better in terms of structure and function.

SARS-CoV-2-specific memory T cells that cross-react with common cold coronaviruses (CCCs) are present in both healthy donors and COVID-19 patients. However, whether these cross-reactive T cells play a role in COVID-19 pathogenesis versus protection remain to be fully elucidated. In this study, we characterized cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells, targeting genome-wide conserved epitopes in a cohort of 147 non-vaccinated COVID-19 patients, divided into six groups based on the degrees of disease severity. We compared the frequency, phenotype, and function of these SARS-CoV-2-specific CD4+ and CD8+ T cells between severely ill and asymptomatic COVID-19 patients and correlated this with α-CCCs and β-CCCs co-infection status. Compared with asymptomatic COVID-19 patients, the severely ill COVID-19 patients and patients with fatal outcomes: (i) Presented a broad leukocytosis and a broad CD4+ and CD8+ T cell lymphopenia; (ii) Developed low frequencies of functional IFN-γ-producing CD134+CD138+CD4+ and CD134+CD138+CD8+ T cells directed toward conserved epitopes from structural, non-structural and regulatory SARS-CoV-2 proteins; (iii) Displayed high frequencies of SARS-CoV-2-specific functionally exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells; and (iv) Displayed similar frequencies of co-infections with β-CCCs strains but significantly fewer co-infections with α-CCCs strains. Interestingly, the cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcome seen in asymptomatic COVID-19 patients. Our results demonstrate that, the critically ill COVID-19 patients displayed fewer co-infection with α-CCCs strain, presented broad T cell lymphopenia and higher frequencies of cross-reactive exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells. In contrast, the asymptomatic COVID-19 patients, appeared to present more co-infections with α-CCCs strains, associated with higher frequencies of functional cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells. These findings support the development of broadly protective, T-cell-based, multi-antigen universal pan-Coronavirus vaccines.KEY POINTSA broad lymphopenia and lower frequencies of SARS-CoV-2-specific CD4+ and CD8+ T-cells were associated with severe disease onset in COVID-19 patients.High frequencies of phenotypically and functionally exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells, co-expressing multiple exhaustion markers, and targeting multiple structural, non-structural, and regulatory SARS-CoV-2 protein antigens, were detected in severely ill COVID-19 patients.Compared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented more functional cross-reactive CD4+ and CD8+ T cells targeting conserved epitopes from structural, non-structural, and regulatory SARS-CoV-2 protein antigens.The cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcomes seen in asymptomatic COVID-19 patients.Compared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented higher rates of co-infection with the α-CCCs strains.Compared to patients with mild or asymptomatic COVID-19, severely ill symptomatic patients and patients with fatal outcomes had more exhausted SARS-CoV-2-speccific CD4+ and CD8+ T cells that preferentially target cross-reactive epitopes that share high identity and similarity with the β-CCCs strains.

The purpose of this study is to evaluate the concentration of vascular endothelial growth factor (VEGF) in the vitreous humor of patients with primary rhegmatogenous retinal detachment (RRD). This is a prospective case control study. Eighteen patients with primary RRD without proliferative vitreoretinopathy C (PVR C) were enrolled as cases, and twenty-two non-diabetic retinopathy patients who were candidates for complete pars plana vitrectomy due to Macular Hole or Epiretinal Membrane were included as the control group. Undiluted vitreal samples were collected during the initiation of Pars Plana Vitrectomy (PPV) prior to any infusion into the posterior cavity. Vitreous samples were also collected from 21 fresh cadaveric globes. The vitreous concentration of VEGF was measured by enzyme-linked immunosorbent assay (ELISA) technique and compared between these two groups. The vitreal concentration of VEGF was 0.643 ± 0.088 ng/mL in the RRD group. Measured concentrations of VEGF in controls were 0.043 ± 0.104 ng/mL, and in cadaveric eyes they were 0.033 ± 0.058 ng/mL. The mean VEGF concentration in the RRD group was statistically higher than in the control group (p < 0.0001) and cadaveric eyes (p < 0.0001). Our study shows that vitreal VEGF concentrations significantly increase in patients with RRD.

Topics change as time flows. This is especially true in retinal therapeutics that merely 25 years ago was mainly a surgical field and in two decades has been transformed into a classic pharmacologic medical field. That said, the classic questions of pharmacology such as pharmacokinetics, pharmacodynamics, dosing and delivery systems currently engage most retina specialists. It was therefore easy for us to focus the 2018 ISOPT Clinical retinal discussions on delivery systems, drug efficacy and classic questions such as: have we reached the unbreakable glass ceiling of efficacy in wet age-related macular degeneration (AMD)? Can we aim our target to achieve an even higher effect? Can it be reached by new chemical/biological entities or would delivery system allow us to reach higher points of efficacy? The discussion also addressed the issue of dry AMD and the glorious parade of failures so far, and how do we measure success and failure via relevant endpoints.

Since mitochondrial dysfunction is implicated in the pathogenesis of AMD, this study is based on the premise that repurposing of mitochondria-stabilizing FDA-approved drugs such as PU-91, might rescue AMD RPE cells from AMD mitochondria-induced damage. The PU-91 drug upregulates PGC-1α which is a critical regulator of mitochondrial biogenesis. Herein, we tested the therapeutic potential of PU-91 drug and examined the additive effects of treatment with PU-91 and esterase inhibitors i.e., EI-12 and EI-78, using the in vitro transmitochondrial AMD cell model. This model was created by fusing platelets obtained from AMD patients with Rho0 i.e., mitochondria-deficient, ARPE-19 cell lines. The resulting AMD RPE cell lines have identical nuclei but differ in their mitochondrial DNA content, which is derived from individual AMD patients. Briefly, we report significant improvement in cell survival, mitochondrial health, and antioxidant potential in PU-91-treated AMD RPE cells compared to their untreated counterparts. In conclusion, this study identifies PU 91 as a therapeutic candidate drug for AMD and repurposing of PU-91 will be a smoother transition from lab bench to clinic since the pharmacological profiles of PU-91 have been examined already.

PurposeThis article aims to analyse the key regulatory guidelines across the globe concerning biosimilars.Materials and methodsReview of the current literature.ResultsBiosimilars are well regulated with the majority of regulators having enforced the guidelines for the development and approval, and new biosimilar drugs are appearing on the horizon to provide a therapeutic option to a wider population base because of its cost-effectiveness and proven safety. Due to their extensive analytical data, clinical data and pharmacovigilance studies, their development should not be considered similar to generic drugs.ConclusionThis review discusses the biosimilars, their regulation globally and their difference from generics from ophthalmic perspective.

Purpose: This article identifies subclinical microvascular changes in systemic lupus erythematosus (SLE) patients using vascular perfusion densities derived from optical coherence tomography angiography (OCTA). Methods: A retrospective review was performed on individuals with SLE (10 eyes of 5 patients) and age-matched controls imaged with a spectral-domain OCT system (XR Avanti, Optovue, Inc). A split-spectrum amplitude-decorrelation algorithm (SSADA) generated OCTA of the superficial retinal capillaries, deep retinal capillaries, and foveal avascular zone (FAZ). Skeletonized OCTAs were used to create capillary vessel density (VD) values for each image. VD values were compared with clinical staging, and groups were compared using Kruskal–Wallis and Mann–Whitney tests. Results: Both the superficial (SCP) and deep capillary plexus (DCP) had a statistically significant decrease in VD in the SLE group when compared with the control group ( P < .05). The average VD ± SD for normal individuals in the 3 mm × 3 mm scans was 26.11 ± 1.2 and 37.45 ± 1.8 for the SCP and DCP, respectively. For SLE patients the mean ± SD was 18.46 ± 0.84 and 30.22 ± 1.5 for SCP and DCP, respectively. The mean FAZ was found to be 0.207 mm ± 0.02 for healthy controls and 0.350 mm ± 0.02 for SLE patients ( P < .001). Conclusions: In this paper we demonstrate a significantly enlarged FAZ and decreased VD in a small sample of patients with lupus. The SCP VD demonstrated a dose-response–type negative relationship with increased systemic lupus severity. Larger-sample, prospective studies may allow us to further characterize subclinical SLE pathology with OCTA, and OCTA may further provide a means for monitoring the severity or progression of other microvascular diseases.

Emblica officinalis Gaetrn (i.e., Phyllanthus emblica/ Indian gooseberry/ Amla) (EO) has been used extensively as a nutraceutical in several diseases since it is known to boost immunity and offers numerous health benefits such as antioxidant, anti-inflammatory, and anti-aging effects. The goal of our study was to test the hypothesis that EO will rescue human AMD RPE transmitochondrial cells from mitochondria-induced cellular damage. AMD RPE transmitochondrial cell lines were created by fusion of mitochondria DNA-deficient APRE-19 (Rho0) cells with platelets isolated from AMD patients, and therefore had identical nuclei but differed in mitochondrial DNA content. These AMD RPE cells were treated with EO extract followed by characterization of effects of EO using cellular and molecular assays. Herein, EO significantly improved live cell number and mitochondrial membrane potential, reduced apoptosis and oxidative stress, down-regulated VEGF, and up-regulated PGC-1α. In conclusion, EO improved cellular and mitochondrial health, thereby playing a key cytoprotective role in AMD in vitro. Further studies are required to examine the mechanisms that mediate the cytoprotective effects of EO.