Treatment Of Retinal Diseases Research Articles

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases.

The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis - traditionally thought of as uncontrolled cell death - in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments.

Highly Retina-Permeating and Long-Acting Resveratrol/Metformin Nanotherapeutics for Enhanced Treatment of Macular Degeneration.

The development of therapeutics for effective treatments of retinal diseases is significantly constrained by various biological barriers. We herein report a nanomedicine strategy to develop nanotherapeutics featured with not only high retinal permeability but also sustained bioactive delivery. Specifically, the nanotherapeutics are rationally designed via aminolysis of resveratrol-encapsulated polycaprolactone nanoparticles (R@PCL NPs), followed by the formation of amide linkages with carboxyl-terminated transacting activator of transcription cell penetrating peptide (T) and metformin (M). The R@PCL-T/M NP nanotherapeutics are demonstrated in vitro to possess persistent drug release profiles, good ocular biocompatibility, and potent bioactive activities for targeting prevailing risk factors associated with retinal diseases. In vivo studies indicate that single-dose intravitreal administration of the R@PCL-T/M NPs can effectively improve retinal permeability (∼15-fold increase), prevent loss of endogenous antioxidants, and suppress the growth of abnormal vessels in the retina with macular degeneration for 56 days. This high treatment efficacy can be ascribed to the enhanced retinal permeability of the nanotherapeutics in conjunction with the sustained pharmacological activity of the dual drugs (R and M) in the retinal pigment epithelial region. These findings show a great promise for the development of pharmacological nanoformulations capable of targeting the retina and thereby treating complex posterior segment diseases with improved efficacies.

Immunogenicity With Ranibizumab Biosimilar SB11 (Byooviz) and Reference Product Lucentis and Association With Efficacy, Safety, and Pharmacokinetics

SB11 and reference ranibizumab (RBZ) are monoclonal anti-vascular endothelial growth factor (VEGF)-A antibodies approved for the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. The association of ranibizumab immunogenicity and treatment outcomes in patients with nAMD is unclear but relevant regarding concerns about immunogenicity of anti-VEGF biological products. To examine the association of immunogenicity to ranibizumab products (SB11 and RBZ) with efficacy, safety, and pharmacokinetics. This was a post hoc analysis of a randomized, double-masked, parallel-group phase 3 equivalence study with participants from 75 centers in 9 countries conducted from March 14, 2018, to December 9, 2019. Included were participants 50 years or older with nAMD and active subfoveal choroidal neovascularization lesions. Intravitreal injection of SB11 or RBZ, 0.5 mg, every 4 weeks through week 48. Serum antidrug antibodies (ADAs) were analyzed during the study period until week 52 to measure immunogenicity. Analyses were performed on immunogenicity (overall ADA positivity) with best-corrected visual acuity (BCVA) and central subfield thickness (CST). Adverse events associated with intraocular inflammation (IOI) and serum ranibizumab levels were compared between overall ADA-positive and ADA-negative participants. A total of 705 participants (mean [SD] age, 74.1 [8.5] years; 403 female individuals [57.2%]) were included in the study. The overall incidence of ADA-positivity was 32 of 657 (4.9%) at week 52. The least-squares mean (SE) differences between overall ADA-positive and ADA-negative participants up to week 52 for BCVA and CST, respectively, were 1.6 (2.2) letters (95% CI, -2.7 to 5.8; P = .46) and 3 (13) μm (95% CI, -23 to 29; P = .83). IOI-related events occurred in 1 of 32 overall ADA-positive participants (3.1%) and 4 of 620 overall ADA-negative participants (0.6%). Mean (SD) serum ranibizumab concentrations over time were slightly lower in overall ADA-positive participants compared with those of ADA-negative participants, with a maximum value of 1389.3 (875.4) pg/mL at week 16 vs 1665.4 (1124.0) pg/mL at week 36, respectively. Results of this post hoc analysis of an equivalence trial suggest that immunogenicity was not associated with efficacy and safety of SB11 and RBZ in participants with nAMD. With a low overall ADA incidence, no clear association was identified between overall ADA positivity and pharmacokinetics. These findings support the biosimilarity of SB11 and RBZ, with no safety concern identified for SB11 vs RBZ associated with immunogenicity. ClinicalTrials.gov Identifier: NCT03150589.

Oral administration of CU06-1004 attenuates vascular permeability and stabilizes neovascularization in retinal vascular diseases

Retinal vascular diseases are the leading cause of blindness worldwide. These diseases have common disease mechanisms including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation. Treatment of these diseases with laser therapy, anti-VEGF injections and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying cause of the pathology and may have harmful side effects. Pathological processes that damage retinal vessels result in vascular occlusion and impairment of the barrier properties of retinal endothelial cells, leading to excessive vascular leakage. Therefore, a new therapeutic approach is needed for the treatment of retinal vascular disease. We were able to confirm that oral administration of CU06-1004, an endothelial dysfunction blocker, inhibited retinal vascular leakage induced by vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). Interestingly, oral administration of CU06-1004 prevented excessive vascular leakage in the diabetic retinopathy model. In addition, CU06-1004 inhibited angiogenesis and confirmed vascular stabilization in the oxygen-induced retinopathy model and laser-induced CNV model. Taken together, CU06-1004 could be a potential therapeutic agent for the treatment of retinal vascular diseases.

Both non-coated and polyelectrolytically-coated intraocular collagen-alginate composite gels enhanced photoreceptor survival in retinal degeneration

Treatments of vision-threatening retinal diseases are often hampered by drug delivery difficulties. Polyelectrolytically-coated alginate encapsulated-cell therapy (ECT) systems have shown therapeutic efficacy through prolonged in vivo drug delivery but still face various biocompatibility, viability, drug delivery and mechanical stability issues in clinical trials. Here, novel, injectable alginate-poly-l-lysine (AP)-coated composite alginate-collagen (CAC) ECT gels were developed for sustained ocular drug delivery, and their long-term performance was compared with non-coated CAC ECT gels. All optimised AP-coated gels (AP1- and AP5.5-CAC ECT: 2 mg/ml collagen, 1.5% high molecular weight alginate, 50,000 cells/gel, with 0.01% or 0.05% poly-l-lysine coating for 5 min, followed by 0.15% alginate coating) and non-coated gels showed effective cell proliferation control, cell viability support and continuous delivery of bioactive glial cell-derived neurotrophic factor (GDNF) with no significant gel degradation in vitro and in rat vitreous. Most importantly, intravitreally injected gels demonstrated therapeutic efficacy in Royal College of Surgeons rats with retinal degeneration, resulting in reduced photoreceptor apoptosis and retinal function loss. At 6 months post-implantation, no host-tissue attachment or ingrowth was detected on the retrieved gels. Non-coated gels were mechanically more stable than AP5.5-coated ones under the current cell loading. This study demonstrated that both coated and non-coated ECT gels can serve as well-controlled, sustained drug delivery platforms for treating posterior eye diseases without immunosuppression.

Considerations for the Use of Photobiomodulation in the Treatment of Retinal Diseases.

Photobiomodulation (PBM) refers to the beneficial effect produced from low-energy light irradiation on target cells or tissues. Increasing evidence in the literature suggests that PBM plays a positive role in the treatment of retinal diseases. However, there is great variation in the light sources and illumination parameters used in different studies, resulting in significantly different conclusions regarding PBM's therapeutic effects. In addition, the mechanism by which PBM improves retinal function has not been fully elucidated. In this study, we conducted a narrative review of the published literature on PBM for treating retinal diseases and summarized the key illumination parameters used in PBM. Furthermore, we explored the potential molecular mechanisms of PBM at the retinal cellular level with the goal of providing evidence for the improved utilization of PBM in the treatment of retinal diseases.

A hypothetical therapeutic effect of light peripheral panretinal photocoagulation in neovascular age-related macular degeneration.

Vascular endothelial growth factor (VEGF) is a significant modulator of ocular angiogenesis, including that of neovascular age-related macular degeneration (nAMD). Intravitreal injection of anti-VEGF is the benchmark treatment for most retinal vascular diseases, including nAMD, diabetic maculopathy, and macular edema secondary to retinal venous occlusion. Anti-VEGF treatment is a high-frequency, time-consuming, non-cost-effective therapy, especially in countries and regions with limited resources. This treatment is easily restricted, and in practice, maintaining long-term periodic care is challenging for patients. Light peripheral panretinal photocoagulation (PPRP) is applied in a mild form (barely visible mild light gray mark) anterior to the equator so as not to jeopardize the visual field. PPRP lessens the ischemia that causes neovascularization and decreases the metabolic demand in the peripheral retina. PPRP reduces serum angiopoietin-2 and VEGF levels in patients with type 2 diabetes mellitus with proliferative diabetic retinopathy. We propose using light PPRP to suppress VEGF secretion, aiming to attenuate the VEGF drive and halt choroidal neovascular growth in eyes with nAMD. Our regimen is based on two concepts: first, nAMD is a diffuse or generalized disease that affects the posterior segment; and second, PPRP is very effective in regressing diabetic retinopathy. PPRP has reportedly been successful in cases of macular edema (diabetic or following venous occlusion) resistant to VEGF antagonists. Light PPRP may be used as prophylaxis, adjunctive treatment, or monotherapy in nAMD when intravitreal injections of VEGF antagonists are not feasible. The established light PPRP therapy could be promising as a one-time, cost-effective therapy or prophylaxis in patients with nAMD or at high risk. This proposed modality could be suitable for patients who have injection phobia or prefer a one-time affordable therapy to the long-term monthly visits to retinologists. Future trials are necessary to verify the safety and efficacy of this proposed treatment modality in selected patients with nAMD.

Induced Pluripotent Stem Cells and Genome-Editing Tools in Determining Gene Function and Therapy for Inherited Retinal Disorders.

Inherited retinal disorders (IRDs) affect millions of people worldwide and are a major cause of irreversible blindness. Therapies based on drugs, gene augmentation or transplantation approaches have been widely investigated and proposed. Among gene therapies for retinal degenerative diseases, the fast-evolving genome-editing CRISPR/Cas technology has emerged as a new potential treatment. The CRISPR/Cas system has been developed as a powerful genome-editing tool in ophthalmic studies and has been applied not only to gain proof of principle for gene therapies in vivo, but has also been extensively used in basic research to model diseases-in-a-dish. Indeed, the CRISPR/Cas technology has been exploited to genetically modify human induced pluripotent stem cells (iPSCs) to model retinal disorders in vitro, to test in vitro drugs and therapies and to provide a cell source for autologous transplantation. In this review, we will focus on the technological advances in iPSC-based cellular reprogramming and gene editing technologies to create human in vitro models that accurately recapitulate IRD mechanisms towards the development of treatments for retinal degenerative diseases.

Retinal Degeneration: Molecular Mechanisms and Therapeutic Strategies.

Retinal degenerative diseases are the main retinal diseases that threaten vision. Most retinal degenerative diseases are inherited diseases, including autosomal recessive inheritance, autosomal dominant inheritance, X-linked inheritance, and mitochondrial inheritance; therefore, emerging gene therapy strategies may provide an alternative method of treatment. Currently, three viral vectors are usually used in gene therapy studies: adenovirus, lentivirus, and adeno-associated virus. Other gene therapies have their own advantages, such as DNA nanoparticles, antisense oligonucleotides, and gene editing therapies. In addition, retinal degenerative diseases are often accompanied by abnormalities of retinal cells, including photoreceptor and retinal pigment epithelial cells. At present, stem cell transplantation is a promising new treatment for retinal degenerative diseases. Common sources of stem cells include retinal progenitor cells, induced pluripotent stem cells, embryonic stem cells, and mesenchymal stem cells. In addition, retina explant cultures in vitro can be used as an effective platform for screening new therapies for retinal degenerative diseases. Drugs that actually reach the retinal layer are more controlled, more consistent, and less invasive when using retinal explants. Furthermore, studies have shown that the imbalance of the gut microbiota is closely related to the occurrence and development of diabetic retinopathy. Therefore, the progression of diabetic retinopathy may be restrained by adjusting the imbalance of the gut microbiota. The purpose of this review is to discuss and summarize the molecular mechanisms and potential therapeutic strategies of retinal degenerative diseases.

Eye drops for retinal disease

AbstractUsing topical application to deliver drugs to the posterior segment of the eye remains a challenge. Posterior segment diseases are currently treated by intravitreal injection or implant. Eye drop formulations based on γ‐cyclodextrin (γCD)‐based nanoparticle aggregates were developed and deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye in animal models and clinical studies. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops showed clinical effect in a range of human conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, inflammation after cataract surgery and postoperative treatment in trabeculectomy. A multicentre, double‐masked, parallel‐group, randomized, Phase 2 study was performed to evaluate topical dexamethasone ophthalmic suspension in diabetic macular edema (DME). One hundred and forty four patients aged 18–85 years with DME of <3 years duration, ETDRS central subfield thickness ≥ 310 μm by SD‐OCT and ETDRS letter score ≤ 73 and ≥ 24 in the study eye were randomized 2:1 to OCS‐01 or matching vehicle, 1 drop 3 times/day for 12 weeks. Efficacy was evaluated as change from baseline to Week 12 of ETDRS letter score and central macular thickness (CMT). Mean CMT showed a greater decrease from baseline with OCS‐01 (N = 99) than vehicle (N = 45) at Week 12 (−53.6 vs −16.8 μm, p = 0.0115). Mean change in ETDRS letter score from baseline to Week 12 met the p was +2.6 letters with topical OCS‐01 and 1 letter with vehicle (p = 0.125). In a post‐hoc analysis, there was a greater difference in patients with baseline BCVA ≤65 letters, the OCS‐01 group improved 3.8 letters compared with 0.9 letters with vehicle. OCS‐01 was well‐tolerated, and increased intraocular pressure was the most common adverse event. Cyclodextrin nanoparticle eye drops deliver drugs to the retina in therapeutically relevant concentrations and promise a non‐invasive alternative in drug treatment of retinal diseases.

Optogenetic Therapy for Visual Restoration.

Optogenetics is a recent breakthrough in neuroscience, and one of the most promising applications is the treatment of retinal degenerative diseases. Multiple clinical trials are currently ongoing, less than a decade after the first attempt at visual restoration using optogenetics. Optogenetic therapy has great value in providing hope for visual restoration in late-stage retinal degeneration, regardless of the genotype. This alternative gene therapy consists of multiple elements including the choice of target retinal cells, optogenetic tools, and gene delivery systems. Currently, there are various options for each element, all of which have been developed as a product of technological success. In particular, the performance of optogenetic tools in terms of light and wavelength sensitivity have been improved by engineering microbial opsins and applying human opsins. To provide better post-treatment vision, the optimal choice of optogenetic tools and effective gene delivery to retinal cells is necessary. In this review, we provide an overview of the advancements in optogenetic therapy for visual restoration, focusing on available options for optogenetic tools and gene delivery methods.

Noninvasive Delivery of Self-Regenerating Cerium Oxide Nanoparticles to Modulate Oxidative Stress in the Retina.

Diseases affecting the retina, such as age-related macular degeneration (AMD), diabetic retinopathy, macular edema, and retinal vein occlusions, are currently treated by the intravitreal injection of drug formulations. These disease pathologies are driven by oxidative damage due to chronic high concentrations of reactive oxygen species (ROS) in the retina. Intravitreal injections often induce retinal detachment, intraocular hemorrhage, and endophthalmitis. Furthermore, the severe eye pain associated with these injections lead to patient noncompliance and treatment discontinuation. Hence, there is a critical need for the development of a noninvasive therapy that is effective for a prolonged period for treating retinal diseases. In this study, we developed a noninvasive cerium oxide nanoparticle (CNP) delivery wafer (Cerawafer) for the modulation of ROS in the retina. We fabricated Cerawafer loaded with CNP and determined its SOD-like enzyme-mimetic activity and ability to neutralize ROS generated in vitro. We demonstrated Cerawafer's ability to deliver CNP in a noninvasive fashion to the retina in healthy mouse eyes and the CNP retention in the retina for more than a week. Our studies have demonstrated the in vivo efficacy of the Cerawafer to modulate ROS and associated down-regulation of VEGF expression in the retinas of very-low-density lipoprotein receptor knockout (vldlr-/-) mouse model. The development of a Cerawafer nanotherapeutic will fulfill a hitherto unmet need. Currently, there is no such therapeutic available, and the development of a Cerawafer nanotherapeutic will be a major advancement in the treatment of retinal diseases.

Hydrogen sulfide protects retinal pigment epithelium cells against ferroptosis through the AMPK- and p62-dependent non-canonical NRF2-KEAP1 pathway

Oxidative stress-induced ferroptosis of retinal pigment epithelium (RPE) cells contributes to retinal degenerative diseases. The antioxidant molecule hydrogen sulfide (H2S) regulates oxidative stress response, but its effect on the ferroptosis of RPE cells is unclear. In this study, sodium hydrosulfide (NaHS) was used as an exogenous H2S donor to intervene tert-butyl hydroperoxide (t-BHP)-induced ferroptosis of APRE-19 cells. We found that NaHS pretreatment attenuates t-BHP-induced oxidative stress and ferroptosis. Analysis of mRNA-sequencing coupled with FerrDb database identified nuclear factor erythroid-2-related factor 2 (NRF2) as a primary target for the cytoprotective role of H2S. NRF2 inhibitor ML385 reverses the effects of H2S on ferroptosis. Biochemical analysis revealed that H2S stabilizes NRF2. H2S decreases the interaction between NRF2 and KEAP1, but enhances the interaction between KEAP1 and p62. These results suggest that H2S activates the non-canonical NRF2-KEAP1 pathway. Further study demonstrated that H2S stimulates AMPK to interact and phosphorylate p62. Additionally, inhibiting AMPK or knocking down p62 blocks the effects of H2S. We speculate that targeting the non-canonical NRF2-KEAP1 pathway by H2S-based drug may benefit the treatment of retinal degenerative diseases.

3K3A-Activated Protein C Prevents Microglia Activation, Inhibits NLRP3 Inflammasome and Limits Ocular Inflammation.

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with pleiotropic cytoprotective properties albeit without the bleeding risks. The anti-inflammatory activities of 3K3A-APC were demonstrated in multiple preclinical injury models, including various neurological disorders. We determined the ability of 3K3A-APC to inhibit ocular inflammation in a murine model of lipopolysaccharide (LPS)-induced uveitis. Leukocyte recruitment, microglia activation, NLRP3 inflammasome and IL-1β levels were assessed using flow cytometry, retinal cryosection histology, retinal flatmount immunohistochemistry and vascular imaging, with and without 3K3A-APC treatment. LPS triggered robust inflammatory cell recruitment in the posterior chamber. The 3K3A-APC treatment significantly decreased leukocyte numbers and inhibited leukocyte extravasation from blood vessels into the retinal parenchyma to a level similar to controls. Resident microglia, which underwent an inflammatory transition following LPS injection, remained quiescent in eyes treated with 3K3A-APC. An inflammation-associated increase in retinal thickness, observed in LPS-injected eyes, was diminished by 3K3A-APC treatment, suggesting its clinical relevancy. Finally, 3K3A-APC treatment inhibited inflammasome activation, determined by lower levels of NLRP3 and its downstream effector IL-1β. Our results highlight the anti-inflammatory properties of 3K3A-APC in ocular inflammation and suggest its potential use as a novel treatment for retinal diseases associated with inflammation.

Model predictive control for retinal laser treatment at 1 kHz

Abstract Laser photocoagulation is a technique applied in the treatment of retinal disease, which is often done manually or using simple control schemes. We pursue an optimization-based approach, namely Model Predictive Control (MPC), to enforce bounds on the peak temperature and, thus, to ensure safety during the medical treatment procedure – despite the spot-dependent absorption of the tissue. The desired laser repetition rate of 1 kHz is renders the requirements on the computation time of the MPC feedback a major challenge. We present a tailored MPC scheme using parametric model reduction, an extended Kalman filter for the parameter and state estimation, and suitably tuned stage costs and verify its applicability both in simulation and experiments with porcine eyes. Moreover, we give some insight on the implementation specifically tailored for fast numerical computations.

Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases.

Retinal ischemia, often associated with various disorders such as diabetic retinopathy (DR), retinal vein occlusion, glaucoma, optic neuropathies, stroke, and other retinopathies, is a major cause of visual impairment and blindness worldwide. As proper blood supply to the retina is critical to maintain its high metabolic demand, any impediment to blood flow can lead to a decrease in oxygen supply, resulting in retinal ischemia. In the pathogenesis of DR, including diabetic macular edema (DME), elevated blood glucose leads to blood-retina barrier (BRB) disruptions, vascular leakage, and capillary occlusion and dropouts, causing insufficient delivery of oxygen to the retina, and ultimately resulting in visual impairment. Other potential causes of DR include neuronal dysfunction in the absence of vascular defect, genetic, and environmental factors. The exact disease progression remains unclear and varies from patient to patient. Vascular leakage leading to edema clearly links to visual impairment and remains an important target for therapy. Despite recent advances in the treatment of DME and DR with anti-VEGFs, effective therapies with new mechanisms of action to address current treatment limitations regarding vessel regeneration and reperfusion of ischemic retinal areas are still needed. The Wnt signaling pathway plays a critical role in proper vascular development and maintenance in the retina, and thus provides a novel therapeutic approach for the treatment of diabetic and other retinopathies. In this review, we summarize the potential of this pathway to address treatment gaps with current therapies, its promise as a novel and potentially disease modifying therapy for patients with DR and opportunities in other retinal vascular diseases.

Pluripotent Stem Cells in Clinical Cell Transplantation: Focusing on Induced Pluripotent Stem Cell-Derived RPE Cell Therapy in Age-Related Macular Degeneration.

Human pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represent valuable cell sources to replace diseased or injured tissues in regenerative medicine. iPSCs exhibit the potential for indefinite self-renewal and differentiation into various cell types and can be reprogrammed from somatic tissue that can be easily obtained, paving the way for cell therapy, regenerative medicine, and personalized medicine. Cell therapies using various iPSC-derived cell types are now evolving rapidly for the treatment of clinical diseases, including Parkinson's disease, hematological diseases, cardiomyopathy, osteoarthritis, and retinal diseases. Since the first interventional clinical trial with autologous iPSC-derived retinal pigment epithelial cells (RPEs) for the treatment of age-related macular degeneration (AMD) was accomplished in Japan, several preclinical trials using iPSC suspensions or monolayers have been launched, or are ongoing or completed. The evolution and generation of human leukocyte antigen (HLA)-universal iPSCs may facilitate the clinical application of iPSC-based therapies. Thus, iPSCs hold great promise in the treatment of multiple retinal diseases. The efficacy and adverse effects of iPSC-based retinal therapies should be carefully assessed in ongoing and further clinical trials.

Влияние интравитреального введения эпидермального фактора роста на морфофункциональное состояние глаза кролика

Purpose. To study the morphofunctional state of the rabbit eye after intravitreal injection of epidermal growth factor. Material and methods. In an experiment on rabbits, intravitreal course administration of Eberprot-P containing recombinant epidermal growth factor (EGF) at a dose of 100 ng was carried out. 7 and 30 days after each injection, biomicroscopy and ophthalmoscopy of the eye, optical coherence tomography (OCT) of the fundus in vivo were performed. Morphological studies were performed according to the generally accepted method with staining of histological preparations with hematoxylin and eosin. The cell density of the ganglionic layer, the inner and outer nuclear layers of the retina was assessed. SPSS software for Windows was used for statistical analysis. Results. Biomicroscopic and ophthalmoscopic studies of the intraocular structures of the experimental eyes did not reveal signs of edema or intraocular inflammation, toxic or irritant effects of intravitreal injection. There were no pathological changes in the form of cataracts, Tyndall's phenomenon in the anterior chamber moisture, vitreous opacities, retinal infiltrates. According to OCT data, the retinal thickness remained unchanged: 158 ± 5µm versus the control 158 ± 3µm (p = 1.0), no retinal wrinkling effects were detected. The morphological picture of the intraocular tissues of the eye after intravitreal injection was characterized by the absence of any pathological changes in the architectonics of the layers and cellular structures of the retina. Histomorphometric analysis showed no difference in the cell density of the ganglion layer, inner and outer nuclear layers of the retina of the experimental and control eyes of animals. Conclusion. Intravitreal application of EGF in rabbits does not cause intraocular specific inflammation or any destructive effects in the retina, which indicates the potential for its clinical use in the treatment of dystrophic retinal diseases. Keywords: epidermal growth factor, retina, intravitreal injection, morphology, histomorphometry

A systematic review and meta-analysis of the effect of intravitreal VEGF inhibitors on cardiorenal outcomes.

Vascular endothelial growth factor inhibitors (VEGFis) have transformed the treatment of many retinal diseases, including diabetic maculopathy. Increasing evidence supports systemic absorption of intravitreal VEGFi and development of significant cardiorenal side effects. We conducted a systematic review and meta-analysis (PROSPERO: CRD42020189037) of randomised controlled trials of intravitreal VEGFi treatments (bevacizumab, ranibizumab and aflibercept) for any eye disease. Outcomes of interest were cardiorenal side effects (hypertension, proteinuria, kidney function decline and heart failure). Fixed effects meta-analyses were conducted where possible. There were 78 trials (81 comparisons; 13 175 participants) that met the criteria for inclusion: 47% were trials in diabetic eye disease. Hypertension (29 trials; 8570 participants) was equally common in VEGFi and control groups {7.3 versus 5.4%; relative risk [RR] 1.08 [95% confidence interval (CI) 0.91-1.28]}. New or worsening heart failure (10 trials; 3384 participants) had a similar incidence in VEGFi and control groups [RR 1.03 (95% CI 0.70-1.51)]. Proteinuria (5 trials; 1902 participants) was detectable in some VEGFi-treated participants (0.2%) but not controls [0.0%; RR 4.43 (95% CI 0.49-40.0)]. Kidney function decline (9 trials; 3471 participants) was similar in VEGFi and control groups. In participants with diabetic eye disease, the risk of all-cause mortality was higher in VEGFi-treated participants [RR 1.62 (95% CI 1.04-2.46)]. In trials of intravitreal VEGFi, we did not identify an increased risk of cardiorenal outcomes, although these outcomes were reported in only a minority of cases. There was an increased risk of death in VEGFi-treated participants with diabetic eye disease. Additional scrutiny of post-licensing observational data may improve the recognition of safety concerns in VEGFi-treated patients.