Therapy For Age-related Macular Degeneration Research Articles

Retinal pigment epithelium in the pathogenesis of age-related macular degeneration and photobiomodulation as a potential therapy?

The retinal pigment epithelium (RPE) comprises a monolayer of cells located between the neuroretina and the choriocapillaries. The RPE serves several important functions in the eye: formation of the blood-retinal barrier, protection of the retina from oxidative stress, nutrient delivery and waste disposal, ionic homeostasis, phagocytosis of photoreceptor outer segments, synthesis and release of growth factors, reisomerization of all-trans-retinal during the visual cycle, and establishment of ocular immune privilege. Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. Dysfunction of the RPE has been associated with the pathogenesis of AMD in relation to increased oxidative stress, mitochondrial destabilization and complement dysregulation. Photobiomodulation or near infrared light therapy which refers to non-invasive irradiation of tissue with light in the far-red to near-infrared light spectrum (630-1000 nm), is an intervention that specifically targets key mechanisms of RPE dysfunction that are implicated in AMD pathogenesis. The current evidence for the efficacy of photobiomodulation in AMD is poor but its safety profile and proposed mechanisms of action motivate further research as a novel therapy for AMD.

Real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors.

Clinical trials identified intravitreal vascular endothelial growth factor inhibitors (anti-VEGF agents) have the potential to stabilise or even improve visual acuity outcomes in neovascular age-related macular degeneration (AMD), a sight-threatening disease. Real-world evidence allows us to assess whether results from randomised controlled trials can be applied to the general population. We describe the development of global registries, in particular the Fight Retinal Blindness! registry that originated in Australia, the United Kingdom AMD Electronic Medical Records User Group and the IRIS registry in the USA. Real-world observations relating to efficacy, safety and resource utilisation of intravitreal anti-VEGF therapy for neovascular AMD are then summarised. Novel observations that would have been challenging to identify in a clinical trial setting are then highlighted, including the risk of late disease reactivation, outcomes in second versus first treated eyes, and the increased risk of posterior capsular rupture during cataract surgery in patients who have received intravitreal anti-VEGF therapy. We conclude by exploring future directions in the field. This includes the development of a global consensus on real-world outcome measures to allow greater comparison of results. Real-world neovascular AMD outcome registries can be linked with other databases to determine systemic safety or genetic predictors of treatment efficacy. Machine learning offers opportunities to extract useful insights from "Big Data" often collected in these registries. Real-world registries could be used by drug regulatory authorities and industry as an alternative to more costly and time-consuming phase 4 clinical trials, potentially allowing medication costs to be based on outcomes achieved.

Anti-VEGF therapy for age-related macular degeneration

To evaluate the clinical effectiveness of aflibercept in treatment of patients with neovascular age-related macular degeneration (nAMD). The first group included 156 treatment-naive nAMD patients (156 eyes). The second group consisted of 29 patients (38 eyes) with nAMD who had previously received at least 3 loading injections of 0.5 mg ranibizumab but exhibited no morphological effect from the therapy. All patients included in the study were treated with 2.0 mg aflibercept. The follow-up period was 13 months. In the first group, the average number of injections was 5.1±0.39. A change in best corrected visual acuity (BCVA) after three loading injections was observed in all eyes of the group and amounted to 0.43±0.2. The final visual acuity was 0.47±0.22. After the first injection, central retinal thickness (CRT) in all patients of the group decreased to 346.14±54.53 μm; by the end of treatment it was 281.64±34 μm. Dry macula was achieved in 109 patients (69.9%), which corresponded to the highest BCVA of 0.84±0.14. In 26 patients (16.7%), subretinal fluid (SRF) remained and visual acuity was 0.57±0.22; 14 patients (9%) had pigment epithelium detachment (PED) and visual acuity of 0.63±0.08. Presence of residual intraretinal fluid (IRF) in 7 patients (4.5%) reliably defined the lowest functional result of 0.1±0.22. In the second group, 100% of patients after the first injection of aflibercept had decreased retinal thickness (by an average of 36.99 μm), while the increase in visual acuity was noted only after 3 injections in 67.5% of the eyes. By the end of the follow-up, CRT was 231.44±18.4 μm, decreased on average by 83.65 μm, and the final BCVA was 0.31±0.19. The number of injections was 5.7±1.7. Aflibercept can be used as the first choice drug in the treatment of nAMD for it improves the anatomical parameters of the retina and the visual functions.

Cell Transplantation for Retinal Degeneration: Transition from Rodent to Nonhuman Primate Models.

Transplantation of potentially therapeutic cells into the subretinal space is a promising prospective therapy for the treatment of retinal degenerative diseases including age-related macular degeneration (AMD). In rodent models with photoreceptor degeneration, subretinal transplantation of cell suspensions has repeatedly been demonstrated to rescue behaviorally measured vision, maintain electrophysiological responses from the retina and the brain, and slow the degeneration of rod and cone photoreceptors for extended periods. These studies have led to the initiation of a number of FDA-approved clinical trials for application of cell-based therapy for AMD and other retinal degenerative diseases. However, translation from rodent models directly into human clinical trials skips an important intermediary preclinical step that is needed to address critical issues for intraocular cell transplantation. These include determination of the most appropriate and least problematic surgical approach, the application of treatment in an eye with similar size and structure including the presence of a macula, and a thorough understanding of the immunological considerations regarding graft survival and the consequences of grafted cell rejection. This chapter will review these and related issues and will document current efforts to address these concerns.

Polarized Human Retinal Pigment Epithelium Exhibits Distinct Surface Proteome on Apical and Basal Plasma Membranes.

Surface proteins localized on the apical and basal plasma membranes are required for a cell to sense its environment and relay changes in ionic, cytokine, chemokine, and hormone levels to the inside of the cell. In a polarized cell, surface proteins are differentially localized on the apical or the basolateral sides of the cell. The retinal pigment epithelium (RPE) is an example of a polarized cell that performs a variety of functions that are dependent on its polarized state including trafficking of ions, fluid, and metabolites across the RPE monolayer. These functions are absolutely crucial for maintaining the health and integrity of adjacent photoreceptors, the photosensitive cells of the retina. Here we present a series of approaches to identify and validate the polarization state of cultured primary human RPE cells using immunostaining for RPE apical/basolateral markers, polarized cytokine secretion, electrophysiology, fluid transport, phagocytosis, and identification of plasma membrane proteins through cell surface capturing technology. These approaches are currently being used to validate the polarized state and the epithelial phenotype of human induced pluripotent stem (iPS) cell derived RPE cells. This work provides the basis for developing an autologous cell therapy for age-related macular degeneration using patient specific iPS cell derived RPE.

Association of Mortality with Ocular Diseases and Visual Impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13

To evaluate the association of mortality with visual acuity (VA) impairment, age-related macular degeneration (AMD), and cataract surgery. Cohort study. Participants with at least intermediate AMD enrolled in a randomized controlled clinical trial of lutein/zeaxanthin and/or omega-3 fatty acids, the Age-Related Eye Disease Study 2 (AREDS2), for treatment of AMD and cataract. Baseline and annual eye examinations included best-corrected visual acuity (BCVA) assessments, slit-lamp examinations, and stereoscopic fundus photographs that were centrally graded for development of late AMD (central geographic atrophy or neovascular AMD) or pseudophakia. Cause-specific mortality was determined on the basis of the International Classification of Diseases 9th or 10th Revision codes. Risk of all-cause and cause-specific mortality was assessed with Cox proportional hazards models adjusted for age, sex, AMD severity, VA, history of cataract surgery, and assigned AREDS2 study treatment. Analyses included baseline covariates: race, education, smoking status, diabetes, and cardiovascular disease. During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared with participants with no or few drusen (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.21-2.01; P < 0.001). Poorer survival was associated with bilateral cataract surgery before enrollment compared with baseline bilateral phakia (HR, 1.63; 95% CI, 1.29-2.07; P < 0.001) and with BCVA of less than 20/40 compared with participants with 20/40 or better (HR, 1.56; 95% CI, 1.06-2.30; P= 0.024), adjusted for age, sex, and statistically significant covariates. Participants who received antivascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR, 0.71; 95% CI, 0.57-0.88; P= 0.002). The association between all-cause mortality and AREDS2 treatment whether assessing the main or individual treatment effect was not significantly different (omega-3 fatty acids main effect HR, 1.18; 95% CI, 0.96-1.45; P= 0.12; lutein/zeaxanthin main effect HR, 1.04; 95% CI, 0.85-1.28; P= 0.71). In AREDS2, the presence of late AMD, bilateral cataract surgery, and VA less than 20/40 was associated with decreased survival. However, oral supplementation with omega-3 fatty acids, lutein plus zeaxanthin, zinc, or beta-carotene had no statistically significant impact on mortality.

Age-related macular degeneration: using morphological predictors to modify current treatment protocols.

To assess predictors of treatment response in neovascular age-related macular degeneration (AMD) in an attempt to develop a patient-centric treatment algorithm. We conducted a systematic search using PubMed, EMBASE and Web of Science for prognostic indicators/predictive factors with the key words: 'age related macular degeneration', 'neovascular AMD', 'choroidal neovascular membrane (CNV)', 'anti-vascular endothelial growth factor (anti-VEGF)', 'aflibercept', 'ranibizumab', 'bevacizumab', 'randomized clinical trials', 'post-hoc', 'prognostic', 'predictive', 'response' 'injection frequency, 'treat and extend (TAE), 'pro re nata (PRN)', 'bi-monthly' and 'quarterly'. We only included studies that had an adequate period of follow-up (>1year), a single predefined treatment regimen with a predetermined re-injection criteria, an adequate number of patients, specific morphological [optical coherence tomography (OCT)] criteria that predicted final visual outcomes and injection frequency and did not include switching from one drug to the other. We were able to identify seven prospective studies and 16 retrospective studies meeting our inclusion criteria. There are several morphological and demographic prognostic indicators that can predict response to therapy in wet AMD. Smaller CNV size, subretinal fluid (SRF), retinal angiomatous proliferation (RAP) and response to therapy at 12weeks (visual, angiographic or OCT) can all predict good visual outcomes in patients receiving anti-VEGF therapy. Patients with larger CNV, older age, pigment epithelial detachment (PED), intraretinal cysts (IRC) and vitreomacular adhesion (VMA) achieved less visual gains. Patients having VMA/VMT required more intensive treatment with increased treatment frequency. Patients with both posterior vitreous detachment (PVD) and SRF require infrequent injections. Patients with PED are prone to recurrences of fluid activity with a reduction in visual acuity (VA). A regimen that involves less intensive therapy and extended follow-up intervals (4weekly) can be suggested for patients who show adequate visual response and have both SRF and PVD at baseline. In addition, patients with poor prognostic indicators such as IRC, VMA, large CNV size, older age and poor response at 12weeks should be extended very cautiously with the possibility of fixed monthly/bimonthly (every 2months) treatments if they fail to achieve dryness. Patients with PED at baseline should receive monthly/bimonthly injections of anti-VEGF therapy or can be extended very cautiously (two weekly intervals) using a TAE protocol.

Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway.

The design of efficient therapies for age-related macular degeneration (AMD) is limited by our understanding of the pathogenesis of basal deposits, which form between retinal pigment epithelium (RPE) and Bruch's membrane (BrM) early in disease, and involve activation of the complement system. To investigate the roles of BrM, RPE and complement in an AMD, we generated abnormal extracellular matrix (ECM) using CRISPR-edited ARPE-19 cells. We introduced to these cells the p.R345W mutation in EFEMP1, which causes early-onset macular degeneration. The abnormal ECM binds active complement C3 and causes the formation of basal deposits by normal human fetal (hf)RPE cells. Human fetal RPE (hfRPE) cells grown on abnormal ECM or BrM explants from AMD donors show chronic activation of the alternative complement pathway by excessive deposition of C3b. This process is exacerbated by impaired ECM turnover via increased matrix metalloproteinase-2 activity. The local cleavage of C3 via convertase-independent mechanisms can be a new therapeutic target for early AMD.

Geographic and Demographic Variation in Use of Ranibizumab Versus Bevacizumab for Neovascular Age-related Macular Degeneration in the United States

To examine demographic and geographic variation in the use of ranibizumab and bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) among Medicare beneficiaries. Retrospective cohort study. Using a 100% sample of Medicare claims data, we evaluated Medicare beneficiaries (N= 195 812) with an index claim for neovascular AMD between July 1, 2006, and June 30, 2009, to determine whether beneficiaries first received ranibizumab or bevacizumab following initial diagnosis. The overall proportion of beneficiaries that first received ranibizumab for neovascular AMD was 35%, and varied significantly (0.9%-84.6%) across the 306US hospital referral regions (median= 33%, interquartile range=17%-49%). Based on hierarchical logistic regression models, the likelihood of receiving ranibizumab declined over time (adjusted odds ratio (aOR) comparing treatment in 2009 vs 2006= 0.39, P < .001). After we controlled for year of treatment, black beneficiaries were 45% less likely to receive ranibizumab compared to non-blacks (P < .0001). Beneficiaries residing in urban areas (aOR vs isolated rural towns=1.12, P < .001), in zip codes with higher median incomes, and in the New England and East South Central census regions (aOR vs Pacific census region= 5.57, P<.001; aOR= 3.58, P < .001, respectively) had increased odds of receiving ranibizumab. The odds of receiving bevacizumab vs ranibizumab as initial therapy for neovascular AMD among US Medicare beneficiaries varied substantially across geographic and demographic groups. Relatively fewer patients received ranibizumab for initial neovascular AMD treatment in 2009 vs 2006. Future research should study the drivers of variation in utilization of these interventions, the extent this variation indicates differential access to these agents, and whether treatment choice impacts patient outcomes.

Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System.

Gene therapies will only become a widespread tool in the clinical treatment of human diseases with the advent of gene transfer vectors that integrate genetic information stably, safely, effectively, and economically. Two decades after the discovery of the Sleeping Beauty (SB) transposon, it has been transformed into a vector system that is fulfilling these requirements. SB may well overcome some of the limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are being used in the majority of ongoing clinical trials. The SB system has achieved a high level of stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, representing crucial steps that may permit its clinical use in the near future. This article reviews the most important aspects of SB as a tool for gene therapy, including aspects of its vectorization and genomic integration. As an illustration, the clinical development of the SB system toward gene therapy of age-related macular degeneration and cancer immunotherapy is highlighted.

Development of a Refined Protocol for Trans-scleral Subretinal Transplantation of Human Retinal Pigment Epithelial Cells into Rat Eyes.

Degenerative retinal diseases such as age-related macular degeneration (AMD) are the leading cause of irreversible vision loss worldwide. AMD is characterized by the degeneration of retinal pigment epithelial (RPE) cells, which are a monolayer of cells functionally supporting and anatomically wrapping around the neural retina. Current pharmacological treatments for the non-neovascular AMD (dry AMD) only slow down the disease progression but cannot restore vision, necessitating studies aimed at identifying novel therapeutic strategies. Replacing the degenerative RPE cells with healthy cells holds promise to treat dry AMD in the future. Extensive preclinical studies of stem cell replacement therapies for AMD involve the transplantation of stem cell-derived RPE cells into the subretinal space of animal models, in which the subretinal injection technique is applied. The approach most frequently used in these preclinical animal studies is through the trans-scleral route, which is made difficult by the lack of direct visualization of the needle end and can often result in retinal damage. An alternative approach through the vitreous allows for direct observation of the needle end position, but it carries a high risk of surgical traumas as more eye tissues are disturbed. We have developed a less risky and reproducible modified trans-scleral injection method that uses defined needle angles and depths to successfully and consistently deliver RPE cells into the rat subretinal space and avoid excessive retinal damage. Cells delivered in this manner have been previously demonstrated to be efficacious in the Royal College of Surgeons (RCS) rat for at least 2 months. This technique can be used not only for cell transplantation but also for delivery of small molecules or gene therapies.

Development of a Refined Protocol for Trans-scleral Subretinal Transplantation of Human Retinal Pigment Epithelial Cells into Rat Eyes

Degenerative retinal diseases such as age-related macular degeneration (AMD) are the leading cause of irreversible vision loss worldwide. AMD is characterized by the degeneration of retinal pigment epithelial (RPE) cells, which are a monolayer of cells functionally supporting and anatomically wrapping around the neural retina. Current pharmacological treatments for the non-neovascular AMD (dry AMD) only slow down the disease progression but cannot restore vision, necessitating studies aimed at identifying novel therapeutic strategies. Replacing the degenerative RPE cells with healthy cells holds promise to treat dry AMD in the future. Extensive preclinical studies of stem cell replacement therapies for AMD involve the transplantation of stem cell-derived RPE cells into the subretinal space of animal models, in which the subretinal injection technique is applied. The approach most frequently used in these preclinical animal studies is through the trans-scleral route, which is made difficult by the lack of direct visualization of the needle end and can often result in retinal damage. An alternative approach through the vitreous allows for direct observation of the needle end position, but it carries a high risk of surgical traumas as more eye tissues are disturbed. We have developed a less risky and reproducible modified trans-scleral injection method that uses defined needle angles and depths to successfully and consistently deliver RPE cells into the rat subretinal space and avoid excessive retinal damage. Cells delivered in this manner have been previously demonstrated to be efficacious in the Royal College of Surgeons (RCS) rat for at least 2 months. This technique can be used not only for cell transplantation but also for delivery of small molecules or gene therapies.

Steroid Therapy in Wet-Form (Neovascular) Age-Related Macular Degeneration

Wet-form (neovascular) age-related macular degeneration (AMD) is characterized by the development of choroidal neovascularization. Pathogenesis of disease involves inflammation, angiogenesis, and fibrosis through complex mechanisms that have interactions among different cytokines. Although anti- VEGF agents are the gold standard in treatment, the main goal of the effective treatment for wet AMD is to inhibit all mechanisms involved in pathogenesis, including inflammatory cascades. In addition to the anti-inflammatory effects steroids reduce the permeability of choroidal cells and are anti-angiogenic via suppressing vascular endothelial growth factor expression. Triamcinolone and dexamethasone are the steroids used in monotherapy and combination therapy in wet AMD; nevertheless studies had shown that these steroids may stabilize or gain vision and provide fewer treatment procedures.

Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage

Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated. In this study, we characterized mitochondrial and cellular damage in transmitochondrial cybrid cell lines that contain identical nuclei but possess mitochondria from either AMD or age-matched normal (Older-normal (NL)) subjects. AMD cybrids showed (1) reduced levels of cell viability, lower mtDNA copy numbers, and downregulation of mitochondrial replication/transcription genes and antioxidant enzyme genes; and (2) elevated levels of genes related to apoptosis, autophagy and ER-stress along with increased mtDNA fragmentation and higher susceptibility to amyloid-β-induced toxicity compared to NL cybrids. In AMD cybrids, HNG protected the AMD mitochondria, reduced pro-apoptosis gene and protein levels, upregulated gp130 (a component of the HN receptor complex), and increased the protection against amyloid-β-induced damage. In summary, in cybrids, damaged AMD mitochondria mediate cell death that can be reversed by HNG treatment. Our results also provide evidence of Humanin playing a pivotal role in protecting cells with AMD mitochondria. In the future, it may be possible that AMD patient’s blood samples containing damaged mitochondria may be useful as biomarkers for this condition. In conclusion, HNG may be a potential therapeutic target for treatment of dry AMD, a debilitating eye disease that currently has no available treatment. Further studies are needed to establish HNG as a viable mitochondria-targeting therapy for dry AMD.

Magnetic nanoparticles conjugated with "RPE cell -MCP-1 antibody -VEGF antibody" compounds for the targeted therapy of age-related macular degeneration: a hypothesis.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly throughout the world. Treatment of AMD utilizing retinal pigment epithelium (RPE) transplantation represents a promising therapy. However, simplex RPE transplantation can only replace the diseased RPE cells, but has no abilities to stop the development of AMD. It has been indicated that oxidization triggers the development of AMD by inducing the dysfunction and degeneration of RPE cells, which results in the upregulation of local monocyte chemotactic protein-1 (MCP-1) expression. MCP-1 induces macrophage recruiment which triggers local inflammation. As a result, the expression of vascular endothelial growth factor (VEGF) is upregulated by MCP-1 mediated inflammation and results in the formation of choroidal neovascularization (CNV). We accordingly propose a targeted therapy of AMD by subretinal transplanting the compound of RPE cell, MCP-1 antibody, and VEGF antibody and using a magnetic system to guide RPE cell compounds conjugated with superparamagnetic iron oxide nanoparticles (SPIONs). Furthermore, SPION-labelled RPE cells can be tracked and detected in vivo by non-invasive magnetic resonance imaging (MRI). This novel RPE cell transplantation methodology seems very promising to provide a new therapeutic approach for the treatment of AMD.

Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning.

PurposeTo evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD).MethodsWe retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid (“good response”) was achieved and whether recurrence was observed within 3 months (“dependent”) after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA) for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey’s test to evaluate the difference between baseline and postinjection VA.ResultsAmong the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001), and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months.ConclusionThe evaluation of response to and dependence on anti-vascular endothelial growth factor therapies in AMD was useful and practical in managing therapeutic protocols to obtain a good VA.

Nutritional Therapy in Dry-form (Non-Neovascular) Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a progressive degenerative disorder of the macula in which central vision becomes impaired and leading cause of blindness in adults older than 55 years. Multiple factors have been proposed for the pathogenesis of AMD including genetic susceptibility interacting with environmental and systemic health factors. Nowadays, treatment options for dry-form AMD are limited. Among these treatments, nutritional therapy is at the forefront. This review mentions about the nutritional therapy in dry-type AMD.

Cell Therapy for Age-Related Macular Degeneration: A New Vision for the Bone Marrow?

In this issue of Molecular Therapy, Qi et al.1 report that a cell therapy can improve retinal structure and vision in a mouse model of age-related macular degeneration (AMD). AMD is the leading cause of severe and irreversible central vision loss in the elderly, affecting over 1.7 million Americans.2 The authors made use of bone marrow-derived cells (BMDCs) that had been engineered to stably express RPE65 protein (BMDC-RPE65). RPE65 is a marker of the retinal pigment epithelium (RPE) that degenerates in AMD.

Retinal Nerve Fiber Loss in Anti-VEGF Therapy for Age-Related Macular Degeneration Can Be Decreased by Anterior Chamber Paracentesis

Purpose: To analyze peripapillary retinal nerve fiber layer thickness (RNFLT) change after long-term intravitreal anti-VEGF therapy. Patients with regular anterior chamber paracentesis (ACP) prior to intravitreal injections (IVIs) were compared to those without ACP. Methods: Neovascular age-related macular degeneration (nAMD) was treated in a pro re nata regimen with a minimum of 9 IVIs. RNFLT change was determined in spectral domain optical coherence tomography. Results: In 32 patients without ACP, mean RNFLT loss (-2.16 ± 3.60 µm) was significantly higher than in 44 patients with regular ACP (0.16 ± 3.60; p = 0.029). Both groups were comparable in age (75.0 vs. 76.8 years; p = 0.35), number of IVIs (16.2 vs. 16.6; p = 0.98), and observational time (30.0 vs. 32.3 months; p = 0.32). In patients without ACP, RNFLT loss was higher compared to IVI-naive fellow eyes (p = 0.005), whereas in ACP patients, no difference was detected (p = 0.5). Conclusions: A moderate RNFLT loss is found in nonglaucomatous patients after injection therapy for nAMD. As it is decreased with regular ACP, tight management of intraocular pressure seems advisable.

Technical approaches to induce selective cell death of pluripotent stem cells.

Despite the recent promising results of clinical trials using human pluripotent stem cell (hPSC)-based cell therapies for age-related macular degeneration (AMD), the risk of teratoma formation resulting from residual undifferentiated hPSCs remains a serious and critical hurdle for broader clinical implementation. To mitigate the tumorigenic risk of hPSC-based cell therapy, a variety of approaches have been examined to ablate the undifferentiated hPSCs based on the unique molecular properties of hPSCs. In the present review, we offer a brief overview of recent attempts at selective elimination of undifferentiated hPSCs to decrease the risk of teratoma formation in hPSC-based cell therapy.