Therapy For Age-related Macular Degeneration Research Articles

Cell-Based Therapies for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The pathogenesis of AMD involves dysfunction and loss of the retinal pigment epithelium (RPE), a monolayer of cells that provide nourishment and functional support for the overlying photoreceptors. RPE cells in mammals are not known to divide, renew or regenerate in vivo, and in advanced AMD, RPE loss leads to degeneration of the photoreceptors and impairment of vision. One possible therapeutic approach would be to support and replace the failing RPE cells of affected patients, and indeed moderate success of surgical procedures in which relatively healthy autologous RPE from the peripheral retina of the same eye was transplanted under the retina in the macular area suggested that RPE replacement could be a means to attenuate photoreceptor cell loss. This prompted exploration of the possibility to use pluripotent stem cells (PSCs) as a potential source for "healthy and young" RPE cells for such cell-based therapy of AMD. Various approaches ranging from the use of allogeneic embryonic stem cells to autologous induced pluripotent stem cells are now being tested within early clinical trials. Such PSC-derived RPE cells are either injected into the subretinal space as a suspension, or transplanted as a monolayer patch upon scaffold support. Although most of these approaches are at early clinical stages, safety of the RPE product has been demonstrated by several of these studies. Here, we review the concept of cell-based therapy of AMD and provide an update on current progress in the field of RPE transplantation.

Some Features of the Development of AMD and Other Diseases of the Posterior Pole Associated with the Virus Carrier and the Novel Coronavirus Disease COVID-19

This article highlights main aspects of pathogenesis of age-related macular degeneration (AMD) and the connection between SARS-CoV-2 and diseases of the posterior pole of the eyes. Background: A novel coronavirus disease COVID-19 is actual nowadays due to its multiple organ damage, including eye tissues. Retina is also a target organ. AMD is the most common cause of central vision loss and its development is connected not only with ageing, but also with some other factors. Last years ophthalmological community considers virus infection to be a predictor and trigger for developing of AMD. Objective: Several theories have been proposed for the development of AMD. The most common theories are vascular due to pathogenetically significant decrease in blood flow in the pool of the carotid arteries; metabolic disorders (systemic and local); oxidative stress in endothelial cells; hereditary predisposition. Inflammation as a pathogenetic mechanism appeared in a novel light of discoveries in developing of not only AMD, but also some other eye diseases. The connection between SARS-CoV-2 and diseases of the posterior pole known nowadays are conjunctivitis, central retinal vein occlusion, isolated inflammatory optic neuritis, acute bilateral demyelinating optic neuritis. Thus, the question is still open. Conclusion: no single theory of the development of AMD can absolutely explain the diversity of pathological changes in of the retina and choroid tissues. Further study of the role of each factor of pathogenesis– from molecular to tissue will allow the development of fundamentally novel and perspective directions of AMD therapy.

Integrated Analysis of DNA methylation and transcriptome profile to identify key features of age-related macular degeneration

ABSTRACT Age-related macular degeneration (AMD) is a common vision-threatening disease. The current study sought to integrate DNA methylation with transcriptome profile to explore key features in AMD. Gene expression data were obtained from the Gene Expression Omnibus (GEO, accession ID: GSE135092) and DNA methylation data were obtained from the ArrayExpress repository (E-MTAB-7183). A total of 456 differentially expressed genes (DEGs) and 4827 intragenic differentially methylated CpGs (DMCs) were identified between AMD and controls. DEGs and DMCs were intersected and 19 epigenetically induced (EI) genes and 15 epigenetically suppressed (ES) genes were identified. Immune cell infiltration analysis was performed to estimate the abundance of different types of immune cell in each sample. Enrichment scores of inflammatory response and tumor necrosis factor-alpha (TNFα) signaling via nuclear factor kappa B (NF-κb) were positively correlated with abundance of activated memory CD4 T cells and M1 macrophages. Subsequently, two significant random forest classifiers were constructed based on DNA methylation and transcriptome data. SMAD2 and NGFR were selected as key genes through functional epigenetic modules (FEM) analysis. Expression level of SMAD2, NGFR and their integrating proteins was validated in hydrogen peroxide (H2O2) and TNFα co-treated retinal pigment epithelium (RPE) in vitro. The findings of the current study showed that local inflammation and systemic inflammatory host response play key roles in pathogenesis of AMD. SMAD2 and NGFR provide new insight in understanding the molecular mechanism and are potential therapeutic targets for development of AMD therapy.

Comment on: Safety and efficacy of a nepafenac punctal plug delivery system in controlling postoperative ocular pain and inflammation after cataract surgery

We have read the article by Donnenfeld et al. regarding nepafenac sustained-delivery punctal plugs with great interest.1 The authors present promising results and significant efficacy of the alternative drug delivery system, to be used after cataract surgery instead of topical treatment. Because the outcomes in contemporary cataract surgery partially depend on patient compliance, new therapeutic approaches, such as the one presented in this study, represent an appealing alternative. In the study, patients were randomized after cataract surgery to receive a nepafenac intracanalicular insert or a placebo. Other anti-inflammatory treatment was not permitted preoperatively, intraoperatively, or postoperatively, as stated by the authors. This part of the study design raises some concerns. Routine anti-inflammatory management after cataract surgery, including corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), was not administered in the placebo arm; therefore, the patients in this group were exposed to a higher risk for adverse events.3 Such concerns were confirmed by the results of the study. More patients in the placebo group experienced pain at both day 3 (62% in the placebo group vs 31% in the treatment group) and day 7 (69% in the placebo group vs 33% in the treatment group), and worse visual acuity at day 7.1 The rescue medication protocol appears to provide a safety net for alarming levels of inflammation or pain. However, the same therapeutic hypothesis could be tested in a different research model. We believe that using a noninferiority study design could be beneficial. Since the 1990s, placebo-controlled trials have become ethically controversial if a standard treatment exists.2 A noninferiority trial aims to show that an experimental treatment is not worse than the accepted one.3 The new treatment might be safer, have better secondary endpoints, be easier to administer, or simply be less expensive. In ophthalmology, noninferiority trials are commonly applied for analyzing outcomes of age-related macular degeneration therapy and glaucoma treatment with prostaglandins. We believe that comparing the efficacy of the nepafenac insert with the accepted topical anti-inflammatory treatment is a good alternative in studies such as this one. Patients in the placebo group had worse outcomes, at least short term, and this could have been prevented with a noninferiority study design, while still offering the possibility of robust scientific scrutiny of the proposed treatment.

Multimodal imaging and electroretinography highlights the role of VEGF in the laser-induced subretinal fibrosis of monkey

Age-related macular degeneration (AMD) is a leading cause of blindness. Laser-induced nonhuman primate choroidal neovascularization (CNV) is a widely used animal model of neovascular AMD. Subretinal fibrosis (SFb) is the major limiting factor of effective anti-VEGF therapy for neovascular AMD, yet SFb has never been systematically analyzed in the primate CNV model and if VEGF directly affect SFb is unknown. We recruited a large cohort of rhesus macaques to study the occurrence, multimodal imaging and electroretinography (ERG) features, and related cytokines of SFb. Here we show that among 33 rhesus macaques, 88% CNV eyes developed SFb. Spectral domain optical coherence tomography (SD-OCT) identified four types of subretinal hyper-reflective material (SHRM) of SFb in primate. Multimodal imaging is reliable for monitoring SFb and matches the histological results well. Reduced amplitude of oscillatory potentials correlates with the thinning of inner retina layers and is a possible SFb indicator. Iba1+ microglia/macrophage cells infiltrated in the fibrotic lesions, and aqueous cytokine analysis identified four fibrosis-related factors (GM-CSF, IL-10, TGFβ2 and VEGF). Unexpectedly, we found sustained expression of VEGF may be an important inducer of SFb, and anti-VEGF therapy actually partially suppresses SFb. Taken together, our data suggest the laser-induced primate SFb model, coupled with multimodal imaging and ERG recording, is a useful system to dissect the pathogenesis and explore the rationale of treatment for SFb; and combined therapy with anti-VEGF and anti-fibrosis agents is necessary for AMD treatment.

Ophthalmic Drops with Nanoparticles Derived from a Natural Product for Treating Age-Related Macular Degeneration.

There is a continuing, urgent need for an ophthalmic (eye) drop for the clinical therapy of age-related macular degeneration (AMD), a leading cause of blindness. Here, we report the first formulation of an eye drop that is effective via autophagy for AMD treatment. This eye drop is based on a single natural product derivative (ACD), which is an amphiphilic molecule containing a 6-aminohexanoate group (H2N(CH2)5COO-). We demonstrate that this eye drop reverses the abnormal angiogenesis induced in a primate model of AMD that has the pathological characteristics close to that of human AMD. The ACD molecule was self-assembled in an aqueous environment leading to nanoparticles (NPs) about 9.0 nm in diameter. These NPs were encapsulated in calcium alginate hydrogel. The resulting eye drop effectively slowed the release of ACD and displayed extended release periods in both simulated blood (pH 7.4) and inflammatory (pH 5.2) environments. We show that the eye drop penetrated both the corneal and blood-eye barriers and reached the fundus. With low cellular toxicity, the drop targeted S1,25D3-membrane-associated rapid response steroid-binding protein (1,25D3-MARRS) promoting autophagy in a dose-dependent manner. In addition, the drop inhibited cell migration and tubular formation. On the other hand, when protein 1,25D3-MARRS was knocked down, the eye drop did not exhibit such inhibition functionalities. Our study indicates that the 6-aminohexanoate group on self-assembled NPs encapsulated in hydrogel leads to the positive in vivo outcomes. The present formulation offers a promising approach for clinical treatment of human AMD.

Cell-based therapies for age-related macular degeneration: cell replacement versus paracrine effects.

Cell-based therapies for age-related macular degeneration: cell replacement versus paracrine effects.

Discovery of L-Ergothioneine as a Potential Therapy for Age-related Macular Degeneration by Antioxidants Screening

Discovery of L-Ergothioneine as a Potential Therapy for Age-related Macular Degeneration by Antioxidants Screening

Unsuccessful Trials That Investigated Therapies for Age-Related Macular Degeneration.

Unsuccessful Trials That Investigated Therapies for Age-Related Macular Degeneration.

Recent Developments in the Treatment of Wet Age-related Macular Degeneration.

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness and visual impairment in individuals over the age of 50 years in western societies. More than 25 million people currently suffer from this illness in the world, with an additional 500 000 every year, approximately. It is a multifactorial ocular disease that affects the maculae due to a late-onset progressive neurodegeneration and dysfunction of photoreceptors and retinal pigment epithelium (RPE). There are many subtypes of AMD but basically two broad forms: the nonneovascular (dry, nonexudative) and neovascular (wet, exudative). Exudative AMD is the less common form (about 15%) but tends to progress more rapidly. At the moment, wet AMD is treated primarily on the basis of anti-vascular endothelial growth factor (VEGF) agents, which have led to massive improvement in the prognosis of the disease since they were first introduced. This article focuses on the latest treatment approaches to neovascular AMD. An extensive literature review was performed in order to illustrate the effectiveness of current and future anti-VEGF agents as well as the landmark clinical studies that have been carried out to establish these drugs as a gold standard in the therapy of wet AMD.

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD)

Age-related macular degeneration is an incurable chronic neurodegenerative disease, causing progressive loss of the central vision and even blindness. Up-to-date therapeutic approaches can only slow down he progression of the disease. Objective. Feasibility study for a multilayered, silkfibroin-based, 3D biohybrid retina. Approach. Fabrication of silk fibroin-based biofilms; culture of different types of cells: retinal pigment epithelium, retinal neurons, Müller and mesenchymal stem cells ; creation of a layered structure glued with silk fibroin hydrogel. Main results. In vitro evidence for the feasibility of layered 3D biohybrid retinas; primary culture neurons grow and develop neurites on silk fibroin biofilms, either alone or in presence of other cells cultivated on the same biomaterial; cell organization and cellular phenotypes are maintained in vitrofor the seven days of the experiment. Significance. 3D biohybrid retina can be built using silksilkworm fibroinfilms and hydrogels to be used in cell replacement therapy for AMD and similarretinal neurodegenerative diseases.

Quantitative Analysis of OCT for Neovascular Age-Related Macular Degeneration Using Deep Learning

PurposeTo apply a deep learning algorithm for automated, objective, and comprehensive quantification of OCT scans to a large real-world dataset of eyes with neovascular age-related macular degeneration (AMD) and make the raw segmentation output data openly available for further research.DesignRetrospective analysis of OCT images from the Moorfields Eye Hospital AMD Database.ParticipantsA total of 2473 first-treated eyes and 493 second-treated eyes that commenced therapy for neovascular AMD between June 2012 and June 2017.MethodsA deep learning algorithm was used to segment all baseline OCT scans. Volumes were calculated for segmented features such as neurosensory retina (NSR), drusen, intraretinal fluid (IRF), subretinal fluid (SRF), subretinal hyperreflective material (SHRM), retinal pigment epithelium (RPE), hyperreflective foci (HRF), fibrovascular pigment epithelium detachment (fvPED), and serous PED (sPED). Analyses included comparisons between first- and second-treated eyes by visual acuity (VA) and race/ethnicity and correlations between volumes.Main Outcome MeasuresVolumes of segmented features (mm3) and central subfield thickness (CST) (μm).ResultsIn first-treated eyes, the majority had both IRF and SRF (54.7%). First-treated eyes had greater volumes for all segmented tissues, with the exception of drusen, which was greater in second-treated eyes. In first-treated eyes, older age was associated with lower volumes for RPE, SRF, NSR, and sPED; in second-treated eyes, older age was associated with lower volumes of NSR, RPE, sPED, fvPED, and SRF. Eyes from Black individuals had higher SRF, RPE, and serous PED volumes compared with other ethnic groups. Greater volumes of the majority of features were associated with worse VA.ConclusionsWe report the results of large-scale automated quantification of a novel range of baseline features in neovascular AMD. Major differences between first- and second-treated eyes, with increasing age, and between ethnicities are highlighted. In the coming years, enhanced, automated OCT segmentation may assist personalization of real-world care and the detection of novel structure–function correlations. These data will be made publicly available for replication and future investigation by the AMD research community.

Nanoceria Particles Are an Eligible Candidate to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment Epithelium Cell Death and Autophagy Alterations.

Retinal pigment epithelium (RPE) dysfunction and degeneration underlie the development of age-related macular degeneration (AMD), which is the leading cause of blindness worldwide. In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs or nanoceria), which are anti-oxidant agents with auto-regenerative properties, are able to preserve the RPE. On ARPE-19 cells, we found that CeO2-NPs promoted cell viability against H2O2–induced cellular damage. For the in vivo studies, we used a rat model of acute light damage (LD), which mimics many features of AMD. CeO2-NPs intravitreally injected three days before LD prevented RPE cell death and degeneration and nanoceria labelled with fluorescein were found localized in the cytoplasm of RPE cells. CeO2-NPs inhibited epithelial-mesenchymal transition of RPE cells and modulated autophagy by the down-regulation of LC3B-II and p62. Moreover, the treatment inhibited nuclear localization of LC3B. Taken together, our study demonstrates that CeO2-NPs represent an eligible candidate to counteract RPE degeneration and, therefore, a powerful therapy for AMD.

Unravelling the Role of HSP70 as the Unexplored Molecular Target in Age-Related Macular Degeneration.

The motive behind writing this paper was to highlight the relationship between heat shock protein 70 (HSP70) and age-related macular degeneration (AMD) to explore the potential role of HSP70 as a molecular target in AMD therapy. We performed a comprehensive literature search in various databases and finally found 43 relevant studies related to our objective. In our research, we found that in AMD, oxidative stress causes increased inflammation and excessive apoptosis due to the accumulation of aberrant proteins in retinal pigment epithelium (RPE) cells. The long-lasting overstimulation of the defence system leads to RPE degeneration and results in visual impairment or vision loss. However, after thorough research, it was found that HSP70's role as an immunomodulator, the guardian of the proteolytic pathway and regulator of apoptosis makes it a potential therapeutic target in AMD.

Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities.

PurposeAccumulation of the long noncoding Alu element RNA activates the NLRP3 inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the NLRP3 inflammasome. Currently, the intracellular response of the senescence marker p16Ink4a to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against Alu RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1β and of p16INK4a in RPE cells.MethodsCultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed Alu RNA, and changes in IL-18, IL-1β, and p16Ink4a expression measured in the presences of 3TC or 3,4-(M)CA as a negative control.ResultsTreatment with 3TC markedly reduced Alu RNA-induced expression of IL-18 and IL-1β in human and mouse RPE cells compared with the negative control. Further, Alu RNA-induced p16INK4a expression was suppressed by 3TC in human RPE cells.ConclusionsOur data suggest that Alu RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC.Translational RelevanceFurther verifying this study leads to potential targets for age-related macular degeneration therapy.

The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye

Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1CreERT2:TSPOfl/fl mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.

Polarization-sensitive optical coherence tomography for estimating relative melanin content of autologous induced stem-cell derived retinal pigment epithelium

Transplantation of autologous human induced pluripotent stem cell-derived retinal pigment epithelial (hiPSC-RPE) sheets is a promising therapy for age-related macular degeneration (AMD). As melanin content is a representative feature of healthy RPE, we used polarization-sensitive optical coherence tomography (PS-OCT) to estimate the relative melanin content of RPE in diseased and non-diseased area, and in human iPSC-RPE sheets in vitro and in vivo by evaluating the randomness of polarization (entropy). Two aged Japanese women, one with neovascular AMD that underwent transplantation of an autologous hiPSC-RPE cell sheet and another with binocular dry AMD, were selected for this study. Entropy value was minimal in cells containing no melanin, whereas that of human RPE and hiPSC-RPE sheets was high. En face entropy of the cultured hiPSC-RPE sheet was compared with its grey-scale photo and its values were found to be inversely correlated with the extent of absence of pigmentation in vitro. En face entropy maps were compared to colour fundus photographs, fundus autofluorescence images, and fluorescein angiography images from patients. Entropy values of intact and defective RPEs and of iPSC-RPE transplant areas were determined in vivo using PS-OCT B-scan images. PS-OCT was found to be applicable in the estimation of relative melanin content of cultured and transplanted RPEs in regenerative medicine.

Age-related macular degeneration therapy: a review.

The purpose of this review is to describe the current clinical landscape of potential future therapies for both nonexudative (dry) and exudative (wet) age-related macular degeneration (AMD). We highlight some of the more promising treatments that are furthest along in development. Patients with dry AMD have long been hoping for a highly efficacious treatment that may slow disease progression or even help regain vision. Patients with wet AMD have many effective treatment options but still there are those who have suboptimal responses or are burdened by the high frequency of treatment. We detail exciting new concepts and targets for novel medications. Specifically, for dry AMD we discuss research looking at complement inhibition, neuroprotection, visual cycle modulators, cell-based therapies, and anti-inflammatory agents. For wet AMD we summarize new, potentially more durable anti-vascular endothelial growth factor agents, extended release options, and gene therapy. There are promising new strategies for AMD. Many of the potential new treatments are in or have recently completed phase 2 or phase 3 clinical trials with promising results thus far, including some that have received US Food and Drug Administration approval. Additional therapeutic breakthroughs will likely continue to occur thanks to the number of clinical trials that are nearing the finish line.

Effects of Mitochondrial-Derived Peptides (MDPs) on Mitochondrial and Cellular Health in AMD.

Substantive evidence demonstrates the contribution of mitochondrial dysfunction in the etiology and pathogenesis of Age-related Macular Degeneration (AMD). Recently, extensive characterization of Mitochondrial-Derived Peptides (MDPs) has revealed their cytoprotective role in several diseases, including AMD. Here we summarize the varied effects of MDPs on cellular and mitochondrial health, which establish the merit of MDPs as therapeutic targets for AMD. We argue that further research to delve into the mechanisms of action and delivery of MDPs may advance the field of AMD therapy.

Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

In the present study, we investigated the association between susceptible genetic variants to age-related macular degeneration (AMD) and response to as-needed intravitreal aflibercept injection (IAI) therapy for exudative AMD including both typical neovascular AMD and polypoidal choroidal vasculopathy (PCV) over 12-months. A total of 234 patients with exudative AMD were initially treated with 3 monthly IAI and thereafter as-needed IAI over 12 months. Seven variants of 6 genes including ARMS2 A69S (rs10490924), CFH (I62V:rs800292 and rs1329428), C2-CFB-SKIV2L(rs429608), C3 (rs2241394), CETP (rs3764261) and ADAMTS-9 (rs6795735) were genotyped for all participants using TaqMan technology. After adjusting for age, gender, baseline BCVA and AMD subtype, A (protective) allele of C2-CFB-SKIV2L rs429608 was associated with visual improvement at 12-month (P = 0.003). Retreatment was associated with T(risk) allele of ARMS2 A69S (P = 2.0 × 10−4; hazard ratio: 2.18:95%CI: 1.47-3.24) and C(risk) allele of CFH rs1329428 (P = 2.0 × 10−3; hazard ratio: 1.74:95%CI: 1.16–2.59) after adjusting for the baseline confounders. The need for additional injections was also associated with T allele of ARMS2 A69S (P = 1.0 × 10−5) and C allele of CFH rs1329428 (P = 3.0 × 10−3) after adjusting for the baseline confounders. The variants of ARMS2 and CFH are informative for both physicians and patients to predict recurrence and to quantify the need for additional injections.