Therapy For AMD Research Articles

Endogenous stem cell mobilization and localized immunosuppression synergistically ameliorate DSS-induced Colitis in mice

BackgroundStem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases.MethodsReactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR.ResultsThe delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process.ConclusionThis study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.

Choroidal remodeling following different anti-VEGF therapies in neovascular AMD

The purpose of this study was to investigate choroidal morphology remodeling in AMD-associated type 1 macular neovascularization using two different anti-VEGF drugs. We registered 73 treatment-naïve eyes with a diagnosis of exudative AMD and type 1 MNV. Patients received 3 monthly intravitreal aflibercept (n = 36, aflibercept group [AG]) or brolucizumab (n = 37, brolucizumab group [BG]). Baseline best-corrected visual acuity (BCVA) and anatomical (structural optical coherence tomography) parameters were collected at “T1 control”, before the loading phase (LP) of intravitreal injection, and at “T2 control”, 1 month after the last injection. The main outcomes measured were choroidal vascularity index (CVI), sub-foveal choroidal thickness (SFCT), and central macular thickness (CMT). Our results displayed significant SFCT reduction in both groups between T1 and T2 (p < 0.05), We did not find choroidal vascularity modifications (p > 0.05) after the loading aflibercept injections. Moreover, only the BG displayed a significant choroidal remodeling (stromal choroidal area [SCA], total choroidal area [TCA] and CVI) at T2 (p < 0.05). In particular, a relevant stromal and total choroidal volume reduction was noted, accompanied by an increase in CVI. To conclude, the latter modifications of the choroidal morphology were found significant between two groups (p < 0.05). Our analysis showed a significant impact of brolucizumab on choroidal morphology in eyes affected by type 1 nAMD. This effect was found relevant when compared with aflibercept.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3

PurposeTo compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD).MethodsPatients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold.ResultsOf 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4.ConclusionOn average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration

BackgroundAge-related macular degeneration (AMD), characterized by the degeneration of retinal pigment epithelium (RPE) and photoreceptors, is the leading cause of irreversible vision impairment among the elderly. RPE senescence is an important contributor to AMD and has become a potential target for AMD therapy. HTRA1 is one of the most significant susceptibility genes in AMD, however, the correlation between HTRA1 and RPE senescence hasn’t been investigated in the pathogenesis of AMD.MethodsWestern blotting and immunohistochemistry were used to detect HTRA1 expression in WT and transgenic mice overexpressing human HTRA1 (hHTRA1-Tg mice). RT-qPCR was used to detect the SASP in hHTRA1-Tg mice and ARPE-19 cells infected with HTRA1. TEM, SA-β-gal was used to detect the mitochondria and senescence in RPE. Retinal degeneration of mice was investigated by fundus photography, FFA, SD-OCT and ERG. The RNA-Seq dataset of ARPE-19 cells treated with adv-HTRA1 versus adv-NC were analyzed. Mitochondrial respiration and glycolytic capacity in ARPE-19 cells were measured using OCR and ECAR. Hypoxia of ARPE-19 cells was detected using EF5 Hypoxia Detection Kit. KC7F2 was used to reduce the HIF1α expression both in vitro and in vivo.ResultsIn our study, we found that RPE senescence was facilitated in hHTRA1-Tg mice. And hHTRA1-Tg mice became more susceptible to NaIO3 in the development of oxidative stress-induced retinal degeneration. Similarly, overexpression of HTRA1 in ARPE-19 cells accelerated cellular senescence. Our RNA-seq revealed an overlap between HTRA1-induced differentially expressed genes associated with aging and those involved in mitochondrial function and hypoxia response in ARPE-19 cells. HTRA1 overexpression in ARPE-19 cells impaired mitochondrial function and augmented glycolytic capacity. Importantly, upregulation of HTRA1 remarkably activated HIF-1 signaling, shown as promoting HIF1α expression which mainly located in the nucleus. HIF1α translation inhibitor KC7F2 significantly prevented HTRA1-induced cellular senescence in ARPE-19 cells, as well as improved the visual function in hHTRA1-Tg mice treated with NaIO3.ConclusionsOur study showed elevated HTRA1 contributes to the pathogenesis of AMD by promoting cellular senescence in RPE through damaging mitochondrial function and activating HIF-1 signaling. It also pointed out that inhibition of HIF-1 signaling might serve as a potential therapeutic strategy for AMD.F6p4cFd4Xy8hC-VtNmT8QxVideo

The Architecture of Macular Neovascularizations Predicts Treatment Responses to Anti-VEGF Therapy in Neovascular AMD.

Introduction: Anti-VEGF therapy is an effective option for improving and stabilizing the vision in neovascular age-related macular degeneration (nAMD). However, the response to treatment is markedly heterogeneous. The aim of this study was therefore to analyze the vascular characteristics of type 1,2, and 3 macular neovascularizations (MNV) in order to identify biomarkers that predict treatment response, especially with regard to changes in intraretinal and subretinal fluid. Materials and Methods: Overall, 90 treatment-naive eyes with nAMD confirmed by optic coherence tomography (OCT), fluorescein angiography, and OCT angiography (OCTA) were included in this retrospective study. The MNV detected by OCTA were subjected to quantitative vascular analysis by binarization and skeletonization of the vessel using ImageJ. We determined their area, total vascular length (sumL), fractal dimension (FD), flow density, number of vascular nodes (numN), and average vascular diameter (avgW). The results were correlated with the treatment response to the initial three injections of anti-VEGF and the changes in intraretinal (IRF) and subretinal fluid (SRF) and the occurrence of pigment epithelial detachements (PED). Results: All patients found to have no subretinal or intraretinal fluid following the initial three injections of anti-VEGF showed a significantly smaller MNV area (p < 0.001), a lower sumL (p < 0.0005), and lesser FD (p < 0.005) before treatment than those who still exhibited signs of activity. These parameters also showed a significant influence in the separate analysis of persistent SRF (p < 0.005) and a persistent PED (p < 0.05), whereas we could not detect any influence on changes in IRF. The vascular parameters avgW, numN, and flow density showed no significant influence on SRF/IRF or PED changes. Conclusions: The size, the total vessel length, and the fractal dimension of MNV at baseline are predictors for the treatment response to anti-VEGF therapy. Therefore, particularly regarding the development of new classes of drugs, these parameters could yield new insights into treatment response.

Incidence of adverse events after loading phase of the brolucizumab therapy of neovascular AMD: Real-life evidence in the Czech Republic.

To evaluate the incidence of ocular adverse events after loading phase of the brolucizumab therapy in patients with neovascular age-related macular degeneration (nAMD) in real-life clinical practice - in treatment-naive patients and in patients after switching from another anti-VEGF agent. Another aim was to evaluate treatment outcomes in patients with adverse events. This is a multicentre, retrospective, observational study from 16 application centres in the Czech Republic. Patients diagnosed with nAMD were treated with brolucizumab in a fixed regimen of loading phase (3 injections administered at one-month intervals) and the mean follow-up period was 120 ± 10 days after the first injection. The incidence of adverse events and the development of best corrected visual acuity (BCVA) and central retinal thickness (CRT) in patients with complications were evaluated. A total of 1,098 eyes were followed up, of which 783 were treatment-naive and 315 eyes were after switching from another anti-VEGF agent. Adverse events were recorded in 42 eyes (3.83%), of which 30 eyes were treatment-naive (2.7%) and 12 eyes were post-switch (1.09%). The mean baseline BCVA ± SD was 56.7 ± 10.7 ETDRS chart letters in the group of patients with adverse events, 58.8 ± 10.1 letters in treatment-naive patients, and 51.4 ± 10.2 letters in patients after switch from another anti-VEGF agent. The mean baseline CRT ± SD was 432.2 ± 154.7 μm, being 435.8 ± 137.3 μm in treatment-naive patients and 424.5 ± 186.6 μm in patients after switch from another anti-VEGF agent. At the end of the follow-up, the mean BCVA ± SD was 53.4 ± 9.5 ETDRS charts letters in patients with adverse events, 55.6 ± 10 letters in treatment-naive patients, and 47.6 ± 10 letters in patients after switching from another anti-VEGF agent. The mean CRT ± SD at the end of the follow-up was 300.7 ± 115.7 μm in the total patient cohort, 285.2 ± 78.8 μm in treatment-naive patients and 334.5 ± 165.4 μm in patients after switching from another anti-VEGF agent. We observed the development of adverse events in the form of intraocular inflammation or vasculitis with subsequent decrease in BCVA in 3.83% of cases after loading phase of the brolucizumab therapy. The decrease in BCVA was reversible in most cases after initiation of anti-inflammatory steroid treatment. From a functional and morphological point of view, we did not demonstrate any statistically significant difference between the groups of treatment-naive patients and patients after switching from another anti-VEGF agent.

Vascular Density Changes after Nanosecond Laser Therapy in Dry AMD

Introduction: АМD is a disease of social significance and an increasing incidence. By 2040, patients are expected to reach 300 million. 90% of them have non-exudative form while only10% have exudative AMD. The nanosecond laser (2RT, Ellex) is the first patented therapy for dry AMD. It presents a new hope in the prophylaxis of the more aggressive exudative form. Aim: The aim of this study is to present an innovative treatment for dry AMD; to describe the mechanism of action of 2RT; to show first clinical results and to prove the functional efficiency of the therapy by pre and post treatment analysis of vascular density. Methods: Nanosecond laser (2RT, Ellex) was used. Patients were followed with visual acuity, contrast sensitivity (F.A.C.T.101), Fluorescein angiography (FA)Fundus auto-fluorescens (FAF), OCT, Angio-OCT. Statistical analysis of vascular density (foveal and peri-foveal superficial and deep) was done. Results: A significant improvement in vascular density in the macula was observed 3-6 months after the treatment in all patients with dry AMD. In 40% of cases a reduction of the drusen was observed. No increase of the atrophic changes was observed. Conclusions: The main goal of the treatment is to ameliorate the degenerative process by tissue stimulation and rejuvenation. Vascular density increase after 2RT treatment does prove the functional improvement and efficacy of the therapy.

Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities.

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

Transporter-Mediated Mitochondrial GSH Depletion Leading to Mitochondrial Dysfunction and Rescue with αB Crystallin Peptide in RPE Cells.

Mitochondrial glutathione (mGSH) is critical for cell survival. We recently reported the localization of OGC (SLC25A11) and DIC (SLC25A10) in hRPE. Herein, we investigated the suppression of OGC and DIC and the effect of αB crystallin chaperone peptide co-treatment on RPE cell death and mitochondrial function. Non-polarized and polarized human RPE were co-treated for 24 h with phenyl succinic acid (PS, 5 mM) or butyl malonic acid (BM, 5 mM) with or without αB cry peptide (75 µg/mL). mGSH levels, mitochondrial bioenergetics, and ETC proteins were analyzed. The effect of mGSH depletion on cell death and barrier function was determined in polarized RPE co-treated with PS, OGC siRNA or BM and αB cry peptide. Inhibition of OGC and DIC resulted in a significant decrease in mGSH and increased apoptosis. mGSH depletion significantly decreased mitochondrial respiration, ATP production, and altered ETC protein expression. αB cry peptide restored mGSH, attenuated apoptosis, upregulated ETC proteins, and improved mitochondrial bioenergetics and biogenesis. mGSH transporters exhibited differential polarized localization: DIC (apical) and OGC (apical and basal). Inhibition of mGSH transport compromised barrier function which was partially restored by αB cry peptide. Our findings suggest mGSH augmentation by its transporters may be a valuable approach in AMD therapy.

Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD.

PurposeAnti–vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome.MethodsIsraeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108).ResultsLinear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10−5. The top variant in the gene VWA3A (P = 1.77 × 10−6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was –0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline.ConclusionsAn VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.

Adding a Corticosteroid or Switching to Another Anti-VEGF in Insufficiently Responsive Wet Age-Related Macular Degeneration.

PurposeTo compare the effect of adding a corticosteroid or switching to another anti-VEGF treatment in patients with exudative age-related macular degeneration (eAMD) with persisting intraretinal fluid on anti-VEGF monotherapy.MethodsThis retrospective, interventional case series involved 43 pseudophakic eyes with eAMD and persistent intraretinal fluid on anti-VEGF treatment that switched treatment to a combination of Ozurdex® or Triamcinolone and anti-VEGF therapy (group 1) or to another anti-VEGF agent (group 2). The number of injections, time to re-injection, change in central retinal thickness (CRT), and best-corrected visual acuity (BCVA) from 12 months prior to 12 months after switch to third-line therapy were defined as primary outcomes.ResultsWhereas the treatment demand was reduced (from 8.8±2.2 to 4.6±2.9 injections; p=0.001) and the re-injection interval extended in group 1 (from 1.5±0.4 months to 4.4±3.8 months; p=0.001), these parameters did not change in group 2 (7.4±1.6 to 7.3±2.2; p=0.90 and 1.7±0.3 months to 1.9±0.8 months; p=0.75). Mean CRT decreased from 455.7±30.1 and 427.6±36.0µm (groups 1 and 2, respectively) to 359.1±38.2 and 303.1±44.4µm (intergroup p=0.03). The mean baseline BCVA of 62.6±3.8 letters (group 1) and 63.0±1.9 letters (group 2) remained stable under therapy in both groups (intergroup p=0.67).ConclusionIn eyes with eAMD with persistent intraretinal fluid on anti-VEGF monotherapy despite frequent re-injections, corticosteroids achieved a similar functional and morphological outcome over 12 months as switching to another anti-VEGF therapy, but with a reduced injection burden. In selected cases, corticosteroid treatment may thus be an option for third-line therapy in refractory exudative AMD.

Fabricating retinal pigment epithelial cell sheets derived from human induced pluripotent stem cells in an automated closed culture system for regenerative medicine.

Regenerative medicine has received a lot of attention as a novel strategy for injuries and diseases that are difficult to cure using current techniques. Cell production, which is vital for regenerative medicine, has undergone remarkable progress via breakthroughs in developmental biology and tissue engineering; currently, cell production requires numerous experimental operators performing manual, small-scale cell cultures. Other major obstacles for cell production and regenerative medicine include the variable quality of products based on the experimental procedure, the skills of operators, the level of labor required for production, and costs. Technological developments are required to overcome this, including automation instead of manual culture. Age-related macular regeneration (AMD) is a refractory ocular disease that causes severe deterioration in central vision due to senescence in the retinal pigment epithelium (RPE). Recently, we performed an autologous transplantation of induced pluripotent stem (iPS) cell-derived RPE cell sheets and started clinical research on allografts from RPE cell suspensions differentiated from iPS cells. The use of regenerative therapies for AMD using iPS cell-derived RPE is expected to become more widespread. In the present study, human iPS cell-derived RPE cells were cultured to form RPE cell sheets using equipment with a closed culture module. The quality of the automated cultured RPE cell sheets was confirmed by comparing their morphological and biological properties with those of manually generated RPE cell sheets. As a result, machine-cultured RPE sheets displayed the same quality as manually cultured RPE sheets, showing that iPS cell-derived RPE cell sheets were successfully cultured by an automated process.

Protective Effect of Hydrogen on Sodium Iodate-Induced Age-Related Macular Degeneration in Mice.

Oxidative stress is one of the main causes of AMD. Hydrogen has anti-oxidative stress and apoptotic effects on retinal injury. However, the effect of hydrogen on AMD is not clear. In this study, fundus radiography, OCT, and FFA demonstrated that HRW reduced the deposition of drusen-like structures in RPE layer, prevented retina from thinning and leakage of ocular fundus vasculature induced by NaIO3. ERG analysis confirmed that HRW effectively reversed the decrease of a-wave and b-wave amplitude in NaIO3-mice. Mechanistically, HRW greatly reduced the oxidative stress reaction through decreased MDA levels, increased SOD production, and decreased ROS content. The OGG1 expression was downregulated which is a marker of oxidative stress. Involvement of oxidative stress was confirmed using oxidative stress inhibitor ALCAR. Moreover, oxidative stress reaction was associated with expression of Sirt1 level and HRW significantly inhibited the downregulation of Sirt1 expression. This result was further confirmed with AICAR which restore Sirt1 expression and activity. In addition, NaIO3-induced retinal damage was related to apoptosis via caspase 8 and caspase 9, but not the caspase 3 pathways, which led to upregulation of Bax and p53, downregulation of Bcl-2, and increase in Jc-1-positive cells in mice. However, HRW effectively reversed these effects that apoptosis induced. These results suggest that HRW protects retinal functions against oxidative stress injury through inhibiting downregulation of Sirt1 and reducing retinal apoptosis. Therefore, we speculated that hydrogen administration is a promising treatment for AMD therapy.

Amount of Mononuclear Phagocyte Infiltrate Does Not Predict Area of Experimental Choroidal Neovascularization (CNV).

Purpose: Mononuclear phagocytes (MNPs) are present in neovascular age-related macular degeneration (nv AMD) which is also called choroidal neovascularization (CNV). The number and phenotype of the MNPs depend upon the local environment in the CNV and effect of nv AMD therapy. We investigated ocular cell infiltration and conditions that modulate angiogenesis in a laser-induced mouse CNV model.Methods: We developed assays to quantify MNPs in our established mouse CNV model. One MNP assay quantified the number of subretinal cells peripheral to the CNV lesions. A second assay semiquantitatively assesses the number of MNPs localized to the CNV lesion. We used these assays to measure the effect of toll-like receptor-2 (TLR-2) activation, anti-vascular endothelial growth factor (VEGF) therapy, and chemokine (C-C motif) ligand 2 (Ccl2) genetic deletion on MNP infiltration after laser injury.Results: Laser injury induced blood vessel growth and infiltration of MNPs. Systemic administration of a TLR-2 activating peptide increased laser-induced CNV area, MNP cell numbers, and MNP density over the CNV lesions. Systemic administration of a VEGF antibody reduced CNV area, while Ccl2 genetic deletion increased CNV area. Despite the change in amount of angiogenesis, MNP infiltration was, surprisingly, unchanged in these 2 conditions.Conclusions: MNP quantification provides biological insights for candidate AMD therapies. The number of infiltrating MNP cells does not correlate with the amount of laser-induced CNV area.

Anti-VEGF Monotherapy Versus Photodynamic Therapy and Anti-VEGF Combination Treatment for Neovascular Age-Related Macular Degeneration: A Meta-Analysis.

The purpose of this study was to compare the efficacy and safety of anti-VEGF monotherapy with verteporfin photodynamic therapy (PDT) and anti-VEGF combination treatment in neovascular AMD. This study used a meta-analysis of randomized controlled trials. We included a total of 16 studies that included 587 patients in the monotherapy group and 673 in the combination treatment group. There was no statistical difference between best corrected visual acuity (BCVA) and central retinal thickness (CRT) at end of the study and the proportions of patients who gained ≥15 BCVA letters between the two treatment groups. Nevertheless, combination therapy required fewer anti-VEGF injections than monotherapy. Subgroup analyses showed that CRT at end of the study was thinner in the standard-fluence (SF) PDT combination therapy group than in the monotherapy group (weighted mean difference [WMD]: 17.256; 95% confidence interval [CI]: 5.423∼29.089; P = 0.004). The reduced-fluence (RF) PDT combination therapy group required fewer anti-VEGF injections than the monotherapy group (WMD: 3.217; 95% CI: 2.798∼3.636; P < 0.001), while the number of anti-VEGF treatments between the SF PDT combination therapy and monotherapy groups was not statistically different (WMD: 0.23; 95% CI: -0.016∼0.475; P = 0.067). In the combination therapy group, there was no difference between the PDT + anti-VEGF versus anti-VEGF retreatment regimens. This study indicates that verteporfin PDT and anti-VEGF combination therapy is effective for achieving BCVA gain and CRT reduction comparable with that of anti-VEGF monotherapy. Combination therapy with RF PDT can potentially decrease the number of anti-VEGF injections needed.

Characterization of Human iPSC-RPE on a Prosthetic Bruch's Membrane Manufactured From Silk Fibroin

PurposeRPE cell transplantation as a potential treatment for AMD has been extensively investigated; however, in AMD, ultrastructural damage affects both the RPE and its underlying matrix support, the Bruch's membrane (BrM). An RPE monolayer supported by a surrogate scaffold could thus provide a more effective approach to cell-based therapy for AMD. Toward this goal, we aimed to establish a functional human induced pluripotent stem cell–derived (hiPSC)-RPE monolayer on a Bombyx mori silk fibroin (BMSF) scaffold.MethodsRPE differentiated from five distinct hiPSC lines were cultured on BMSF membrane coated with extracellular matrix (ECM, COL1), and either regular tissue culture plastic or Transwell coated with ECM (LAM-TCP). Morphologic, gene and protein expression, and functional characteristics of the hiPSC-RPE cultured on different membranes were compared in longitudinal experiments spanning 1 day to ≥3 months.ResultsThe hiPSC-RPE monolayers on ECM-coated BMSF and TCP could be maintained in culture for ≥3 months and displayed RPE-characteristic morphology, pigmentation, polarity, and expression of RPE signature genes and proteins. Furthermore, hiPSC-RPE on both ECM-coated BMSF and TCP displayed robust expression and secretion of several basement membrane proteins. Importantly, hiPSC-RPE cells on COL1-BMSF and LAM-TCP showed similar efficacy in the phagocytosis and degradation of photoreceptor outer segments.ConclusionsA biomaterial scaffold manufactured from silk fibroin supports the maturation and long-term survival of a functional hiPSC-RPE monolayer. This has significant implications for both in vitro disease modeling and in vivo cell replacement therapy.

Efficiency of Retinoprotective Dry AMD Therapy with Neuroprotective Therapy: a Randomized Clinical Trials Meta-analysis

Article retracted . Рurpose. А meta-analysis of randomized clinical trials of efficiency and safety of retinalamin water-soluble polypeptide retinal fractions complex neuroprotective therapy in patients with dry age-related macular degeneration (amd), conducted in russia. Мethods. Published results of various clinical trials were searched by a single investigator using the “scientific electronic library” (elibrary.ru). meta-analysis included all clinical trials of retinalamin efficacy, where its route of administration and dosage corresponded with the guidelines for medical use of retinalamin in patients with dry amd. Results. Primary search revealed 320 publications concerning retinalamin. 11 of those presented results of randomized clinical trial that satisfied the requirements, and hence were included into the meta-analysis. beside the parabulbar and intramuscular administration, prescribed officially, retinalamin was also administered subconjunctivally, with electrophoresis and with subcutaneous injections in temporal zone. in three studies the observation period is 3 months, in one study it is 5 months, in four studies it is 6 months, and in two studies it is 12 months. in the rest of studies the observation period is less than 3 months. all the studies present the changes in visual acuity right after the therapy course. meta-analysis revealed a statistically significant visual acuity improvement, best discernible in patients with areds 3 amd stage up to 6 months after retinalamin treatment. the positive dynamics in visual acuity changing persists during the first 3 months. repeated therapy courses in 3–6 months provided further progress. perimetry revealed the increasing of visual field borders and decreasing of central scotomae amount and area; the findings have also improved after the repeated course. the electrophysiology studying showed the positive dynamics as well and correlated with visual acuity changes. optical coherence tomography, blood flow examination and a series of other tests were also used. however, varying diagnostic methods in different trials as well as a low level of statistical data processing, impeded the fulfillment of a comprehensive analysis. Conclusion. Randomized clinical trial meta-analysis proved the efficacy of retinalamin therapy in patients with dry amd

Hot Topics in Dry AMD.

The global prevalence of AMD is projected to be 196 million by the year 2020. Despite substantial progress in the development of new therapies for wet AMD using inhibition of vascular endothelial growth factor (VEGF), the severe visual impairment associated with geographic atrophy in dry AMD remains untreatable. A number of therapeutic options for dry AMD are being developed and are in various stages of clinical trials. Review of literature. Enhancers of choroidal blood flow, neuroprotectants and anti-complement factors are the key targets in the research for the treatment of dry AMD. These molecules aim to promote the function of the retinal pigment epithelium and preserve the photoreceptors. New molecules are being developed for the treatment of dry AMD, and anti-complement therapy appears to be the most promising among them.

Метаанализ клинических исследований эффективности ретинопротекторной терапии «сухой» формы ВМД с применением препарата Ретиналамин® по динамике остроты зрения

Метаанализ клинических исследований эффективности ретинопротекторной терапии «сухой» формы ВМД с применением препарата Ретиналамин® по динамике остроты зрения

Comparing ranibizumab monotherapy and combination with single photodynamic therapy in wet AMD: retreatment and morphologic results.

To evaluate retreatment indications/morphologic responses to ranibizumab monotherapy and combination with verteporfin photodynamic therapy (PDT). A total of 40 patients received 3 monthly intravitreal ranibizumab 0.3 mg injections combined with either PDT or sham PDT at baseline (1:1) followed by as-needed ranibizumab based on predetermined vision/anatomical criteria. Retreatment criteria were visual acuity (VA) loss (59%/58%), central retinal thickness (CRT) increase (27%/26%), or both (14%/16%). One month before retreatment, intraretinal cysts (IRC) were present in 84%/74%, subretinal fluid (SRF) in 70%/63%, and at least one of them in 84%/89% of eyes. A significant decrease in mean leakage area, IRC, and SRF as well as a reduction in presence of hemorrhages and hard exudates occurred in both treatment groups at 12 months (compared to baseline). Retreatment indications were mostly based on VA loss, probably due to the quantitative optical coherence tomography criterion. Intraretinal cysts and SRF were earlier predictors for recurring choroidal neovascularization (CNV) activity than CRT/VA changes. Both treatment strategies were equally potent in reducing CNV activity.