Inner blood-retina barrier involvement in dry age-related macular degeneration(AMD) pathology

Age-relatedmaculardegeneration(AMD)isaprogressiveneurodegenerative disease with a global prevalence of 8.7%in people over the age of 45. It is one of the leading causes of central retinal blindness in the industrialized world leading to loss of an individual’s ability to read, drive and see fine details, such as recognition of faces. By 2040, it is estimated that 288 million individuals worldwide will be diagnosed with AMD due to improved life expectancy(Wong et al., 2014).

Narrative review of risuteganib for the treatment of dry age-related macular degeneration (AMD)

Age-related macular degeneration(AMD)is a leading cause of blindness worldwide.AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neurosensory retina.Currently,there are limited treatment options for dry AMD outside of lifestyle modification and nutrient supplementation.Risuteganib[Luminate(ALG-1001),Allegro Ophthalmics,CA,USA]is an intravitreally administered inhibitor of integrin heterodimersαVβ3,αVβ5,α5β1,andαMβ2.It is currently undergoing clinical trials for the treatment of dry AMD and diabetic macular edema(DME).Preclinical studies have shown that risuteganib has an effect on the pathways for angiogenesis,inflammation,and vascular permeability.Ongoing clinical trials have had promising results showing improvements in patient best corrected visual acuity(BCVA)and reduced central macular thickness measured by optical coherence tomography(OCT).There is a pressing need for treatments for dry AMD and while risuteganib appears to have a potential benefit for patients,more data are needed before one can truly evaluate its efficacy.This narrative review provides a concise summary of the most up to date data regarding the proposed mechanism of action of risuteganib in the treatment of nonexudative AMD and DME as well as the results from recent phase 1 and phase 2 clinical trials.

AB105.Database of retinal images in visually impaired individuals:drusen and age-related macular degeneration(AMD)

Background:With a large portion of older adults living longer,the number of individuals diagnosed with low vision is increasing.The use of optical coherence tomography/scanning laser ophthalmoscope(OCT/SLO)to diagnose retinal disease has become common place in the last 10 years,yet currently there are no OCT/SLO databases for pathological vision.Our aim is to develop a clinical database of individuals who have drusen(i.e.,lipid deposits found under the retina),or have been diagnosed with age-related macular degeneration(AMD),with information as to how the structure of the diseased retina changes over time,as well as measures of visual and cognitive functional performance.Methods:Fundus photographs and retinal scans will be taken using the same model of optos OCT/SLO located in three test sites(MAB-Mackay Rehabilitation Centre,School of Optometry Clinic at the University of Montreal,and the Lighthouse Institute,New York,USA).For each individual entry in the database,demographic and diagnosis information will be available.All OCT/SLO images will be graded according to the Age-related Eye Disease Study standard,in addition to number and size of drusen,severity of geographic atrophy,severity of pigment mottling and presence of choroidal neovascularization.Retinal topography and Raster scans from the OCT/SLO will provide a cross-sectional look at affected retinas.Fixation stability will be recorded using the SLO function,and present four different tasks that are designed to reproduce typical tasks of daily vision,with each task lasting for 10 seconds.The tasks are cross fixation,face recognition,visual search,and reading.These tasks in addition to the retinal scans will be used to determine the eccentricity of a preferred retinal locus from the anatomical fovea,and can be used as an outcome measure for clinical interventions in visually impaired patients.Results:The database will be available to professors training eye-care practitioners and rehabilitation specialists as a teaching tool.Students will be able to familiarize themselves with the retina and a variety of AMD-related pathologies before they start working with patients.The database will also be accessible by researchers interested in studying AMD from basic science to epidemiology,to investigate how drusen and AMD impact visual and cognitive functional performance.Conclusions:The common infrastructure is easily accessible to all VHRN members on request.The database will also be accessible online in 2018(see http://cvl.concordia.ca for more information).

The complexities underlying age-related macular degeneration： could amyloid beta play an important role？

e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.

Efficacy and safety of ranibizumab for wet age-related macular degeneration in Chinese patients

AIM： To evaluate the clinical efficacy and safety of ranibizumab for wet age-related macular degeneration （wAMD） in Chinese patients and to determine the mean number of injections administered over one year of follow-up. METHODS： This single centre, retrospective observational case series study included data from 121 patients with wAMD （121 eyes） who were diagnosed by indirect ophthalmoscopy, fluorescence fundus angiography （FFA）, indocyanine green angiography, and optical coherence tomography. Ranibizumab was injected into the vitreous cavities once per month for 3mo and as needed afterwards. Changes in visual acuity and central foveal thickness （CFT） during the follow-up period were compared, and the mean number of injections over the year was calculated. Patients with one or more adverse events related to the drugs and injections were recorded for further adverse events analysis.RESULTS： The study population included 70 males and 51 females aged between 50 and 87y （mean： 71.32±9.41y）. The mean number of injections over the first year was 5±1 （range： 3-9）. The mean best-corrected visual acuity by Early Treatment Diabetic Retinopathy Study increased from 43.2±19.3 （95%CI： 39.8-46.7） at baseline to 51.7±20.1 （95%CI： 48.1-55.3）, and central foveal thickness （CFT） decreased from 526.5±277.0 μm （95%CI： 476.6-576.4） to 258.2±161.6 μm （95%CI： 229.2-287.3） at 12mo. The differences were statistically significant （P〈0.001）. Visual acuity significantly improved in 34.1% of the patients （38 eyes）, stabilized in 66.1% of the patients （80 eyes）, and significantly decreased in 2.5% of the patients （3 eyes）. CFT at baseline was an independent risk factor of decreased CFT and increased visual acuity. None of the patients had severe adverse events during the follow-up period.CONCLUSION： Ranibizumab can effectively control disease progression and improve visual acuity in patients with wAMD. The disease conditions of most patients stabilized after a one-year treatment with an average of 5 injections.

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 500000 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.

Comment on “Intravitreal conbercept injection for neovascular age-related macular degeneration”

Dear Editor,We would like to address several issues with the study of Wu et al[1],which can be specifically summarized below.The study was retrospectively conducted with a pretty high proportion of patients(23.80%)lost until the end of the followup period.

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C（IL-17RC）,a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration（AMD）,was associated with altered activation of phosphatidylinositide 3-kinase（PI3K）,Akt,and glycogen synthase kinase 3（GSK3）.We wondered whether or not altered PI3 K,Akt,and GSK3 activities could be detected in peripheral blood mononuclear cells（PBMC） obtained from AMD patients.In the patients＇ PBMC,absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed,which was accompanied with increased phosphorylation of GSK3 substrates（e.g.CCAAT enhancer binding protein a,insulin receptor substrate 1,and TAU）,indicative of enhanced GSK3 activation.In addition,decreased protein mass of PI3K85α and tyrosinephosphorylation of PI3K50α was present in PBMC of the AMD patients,suggesting impaired PI3 K activation.Moreover,abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients.These data demonstrate that despite the presence of high levels of IL-17 RC,Wnt-3a and vascular endothelial growth factor,the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients.Thus,measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

Implication of gut microbiome in age-related macular degeneration

Age-related macular degeneration(AMD) is the most common cause of blindness in the United States in adults over 55 years of age and is one of the leading global causes of blindness: at least 196 million of the worldwide population have AMD, and prevalence is projected to rise to 288 million by 2040(Lin et al., 2021). As cases and disease burden increase, improvements in the characterization of AMD pathobiology and exploration of potential therapeutic solutions are necessary first steps in addressing this global health concern.

Macular pigment and serum zeaxanthin levels with Goji berry supplement in early age-related macular degeneration

AIM： To evaluate the efficacy of Goji berry supplementation on improving macular pigment, serum zeaxanthin levels and visual acuity in patients with early age-related macular degeneration （AMD）. METHODS： A total of 114 patients （aged from 51 to 92y, mean age 69.53±8.41y） with early AMD were enrolled in our prospective, randomized controlled study. The included patients were assigned randomly to the Goji group （n=57） with 25 g of Goji berries supplementation per day for 90d and the control group （n=57） with their normal diet for 90d. Macular pigment optical density （MPOD） was measured using heterochromatic flicker photometry （HFP）. The levels of serum lutein （L）/zeaxanthin （Z） were analyzed using high-performance liquid chromatography （HPLC）. MPOD, serum L/Z levels and best corrected visual acuity （BCVA） were recorded at baseline and 90d. RESULTS： In the Goji group, there were no statistically significant differences in the serum L levels between the baseline （0.199±0.149 μmol/mL） and 90d （0.203±0.181 μmol/mL） （t=-0.186, P=0.850）; however the serum Z levels were increased at 90d （0.101±0.087 μmol/mL） compared with those at the baseline （0.029±0.032 μmol/mL） （t=6.412, P〈0.001）. Patients treated with Goji berry for 90d showed an elevated MPOD （0.877±0.202 DU） from the baseline （0.731±0.205 DU） （t=-4.741, P=0.000）. In contrast to the control group, the serum Z levels and MPOD were higher in the Goji group at 90d （both P〈0.05）. At 90d, patients with Goji berry supplementation had a relative decrease in BCVA （0.21±0.18 logMAR） compared with the baseline （0.27±0.20） （t=2.397, P=0.020）. CONCLUSION： Overall, daily supplementation with Goji berry for 90d improves MPOD by increasing serum Z levels rather than serum L levels in early AMD patients. Goji berry may be an effective therapeutic intervention for preventing the progression of early AMD.

VISUAL REHABILITATION IN LOW VISION PATIENTS WITH AGE-RELATED MACULAR DEGENERATION

Using optical visual aids, visual rehabilitation was performed in 14 low vision patients(25 eyes) with age-related macular degeneration. With distance aids, visual acuity improvement appeared in 24 eyes(95%) out of the 25 eyes. Twelve eyes(48%) obtained a visual acuity equal to or better than 0.4. With near visual aids, near acuity of all eyes(100%) was improved. Thirteen eyes(52%) got the near vision equal to or better than 0.5. Ten patients could read No.5 Chinese Reading Card. The reading success rat...

Sodium iodate-induced retina degeneration observed in non-separate sclerochoroid/retina pigment epithelium/retina whole mounts

Background:Sodium iodate(SI)is a chemical widely applied to induce retina degeneration in animal models.SI treatment caused formation of rosettes/folds in the outer nuclear layer(ONL)of the rat retina,but it was previously unclear whether SI also forms rosettes in mice.In addition,SI induced retina degeneration was never addressed in non-separate sclerochoroid/retina pigment epithelium/retina whole mount.Here we displayed features of retina degeneration including rosette formation in mice and developed a morphological analytic assessment using sclerochoroid/retina pigment epithelium/retina whole mounts.Methods:SI was intraperitoneally injected in Sprague-Dawley(SD)rats and C57BL/6J mice using a single dose(50 mg/kg)or with a dose range(10 to 50 mg/kg)in BALB/C mice.Rat retinas were investigated up to 2-week post-injection by histology and whole mounts,and mouse retinas were investigated up to 3-week post-injection by histology,fluorescent staining of sections and/or sclerochoroid/retina pigment epithelium/retina whole mounts for the morphological evaluations of the SI-induced retina damage.Results:SI-induced retina damage caused photoreceptor(PR)degeneration and rosettes/folds formation,as well as retina pigment epithelium degeneration and inward migration.It displayed mixed nuclei from choroid to PRs,due to layer disorganization,as shown by single horizontal images in the sclerochoroid/retina pigment epithelium/retina whole mounts.Measurement of the PR rosette area induced by SI provided a quantitative,morphological evaluation of retina degeneration.Conclusions:The method of non-separate sclerochoroid/retina pigment epithelium/retina whole staining and mount allows us to observe the integral horizontal view of damage from sclera to PR layers,which cannot be addressed by using sectioned and separate whole mount methods.This method is applicable for morphological evaluation of retina damage,especially in the subretinal layer.

Vascular changes in age-related macular degeneration

Age-related macular degeneration(AMD)is considered one of the principal causes of vision impairment among older individuals in developed countries.Assuming this,new technologies which may increment insights elucidating the morphological characteristics of this disorder are expected to improve the visual prognosis in AMD.The development of optical coherence tomography angiography(OCTA)has outstandingly extended our knowledge on the AMD pathophysiology.

Therapeutic potential of translocatorprotein ligands for age-related macular degeneration

Age-related macular degeneration:Agerelated macular degeneration(AMD)is a retinal degenerative disorder,characterized by the irreversible loss of the central vision during ageing.This chronic,progressive disease has been estimated to currently affect around 196 million people worldwide and will increase to 288 million in 2040(Wong,et al.,2014).Early AMD is defined by the presence of drusen underneath the retinal pigment epithelial(RPE)layer.Late AMD can be divided into two groups,"wet AMD"and"dry AMD",depending on the underlying clinical features.

AGE-RELATED MACULAR DEGENERATION: CURRENT ASPECTS OF PATHOGENESIS AND TREATMENT

About 1.1 million people are estimated to have age-related macular degeneration in West Germany. Anatomical aspects of the normal macula and physiological ageing processes in the retina will be discribed including alterations in the choroid, in Bruch's membrane, the pigment epithelium and the sensory retina. Risk factors for the development of age-related macular degeneration are age per se, perhaps ethnologic characteristics, ocular characteristics, and perhaps environmental factors. The histopathology...

Predicting the future:initial treatment response in neovascular age-related macular degeneration correlates strongly with long-term visual acuity

Age-related macular degeneration(AMD)is a sight-threatening disease and responsible for 8.7%of blindness globally(1).Neovascular AMD(nAMD)is characterized by abnormal angiogenesis with these atypical vessels leaking,resulting in fluid accumulation,haemorrhage and fibrosis which can lead to rapid central vision loss(2).Although nAMD makes up 15%of total AMD cases(2),it is responsible for the majority of cases of severe visual loss(3).

Five-year outcomes with anti-vascular endothelial growth factor in neovascular age-related macular degeneration:results of the Comparison of Age-related Macular Degeneration Treatments Trials

Age-related macular degeneration(AMD)is the leading cause of irreversible blindness in the elderly in industrialized countries(1,2).Current treatments for AMD are severely limited and only the wet form can be treated with anti-vascular endothelial growth factor(anti-VEGF).Although anti-VEGF is a palliative treatment,this drug dramatically improves the prognosis for patients with this disease(3).For example,in a population-based study in Denmark,the incidence of legal blindness from AMD was reduced by 50%after 2006(4).

Treatment options for the wet form of age-related macular degeneration--a perspective

Treatment of the wet form of age-related macular degeneration(wet AMD) has been revolutionized a decade ago with the introduction of vascular endothelial growth factor(VEGF) blockers that reduce neovascularization and macular edema. Two approved drugs are marketed for the treatment of wet AMD—ranibizumab and aflibercept, but there is a third drug, bevacizumab, which is widely used offlabel; a cancer drug that also blocks VEGF but was never tested in pivotal trials and never approved for ophthalmic indications including wet AMD. Similarity of bevacizumab to ranibizumab led to off-label use and even to government-sponsored studies comparison the approved ranibizumab head-to-head to the offlabel cancer drug bevacizumab in wet AMD, like the Comparison of Age-related Macular Degeneration Treatments Trials(CATT) study, discussed in this perspective paper. Recent publication of 5-year follow-up from the initial 2-year CATT study provided the occasion to discuss the similarities and differences between these two drugs and the lessons learned from the last decade of anti-VEGF therapy for wet AMD. Clinical efficacy is comparable, with an advantage for ranibizumab. Likewise, safety finding favor ranibizumab over bevacizumab in some aspects. The latest addition of approved anti-VEGF drugs for wet AMD, aflibercept, may provide even more benefit to patients. In this perspective we discuss results of CATT and other longterm follow-up and comparative studies. While all demonstrate clinical benefit of anti-VEGF, all reveal that most patients' loose visual acuity(VA) in real-life situations over 5–7 years. This loss is based on—what we believe—significant under-treatment of wet AMD patients, due to economic or practical limitations and overestimation of perceived risks as geographic atrophy. We compare own data that showed more intensive treatment(more than twice the CATT-follow-up injections) with ranibizumab or aflibercept can maintain a sustained gain in VA in wet AMD patients after 6 years. We encourage retina specialists to treat wet AMD patients more aggressively and frequently in order to provide the maximum benefit for their patients.

Statins for age related macular degeneration: promising but unproven

Statins are used widely to treat hypercholesterolemia and atherosclerotic cardiovascular disease.They have inflammatory and immunomodulatory effects potentially useful for managing systemic autoimmune diseases such as rheumatoid arthritis,lupus erythematosus and multiple sclerosis.Statins also have anti-oxidative and large-vessel endothelial supportive properties that occur independent of their lipid-lowering effects.Additionally,statins can suppress macrophage and microglial activation responsible for initiating inflammatory cytokine release.More than forty percent of adults aged 65 years or older use statins in the United States and Australia,a prevalence that increases with age.The effects of statin usage on ophthalmic practice are probably underrecognized.Cardiovascular disease and age-related macular degeneration(AMD)share common risk factors,consistent with the“vascular model”of AMD pathogenesis that implicates impaired choroidal circulation in Bruch’s membrane lipoprotein accumulation.AMD has a complex multifactorial pathogenesis involving oxidative stress,choroidal vascular dysfunction,dysregulated complement-cascade-mediated inflammation and pro-inflammatory and pro-angiogenic growth factors.Many of these components are hypothetically amenable to the primary(cholesterol lowering)and secondary(anti-inflammatory,anti-oxidative,anti-vasculopathy)effects of statin use.Experimental studies have been promising,epidemiological trails have produced conflicting results and three prospective clinical trials have been inconclusive at demonstrating the value of statin therapy for delaying or preventing AMD.Cumulative evidence to date has failed to prove conclusively that statins are beneficial for preventing or treating AMD.

Novel mitochondrial therapies for the treatment of age-related macular degeneration

The purpose of this article is to review current literature and data regarding treatment options for age-related macular degeneration(AMD)related to mitochondrial therapy.This article considers the presence of flavoprotein fluorescence as a potential biomarker to test the effectiveness of the treatments.We focus primarily on two major mitochondrial targets,nuclear factor erythroid 2-related factor(NFE2L2)and PGC-1α,that function in controlling the production and effects of reactive oxidative species(ROS)directly in the mitochondria.PU-91 is an FDA approved drug that directly targets and upregulates PGC-1αin AMD cybrid cell lines.Although neither NFE2L2 nor PGC1-αhave yet been tested in clinical trials,their effects have been studied in rodent models and offer promising results.MTP-131,or elamipretide®,and metformin are two drugs in phase II clinical trials that focus on the treatment of advanced,non-exudative AMD.MTP-131 functions by associating with cardiolipin(CL)whereas metformin targets adenosine-monophosphate protein kinase(AMPK)in the mitochondria.The current results of their clinical trials are elucidated in this article.The molecular targets and drugs reviewed in this article show promising results in the treatment of AMD.These targets can be further pursued to improve and refine treatment practices of this diagnosis.