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).

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.

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...

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.

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...

AB035.The link between cognitive impairment and drusen quantity in age-related macular degeneration

Background:Age-related macular degeneration(AMD)is a common cause of severe vision impairment in populations over 50 years old.It is characterized by drusen;the accumulation of waste between the retinal pigment epithelium and Bruch’s membrane.Drusen have been identified in the eyes of Alzheimer’s patients,post-mortem.Further,beta-amyloid,best known as a pathological component of the senile plaques in Alzheimer’s disease,has been identified as a component of drusen in AMD.Researchers have also demonstrated an increased prevalence of cognitive impairment in individuals with AMD.The current study uses optical coherence tomography(OCT)and a cognitive assessment to investigate the potential use of drusen as a biomarker of cognitive impairment.The overall number of drusen detectable on the OCT scans of individuals who exhibit mild cognitive impairment is compared to the number of drusen detectable on the OCT scans of individuals who do not exhibit mild cognitive impairment.Methods:To date,10 participants(nine women)aged 74 to 95 years with a diagnosis of AMD and/or drusen have been recruited.The Optos®OCT/SLO imaging system was used to take cross-sectional images of the retina.The images were then manually graded by two trained graders to determine the number of drusen present along the retina.The Montreal Cognitive Assessment(MoCA)was used to assess overall cognitive status.Results:Of the 10 participants,three passed the full MoCA(i.e.scored at or above 26 out of 30 possible points)and seven did not pass,scoring positive for mild cognitive impairment(Mpass=27.33,SDpass=0.58;Mfail=21.86,SDfail=2.55).Preliminary analyses have demonstrated that individuals who pass the MoCA seem to have fewer drusen present overall(Mdn=35)compared to those who score positive for cognitive impairment(Mdn=63).However,a Mann-Whitney U test revealed that these findings are not significant;U=5,P=0.27.Conclusions:The results agree with previous literature demonstrating an increased prevalence of mild cognitive impairment in individuals with AMD.The larger average number of drusen found in individuals who score positive for cognitive impairment points to a difference in retinal abnormalities based on cognitive status.Beyond sample size,the insignificance of the difference between groups at this stage can be explained by the number of individuals who failed the MoCA who have wet AMD(n=5).The wet AMD makes grading of drusen on OCT scans more difficult due to scarring and warping of the retina.This could result in an under-representation of the number of drusen.Data collection is still underway,and an accurate depiction is expected with a larger sample size.Researchers have also suggested the importance of peripherally located drusen and its link to cognitive impairment,therefore,future analysis will consider this as well.

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.

Choriocapillaris in non-neovascular age-related macular degeneration as evaluated by optical coherence tomography angiography

Dramatic advances in retinal imaging technology over the last two decades have significantly improved our understanding of the natural history and pathophysiology of non-neovascular age-related macular degeneration(AMD).Currently,aside from micronutrient supplements,there are no proven treatments for non-neovascular or dry AMD.Recently,a number of pharmacological agents have been evaluated or are under evaluation for treatment of patients with end-stage dry AMD manifesting as geographic atrophy(GA).It may preferable,however,to intervene earlier in the disease before the development of irreversible loss of visual function.Earlier intervention would require a more precise understanding of biomarkers which may increase the risk of progression from early and intermediate stages to the late stage of the disease.The development of optical coherence tomography angiography(OCTA)has allowed the layers of the retinal microcirculation and choriocapillaris(CC)to be visualized and quantified.Flow deficits in the CC have been observed to increase with age,particularly centrally,and these flow deficits appear to worsen with development and progression of AMD.As such,OCTA-based CC assessment appears to be a valuable new biomarker in our assessment and risk-stratification of AMD.Alterations in the CC may also provide new insights into the pathophysiology of the disease.Enhancement of choriocapillaris function may also prove to be a target of future therapeutic strategies or as a biomarker to monitor the effectiveness of therapy.As such,CC imaging may be anticipated to be an integral tool in the management of dry AMD.

AB041.A novel IL-1 receptor modulator prevents photoreceptor loss in a model of age-related macular degeneration

Background:The objective of this study is to evaluate the implications of interleukin-1β(IL-1β)in photoreceptor degeneration using a model of blue light in rodents.Methods:CD-1 mice(12-16 weeks-old)were exposed to blue LED light(6000 lux at 450 nm)for 1 hour and then sacrificed at day 3 post-illumination.Mice were intraperitoneally treated or not with a peptide antagonist of the IL-1βreceptor,named Rytvela(or 101.10)twice per day until sacrifice.Several markers related to the inflammatory process such as F4/80,NLRP3,Caspase-1,IL-1βand glial fibrillary acidic protein(GFAP)were evaluated by immunohistochemistry.Photoreceptor cell death was assessed by TUNEL assay and Caspase-3 immunofluorescence.Results:Immunofluorescence experiments revealed an infiltration of positive F4/80 cells(microglia and macrophages)into the subretinal space in mice exposed to blue light,which was significantly(P<0.01)abrogated with Rytvela treatment.Co-localization of NLRP3,Caspase-1,and IL-1βwith F4/80 positive cells was clearly detected in the subretinal space,suggesting that these inflammatory cells are the main source of IL-1β.Interestingly,GFAP immunoreactivity,a marker of stress in Müller cells,was augmented in retinas exposed to the blue light,and reduced with Rytvela administration.The TUNEL assay showed that Rytvela prevents photoreceptor apoptosis in the retina of mice exposed to blue light.Likewise,co-culture of retinal explants with LPS-ATP activated bone marrow-derived macrophages resulted in a high number of TUNEL positive photoreceptors,which was reduced by treatment with Rytvela.Conclusions:These results show that Rytvela attenuated the inflammatory response and prevented the death of photoreceptors in a model of dry AMD.Modulation of IL-1βsignaling would be a useful therapeutic avenue for dry AMD,for which no approved treatment currently exists.

AB003.Deregulated autophagy and energy-deficient photoreceptors drive angiogenesis in a model of age-related macular degeneration

Autophagy recycles intracellular substrate in part to fuel mitochondria during starvation.Deregulated autophagy caused by dyslipidemia,oxidative stress,and aging is associated with early signs of age-related macular degeneration(AMD),such as lipofuscin and perhaps drusen accumulation.Intracellular nutrient sensors for glucose and amino acids regulate autophagy.The role of lipid sensors in controlling autophagy,however,remains ill-defined.Here we will show that abundant circulating lipids trigger a satiety signal through FA receptors that restrain autophagy and oxidative mitochondrial metabolism.In the presence of excess dietary lipids,fatty acid sensors might protect tissues with high metabolic rates against lipotoxicity,favoring their storage,instead,in adipose tissues.However,sustained exposure to lipid reduces retinal metabolic efficiency.In photoreceptors with high metabolic needs,it predisposes to an energy failure and triggers compensatory albeit pathological angiogenesis,leading to blinding neovascular AMD.

Narrative review-drug delivery in age-related macular degeneration

This narrative review highlights routes of ocular drug delivery for age-related macular degeneration(AMD).AMD is the leading cause of irreversible blindness in industrialized countries and accounts for 8.7%of blindness worldwide.Advanced AMD can be classified into two subtypes:late-stage dry AMD[known as geographic atrophy(GA)]and neovascular AMD(nAMD).GA is often bilateral and results from progressive and irreversible loss of photoreceptors and areas of the retinal pigment epithelium.Wet AMD is characterized by angiogenesis from the choroid to the normally avascular regions underneath the retinal pigment epithelium(RPE)or retina,a process known as choroidal neovascularization(CNV).Various targeted therapeutic options are currently available to reduce the progression rate and maintain vision in patients with nAMD.Intravitreal delivery of anti-VEGF protein treatments to halt CNV is currently the gold-standard of care for nAMD.Subretinal and suprachoroidal delivery approaches are also being explored for gene and molecular therapies.Advancements in nanotechnology and biomaterials have also led to the development of microscopic drug delivery systems,including hydrogels,microparticles,nanoparticles,implants,and liposomes.Gene therapy and stem cell therapy has recently emerged as a potential candidate treatment modality for AMD and other retinal degenerations.New drug targets and modalities have stimulated exciting developments in ocular drug delivery with the promise of greater efficacy and durability of AMD treatment.

Novel treatments and genetics of age-related macular degeneration-a narrative review

Age-related macular degeneration(AMD)remains a leading cause of severe visual impairment in developing countries.Although dry-type AMD and geographic atrophy(GA)are progressive conditions with the associated decrease of visual functions,no well-established treatment regimen was proposed for the disease.Wet-type AMD is effectively treated with intravitreal anti-angiogenic agents,but frequent injections are a major issue for the affected patients.Recent advances in AMD genetics have provided new insights into the pathogenesis and novel therapeutic targets of AMD,but the benefits of using genetic testing and genotype-based risk models for AMD development and progression still lacks evidence.Novel AMD treatments aim to increase the interval among intravitreal injections through new therapeutic agents and modern delivery devices.Simultaneously,gene therapy for dry and wet AMD is widely studied.Although gene therapy possesses a major superiority over other novel treatments regarding a persistent cure of disease,many challenges exist in the way of its broad impact on the ocular health of AMD patients.

AB005.Perspectives on complement injury and choriocapillaris endothelial cell loss in aging and age-related macular degeneration

Genetic studies have revealed that variants in genes that encode regulators of the complement system are major risk factors for the development of age-related macular degeneration(AMD).The biochemical consequences of the common polymorphism in complement factor H(Tyr402His)include increased formation of the membrane attack complex(MAC),which is deposited at the level of the inner choroid and choriocapillaris.Whereas the MAC is normally protective against foreign pathogens,it can also damage resident bystander cells when it is insufficiently regulated.Indeed,human maculas with early AMD show loss of endothelial cells in the choriocapillaris,the principal site of MAC activation.Modeling of MAC injury of choroidal endothelial cells in vitro reveals that these cells are susceptible to cell lysis by the MAC,and that unlysed cells alter their gene expression profile to undergo a pro-angiogenic phenotype that includes increased expression of matrix metalloproteinase-9.Strategies for protecting choriocapillaris endothelial cells from MAC-mediated lysis and for replacing lysed endothelial cells will be discussed.

AB009.The age-related macular degeneration genetic-risk promotes pathogenic subretinal inflammation

Mononuclear phagocytes(MP)comprise a family of cells that include microglial cells(MC),monocytes,and macrophages.The subretinal space,located between the RPE and the photoreceptor outer segments,is physiologically devoid of MPs and a zone of immune privilege mediated,among others,by immunosuppressive RPE signals.Age-related macular degeneration(AMD)is a highly heritable major cause of blindness,characterized by a breakdown of the subretinal immunosuppressive environment and an accumulation of pathogenic inflammatory MPs.Studies in mice and humans suggest that the AMD-associated APOE2 isoform promotes the breakdown of subretinal immunosuppression and increased MP survival.Of all genetic factors,variants of complement factor H(CFH)are associated with greatest linkage to AMD.Using loss of function genetics and orthologous models of AMD,we provide mechanistic evidence that CFH inhibits the elimination of subretinal MPs.Importantly,the AMD-associated CFH402H isoform markedly increased this inhibitory effect on microglial cells,indicating a causal link to disease etiology.Pharmacological acceleration of resolution of subretinal inflammation might be a powerful tool for controlling inflammation and neurodegeneration in late AMD.

AB099.Cognitive impairment and age-related macular degeneration:a possible genetic link

Background:The number of older adults affected by age-related macular degeneration(AMD)and early cognitive changes is on the rise.Recent studies have shown a high co-occurrence of these conditions.This,along with shared risk factors and similar histopathology suggests they may share genetic risk factors as well.The goal of this study was to explore the possibility of known AMD SNPs contributing to the co-morbidity.Methods:Participants(AMD and controls)aged 70 years or older with no known neurological or cognitive impairments were recruited for this study.Visual function was evaluated using ETDRS visual acuity,Mars Contrast sensitivity and the scanning laser ophthalmoscope.Cognitive status was measured using the Mini-Mental State Exam(MMSE)and the Montreal Cognitive Assessment(MoCA).Genotyping was conducted using a panel of AMD single nucleotide polymorphisms(SNPs).Analysis was focused on the CFH Y402H and ARMS2 A69S SNPs due their association with drusen and evidence of their association with cognitive impairment.Results:According to the MMSE,two participants from the AMD group(N=21)and none from the control group(N=18)scored positive for cognitive impairment.The MoCA indicated 33.3%of the AMD group and 27.7%of the control group had MCI.There were no significant differences between MoCA scores based on the carrier versus non-carrier status of either the CFH or ARMS SNPs.The SNP in FADS1(rs174547)that was part of the original panel,but not in the analysis,was found in a large number of participants.All those who scored positive for MCI were homozygous carriers of the FADS1 SNP.Conclusions:Although more people from the AMD group scored positive for MCI,scores between groups were significantly different.The AMD and control groups did differ on which cognitive domains they had difficulty with,indicating those with AMD and MCI may be at a higher risk of converting to AD.There were no significant differences on cognitive scores between CFH and ARMS2 SNP carriers and non-carriers.The FADS1 SNP,not originally intended to be part of this study,will be included in future analyses to explore the possibility of a founder effect and a potential link to mild cognitive impairment(MCI).

A narrative review on the role of abicipar in age-related macular degeneration

In developed countries,age-related macular degeneration(AMD)is the main cause of visual impairment in the elderly.Though the etiology of AMD is still unclear,it has been well understood that vascular endothelial growth factor(VEGF)is involved in the development of aberrant vasculature that represents the neovascular AMD(nAMD).Hence,VEGF inhibition is a more effective way to control nAMD.Pegaptanib,ranibizumab,and aflibercept are three drugs approved by the US Food and Drug Administration(FDA)to treat nAMD.Bevacizumab(an anti-VEGF medication comparable to ranibizumab)is already widely used off label.Existing anti-VEGF medicines are made up of antibodies or pieces of antibodies.Synthetic designed ankyrin repeat proteins(DARPins)imitate antibodies introduced recently by evolutions in bioengineering technology.These agents are designed to have high specificity and affinity to a specific target,smaller molecular size,and better tissue penetration,making them more stable and longer-acting at less concentration.Abicipar pegol(Allergan,Dublin,Ireland)is a DARPin that interlocks all VEGF-A isoforms.It has a greater affinity for VEGF and a longer intraocular half-life than ranibizumab,making it a feasible anti-VEGF agent.This review describes the properties and efficacy of abicipar,the new anti-VEGF agent,in clinical practice,which aims to improve outcomes,safety,and treatment burden of nAMD.

AB023.Characterization of a novel anti-angiogenic protein for the treatment of exudative age-related macular degeneration

Background:Age-related macular degeneration(AMD)is a leading cause of blindness in Canada.The exudative(wet)form of AMD accounts for approximately 15%of AMD patients,but is responsible for the majority of severe vision loss associated with the disease.Wet AMD is characterized by choroidal neovascularization,the abnormal growth of blood vessels from the choroid into the sub-retinal space.Current therapies for exudative AMD directly target and inhibit the vascular endothelial growth factor(VEGF)signaling pathway,a signaling axis that promotes endothelial cell survival.While initially effective at restoring visual acuity,recent studies suggest that chronic use of anti-VEGF therapies can lead to further vision impairment through off-target effects on photoreceptors and other non-vascular tissues.These off-target effects of anti-VEGF therapy highlights the need for alternative treatments for this increasingly common disease.We have recently identified a novel anti-angiogenic protein,AAP1 that inhibits retinal angiogenesis during development.As a regulator of the vasculature,our current work aims to characterize the function of AAP1 in endothelial cells and determine the potential of AAP1 as a therapy for exudative AMD.Methods:To address our aims,we used various in vivo and in vitro models of normal and pathological vascular growth.Mice were injected intravitreally with AAP1 to investigate its effects on developmental and pathological angiogenesis.Using HUVECs,we employed immunofluorescent quantifications to determine the impact of AAP1 on sprouting angiogenesis by measuring cellular proliferation,apoptosis and migration.To investigate the signaling events that mediate the actions of AAP1,we examined key signaling pathways involved in angiogenesis by western blotting and qPCR.Results:We evaluated the role of AAP1 as a regulator of angiogenesis during retinal development and mouse models of AMD.Our pilot data show that AAP1 prevents angiogenesis in vitro and in vivo,and that it can also inhibit pathological neovascularization in experimental models of AMD.In spite of its anti-angiogenic effects,our data show that AAP1 does not adversely affect photoreceptors.Both in vitro and in vivo systems showed a decrease in cellular division,while apoptosis was not affected in response to AAP1 treatment.While cellular migration was reduced in AAP1-treated HUVECs,cellular polarity was not affected.Finally,gene and protein expression of key angiogenic factors were modified in response to AAP1.Conclusions:AAP1 is a potent regulator of angiogenesis.However,in contrast to anti-VEGF agents,our data suggests that AAP1 does not adversely affect the photoreceptors-highlighting the therapeutic potential of this protein.Further data generated from our studies characterizing the mechanism of AAP1 action may lead to a novel treatment option for AMD patients preventing vision loss and improving their quality of life.

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.

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.