Age-related eye disease

As with many organs, compromised function of the eye is accompanied with age and has become increasingly prevalent with the aging population. When decreased visual loss becomes significant, patients’ ability to perform activities of daily living becomes compromised. This decrease in function is met with morbidity and mortality, as well as a large socioeconomic burdon throughout the world. This review summarizes the most common age-related eye diseases, including cataract, glaucoma, diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Although our understanding of the genetic and biochemical pathways of these diseases is sill at its primitive stages, we have become able to help our patients improve the quality of life as they age.     

Age-related eye disease and gender

Worldwide, the prevalence of moderate to severe visual impairment and blindness is 285 millions, with 65% of visually impaired and 82% of all blind people being 50 years and older. Meta-analyses have shown that two out of three blind people are women, a gender discrepancy that holds true for both developed and developing countries. Cataract accounts for more than half of all blindness globally and gender inequity in access to cataract surgery is the major cause of the higher prevalence of blindness in women. In addition to gender differences in cataract surgical coverage, population-based studies on the prevalence of lens opacities indicate that women have a higher risk of developing cataract. Laboratory as well as epidemiologic studies suggest that estrogen may confer antioxidative protection against cataractogenesis, but the withdrawal effect of estrogen in menopause leads to increased risk of cataract in women. For the other major age-related eye diseases; glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy, data are inconclusive. Due to anatomic factors, angle closure glaucoma is more common in women, whereas the dominating glaucoma type; primary open-angle glaucoma (POAG), is more prevalent in men. Diabetic retinopathy also has a male predominance and vascular/circulatory factors have been implied both in diabetic retinopathy and in POAG. For AMD, data on gender differences are conflicting although some studies indicate increased prevalence of drusen and neovascular AMD in women. To conclude, both biologic and socioeconomic factors must be considered when investigating causes of gender differences in the prevalence of age-related eye disease.     

Emerging opportunities for C3 inhibition in the eye

The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3’s functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3’s relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.     

Stem Cell-Based Therapeutic Applications in Retinal Degenerative Diseases

Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated. Gene-replacement therapy has been shown to improve visual function in inherited retinal disease. However, this treatment was less effective with advanced disease. Stem cell-based therapy is being pursued as a potential alternative approach in the treatment of retinal degenerative diseases. In this review, we will focus on stem cell-based therapies in the pipeline and summarize progress in treatment of retinal degenerative disease.     

The role of glial cells and the complement system in retinal diseases and Alzheimer’s disease: common neural degeneration mechanisms

Many age-related degenerative diseases of the central nervous system (CNS) increasingly appear to have similarities in their underlying causes. By applying knowledge between disorders, and in particular between degenerative diseases of different components of the CNS (e.g. the eye and the brain), we can begin to elucidate general mechanisms of neural degeneration. Age-related macular degeneration and glaucoma, two diseases of retinal neurons, which have recently been discussed in view of their common mechanisms with Alzheimer’s disease, highlight this perspective. This review discusses the common roles of the complement system (an immunological system) and glial cells (providing, amongst other functions, trophic support to neurons) in these three disorders. A number of facets of these systems would seem to be involved in the mechanisms of degeneration in at least two of the three diseases considered here. Regulatory proteins of the complement system (such as factor H), neurotrophin levels, and the interaction of microglia with the complement system in particular may be general to all three presentations of neural degeneration. Investigating the functioning of these fundamental systems across different diseases exemplifies the importance of considering advances in knowledge across a wider base than specific disease pathology. This may give insights both for understanding the function of these supporting systems and providing an avenue for developing future therapeutic targets general to neural degenerative diseases.     

The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection

The purpose of this study is to determine the correlation between the distribution of nanoparticles in the vitreous and retina and their surface properties after intravitreal injection. For this purpose, we synthesized seven kinds of nanoparticles through self-assembly of amphiphilic polymer conjugates in aqueous condition. They showed similar size but different surface properties. They were labeled with fluorescent dyes for efficient tracking. After intravitreal injection of these nanoparticles into a rodent eye, their time-dependent distribution in the vitreous and retina was determined in stacking tissue images by confocal microscopy. The results demonstrated that the surface property of nanoparticles is a key factor in determining their distribution in the vitreous and retina after intravitreal injection. In addition, immunohistochemistry and TEM images of retina tissues suggested the important mechanism related with Mülller cells for intravitreally administered nanoparticles to overcome the physical barrier of inner limiting membrane and to penetrate into the deeper retinal structures. Therefore, we expect that this study can provide valuable information for biomedical researchers to develop optimized nanoparticles as drug or gene carriers for retinal and optic nerve disorders such as glaucoma, age-related macular degeneration, and diabetic retinopathy.     

Angiogenesis in eye disease: immunity gained or immunity lost?

The anti-inflammatory nature of the intraocular environment is critical to the immune privilege of the eye. An important part of immune privilege is the induction of apoptosis by two death-inducing ligands (FasL and TRAIL) that can limit the spread of inflammation and control tumor growth. While initial studies focused on control of inflammation and the impact of these molecules on the systemic immune response, more recent studies have extended this concept to pathogenic neovascularization. This process is an important component of several blinding eye disorders including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and corneal disease. These studies showed that the mediators of immune privilege also regulate the extent of angiogenesis. In this article, we will develop the idea that constitutive expression of FasL in the eye, as well as inducible FasL on cells of the immune system, modulates neovascularization in ocular disease. Further, we will present the idea that macrophage participation in this process and their function during disease depends on the microenvironment and the cytokine milieu. These concepts challenge the idea that neovascular eye disease is simply an inflammatory process and support the idea that these diseases may result from the loss or dysfunction of important components of the cellular immune system.     

The role of complement in ocular pathology

Functionally active complement system and complement regulatory proteins are present in the normal human and rodent eye. Complement activation and its regulation by ocular complement regulatory proteins contribute to the pathology of various ocular diseases including keratitis, uveitis and age-related macular degeneration. Furthermore, a strong relationship between age-related macular degeneration and polymorphism in the genes of certain complement components/complement regulatory proteins is now well established. Recombinant forms of the naturally occurring complement regulatory proteins have been exploited in the animal models for treatment of these ocular diseases. It is hoped that in the future recombinant complement regulatory proteins will be used as novel therapeutic agents in the clinic for the treatment of keratitis, uveitis, and age-related macular degeneration.     

抗视网膜脉络膜新生血管性疾病治疗药物靶点的研究进展

新生血管性年龄相关性黄斑变性(nAMD)、糖尿病视网膜病变(DR)等眼底病继发形成新生血管,是致盲的重要原因之一。抗血管内皮生长因子(VEGF)治疗是当前主流疗法。但仍存在部分患者对其疗效欠佳等局限,临床仍需要开发新的药物靶点。     

The role of complement system in ocular diseases including uveitis and macular degeneration

In the normal eye, the complement system is continuously activated at low levels and both membrane-bound and soluble intraocular complement regulatory proteins tightly regulate this spontaneous complement activation. This allows protection against pathogens without causing any damage to self-tissue and vision loss. The complement system and complement regulatory proteins control the intraocular inflammation in autoimmune uveitis and play an important role in the development of corneal inflammation, age-related macular degeneration and diabetic retinopathy. The evidence derived from both animal models and patient studies support the concept that complement inhibition is a relevant therapeutic target in the treatment of various ocular diseases. Currently, several clinical trials using complement inhibitors are going on. It is possible that, in the near future, complement inhibitors might be used as therapeutic agents in eye clinics.     

Mexican clinical experience in ocular anti-angiogenic therapy

Retinal pathological angiogenesis is the leading cause of visual loss in a wide variety of ocular diseases. Some of the examples include: Age-related macular degeneration, diabetic retinopathy and retinopathy associated with prematurity. These last two entities are, in addition, public health problems in developing countries. Recent physiopathological studies, have demonstrated that growth factors play a key role on angiogenesis. Anti-angiogenic therapy came about as an attempt to inhibit the action of growth factors over the process of pathological angiogenesis in order to preserve vision. The objective of this review is to describe Mexico's experience using this therapeutic approach.     

Protein Transport to Choroid and Retina following Periocular Injection: Theoretical and Experimental Study

Ocular neovascularization is a major cause of blindness in several diseases including age-related macular degeneration (choroidal neovascularization) and diabetic retinopathy (retinal neovascularization). Antiangiogenic agents with clinically significant effects exist, but a key question remains: how to effectively deliver drugs to the site of neovascularization. Periocular delivery of drugs or proteins is less invasive and safer than intravitreous delivery, but little is known regarding how and to what extent agents access intraocular tissues after periocular injection. We present a computational model of drug or protein transport into the eye following periocular injection to quantify movement of macromolecules across the sclera of the mouse eye. We apply this model to the movement of green fluorescent protein (GFP) across the mouse eye and fit the results of in vivo experiments to find transport parameters. Using these parameters, the model gives the profile of interstitial GFP concentration across the sclera, choroid and retina. We compare this to predictions of transport following intravitreous injections. We then scale up the model to estimate the transport of GFP into the human choroid and retina; the thicker sclera decreases transscleral delivery. This is the first model of ocular drug delivery to explicitly account for transport properties of each eye layer.     

Emerging therapeutic approaches in the management of retinal angiogenesis and edema

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed.     

Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats

Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy.     

5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids

Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in ω-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of ω-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary ω-3 PUFA.     

Artificial vision through neuronal stimulation

Introduction

The term visual prosthesis refers to any device capable of eliciting visual percepts in an individual through electrical stimulation of any part of the visual system.

Background

Blindness can be due to eye pathology or due to damage of the lateral geniculate or visual cortex. Eye pathology other than diseases that affect the cornea and lens are numerous and some of the leading causes are diabetic retinopathy, age-related macular degeneration, retinal detachment, glaucoma, and retinal vascular occlusions.The visual prosthesis can be divided into non-retinal and retinal approaches. Non-retinal approaches include cortical and optic nerve prosthesis. Retinal approaches are aimed at eye pathologies in which at least part of the optic nerve remains intact whereas when the optic nerve is nearly completely damaged and/or the eye itself is disfigured or degenerated then a non-retinal approach is warranted. The retinal prosthesis can be placed on the surface of the retina, in the subretinal space or in the suprachoroidal space.

Results

Several independent groups related variable degrees of success in promoting visual sensations through electrical stimulation of the visual system.Every technique, equipment and anatomical target has its advantages and disadvantages, and the biological/electrical–mechanical interface is still the aspect of the research towards a chronic, long term, reliable biomimetic implant.

Conclusions

The visual prostheses have achieved significant developments in recent years. We see continued improvement in visual acuity with increasing number and density of electrodes. Even though the visual acuity is still poor relative to normal vision, these subjects can read letters using their implants. Perhaps more importantly, blind patients can use these devices for mobility and orientation.     

A Combined Approach for the Analysis of Ocular Fluid Dynamics in the Presence of Saccadic Movements

One of the main ocular diseases is age-related macular degeneration, actually treated with antibodies injections into the eye. This problem has been faced by computational approaches, taking into account either the influence of the tissues surrounding the vitreous, or the saccades. The aim of this work is to propose a combined fluid dynamic model of the vitreous chamber that analyses the impact of the saccades on the fluid dynamic mechanisms. The ocular vitreous humor was modeled considering liquefaction occurring in presence of age-related macular degeneration. We identified two kinds of boundary conditions, one related to the physiological environment outside the chamber, and one related to the saccades. The scleral hydraulic conductivity was evaluated by means of experimental permeability tests. An exponential decay was used to describe the trend of the scleral hydraulic conductivity with the acting pressure drop. The streamline analysis shows two main stagnant regions on the equatorial plane and peculiar fluid dynamics in absence of saccades. This study demonstrates the major role played by the saccades in determining the fluid dynamic mechanisms inside the vitreous chamber of the eye and represents a powerful tool to investigate vitreous dynamics and its relation to clinical issues.     

Phagocyte dysfunction,tissue aging and degeneration

Immunologically-silent phagocytosis of apoptotic cells is critical to maintaining tissue homeostasis and innate immune balance. Aged phagocytes reduce their functional activity, leading to accumulation of unphagocytosed debris, chronic sterile inflammation and exacerbation of tissue aging and damage. Macrophage dysfunction plays an important role in immunosenescence. Microglial dysfunction has been linked to age-dependent neurodegenerations. Retinal pigment epithelial (RPE) cell dysfunction has been implicated in the pathogenesis of age-related macular degeneration (AMD). Despite several reports on the characterization of aged phagocytes, the role of phagocyte dysfunction in tissue aging and degeneration is yet to be fully appreciated. Lack of knowledge of molecular mechanisms by which aging reduces phagocyte function has hindered our capability to exploit the therapeutic potentials of phagocytosis for prevention or delay of tissue degeneration. This review summarizes our current knowledge of phagocyte dysfunction in aged tissues and discusses possible links to age-related diseases. We highlight the challenges to decipher the molecular mechanisms, present new research approaches and envisage future strategies to prevent phagocyte dysfunction, tissue aging and degeneration.     

Using ultrahigh sensitive optical microangiography to achieve comprehensive depth resolved microvasculature mapping for human retina

This paper presents comprehensive and depth-resolved retinal microvasculature images within human retina achieved by a newly developed ultrahigh sensitive optical microangiography (UHS-OMAG) system. Due to its high flow sensitivity, UHS-OMAG is much more sensitive to tissue motion due to the involuntary movement of the human eye and head compared to the traditional OMAG system. To mitigate these motion artifacts on final imaging results, we propose a new phase compensation algorithm in which the traditional phase-compensation algorithm is repeatedly used to efficiently minimize the motion artifacts. Comparatively, this new algorithm demonstrates at least 8 to 25 times higher motion tolerability, critical for the UHS-OMAG system to achieve retinal microvasculature images with high quality. Furthermore, the new UHS-OMAG system employs a high speed line scan CMOS camera (240 kHz A-line scan rate) to capture 500 A-lines for one B-frame at a 400 Hz frame rate. With this system, we performed a series of in vivo experiments to visualize the retinal microvasculature in humans. Two featured imaging protocols are utilized. The first is of the low lateral resolution (16 μm) and a wide field of view (4?×?3 mm(2) with single scan and 7?×?8 mm(2) for multiple scans), while the second is of the high lateral resolution (5 μm) and a narrow field of view (1.5?×?1.2 mm(2) with single scan). The great imaging performance delivered by our system suggests that UHS-OMAG can be a promising noninvasive alternative to the current clinical retinal microvasculature imaging techniques for the diagnosis of eye diseases with significant vascular involvement, such as diabetic retinopathy and age-related macular degeneration.     

Retinal image restoration by means of blind deconvolution

Retinal imaging plays a key role in the diagnosis and management of ophthalmologic disorders, such as diabetic retinopathy, glaucoma, and age-related macular degeneration. Because of the acquisition process, retinal images often suffer from blurring and uneven illumination. This problem may seriously affect disease diagnosis and progression assessment. Here we present a method for color retinal image restoration by means of multichannel blind deconvolution. The method is applied to a pair of retinal images acquired within a lapse of time, ranging from several minutes to months. It consists of a series of preprocessing steps to adjust the images so they comply with the considered degradation model, followed by the estimation of the point-spread function and, ultimately, image deconvolution. The preprocessing is mainly composed of image registration, uneven illumination compensation, and segmentation of areas with structural changes. In addition, we have developed a procedure for the detection and visualization of structural changes. This enables the identification of subtle developments in the retina not caused by variation in illumination or blur. The method was tested on synthetic and real images. Encouraging experimental results show that the method is capable of significant restoration of degraded retinal images.