|UPDATES IN CLINICAL TRIALS IN RETINA
|Year : 2016 | Volume
| Issue : 1 | Page : 13-26
Update on clinical trials in dry Age-related macular degeneration
Ibrahim Taskintuna1, M.E. A. Abdalla Elsayed2, Patrik Schatz3
1 Division of Vitreoretinal, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
2 Jeddah Eye Hospital, Jeddah, Kingdom of Saudi Arabia
3 Division of Vitreoretinal, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology, Clinical Sciences, Scane County University Hospital, University of Lund, Sweden
|Date of Web Publication||4-Jan-2016|
Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al.Oruba Street, P. O. Box 7191, Riyadh 11462
Source of Support: None, Conflict of Interest: None
| Abstract|| |
This review article summarizes the most recent clinical trials for dry age.related macular degeneration (AMD), the most common cause of vision loss in the elderly in developed countries. A literature search through websites https://www.pubmed.org and https://www.clinicaltrials.gov/, both accessed no later than November 04, 2015, was performed. We identified three Phase III clinical trials that were completed over the recent 5 years Age.Related Eye Disease Study 2 (AREDS2), implantable miniature telescope and tandospirone, and several other trials targeting a variety of mechanisms including, oxidative stress, complement inhibition, visual cycle inhibition, retinal and choroidal blood flow, stem cells, gene therapy, and visual rehabilitation. To date, none of the biologically oriented therapies have resulted in improved vision. Vision improvement was reported with an implantable mini telescope. Stem cells therapy holds a potential for vision improvement. The AREDS2 formulas did not add any further reduced risk of progression to advanced AMD, compared to the original AREDS formula. Several recently discovered pathogenetic mechanisms in dry AMD have enabled development of new treatment strategies, and several of these have been tested in recent clinical trials and are currently being tested in ongoing trials. The rapid development and understanding of pathogenesis holds promise for the future.
Keywords: Age-related Macular Degeneration, Clinical Trials, Retinal Pigment Epithelium
|How to cite this article:|
Taskintuna I, Elsayed MA, Schatz P. Update on clinical trials in dry Age-related macular degeneration. Middle East Afr J Ophthalmol 2016;23:13-26
|How to cite this URL:|
Taskintuna I, Elsayed MA, Schatz P. Update on clinical trials in dry Age-related macular degeneration. Middle East Afr J Ophthalmol [serial online] 2016 [cited 2018 Apr 22];23:13-26. Available from: http://www.meajo.org/text.asp?2016/23/1/13/173134
| Introduction|| |
Age-related macular degeneration (AMD) is the major cause of blindness for the elderly population in the developed world. AMD causes degeneration of photoreceptors and retinal pigment epithelium (RPE) in the macula. Early stage disease is characterized by deposition of drusen under the RPE cells into Bruch's membrane. In late stages, the disease may progress to either geographic atrophy (GA) or neovascular AMD. Loss of photoreceptors and atrophy of RPE with loss of choriocapillaris lead to vision loss in GA, whereas choroidal neovascularization (CNV) is associated with breakthrough of choroidal neovascular vessels through Bruch's membrane and RPE causing hemorrhagic, exudative, or disciform AMD.
Advanced AMD is classified into two categories. GA, i.e., dry or nonexudative AMD, is characterized by a sharply delineated area of RPE atrophy measuring at least 175 µm in one dimension with visible choroidal vessels. CNV, i.e., wet or exudative AMD, on the other hand, manifests as subretinal neovascular membranes, exudates, hemorrhages, subretinal fluid, pigment epithelial detachment, and retinal scarring. This form will not be discussed in the present article, however several risk factors and pathogenetic features seem to be similar for dry and wet AMD.
Other types of dry AMD include drusen [Figure 1] and reticular pseudodrusen (also called subretinal drusenoid deposits). Drusen typically appear with age and are classified as hard and soft drusen. Hard drusen are smaller than 63 µm in diameter with sharp borders and considered a part of normal aging. Soft drusen are larger than 125 µm in diameter usually with indistinct borders. Drusen are located under the RPE whereas reticular pseudodrusen are located subretinally. Our search did not yield any clinical trials performed specifically for the latter.
|Figure 1: Color fundus photography of drusen and corresponding fundus autofluorescence frame showing mild hyperautofluorescence resulting from build-up of hyperautofluorescent debris within drusen|
Click here to view
In addition, there are strictly hereditary forms of drusen that appear at a young age called familial drusen or malattia leventinese or familial dominant drusen or Doyne honeycomb retina dystrophy, caused by a single mutation (Arg345Trp) in the fibulin 3 gene on chromosome 2p (FBLN3). This gene is also known as the epidermal growth factor-containing fibrillin-like extracellular matrix protein-1.
A clinical picture similar to GA can be seen in any end-stage macular pathology leading to retinal and RPE atrophy, for example, after inflammatory lesions or in the context of myopic degeneration.
The prevalence of advanced AMD is 0.2% in individuals aged 55–64 years and increases to 13% in those older than 85 years according to population-based studies such as the Beaver Dam Eye Study, the Rotterdam Study, and the Blue Mountains Eye Study.
AMD is a multifactorial disease with many risk factors. These include age, smoking,, dietary fats, and genetic polymorphisms, including the genes ARMS2, HTRA1, and complement factor H (CFH).
The etiology and pathophysiology of AMD are not understood well. Much of the scientific literature on AMD point to inflammation markers such as cytokines interleukin-1β (IL-1β), IL-18, IL-17, complement system (CS), macrophages, and recently, inflammasomes of the innate immune system.,,, However, it remains unknown whether AMD is a consequence of inflammation or inflammation is due to the initial change of metabolic abnormalities, hypoxia, and oxidative stress. Molecular and ultrastructural studies point to pyroptosis as the cause of cell death in AMD.
A previous publication summarized the clinical trials in dry AMD until about 2010. Trials that are more recent for dry AMD are reviewed here, based on published results available through a literature search in PubMed (www.pubmed.org accessed November 4, 2015). Details regarding the study design for these published studies were also retrieved from https://clinicaltrials.gov/, accessed November 4, 2015.
| Pathophysiology|| |
Age-related macular degeneration and innate immune system
The innate immune system includes physical barriers, circulatory proteins (mainly the CS), and innate response cells such as monocytes and neutrophils, and pattern recognition receptors (PRRs) expressed by innate immunity cells.
Macrophages are innate immune cells associated with phagocytosis and antigen presentation in both subacute and chronic inflammation and wound healing. They are mainly observed in or near drusen, Bruch's membrane, neovascular, and GA AMD.,
Macrophages secrete numerous molecules for regulating inflammation, phagocytosis, cell growth and death. They play a major role in innate immunity and this involvement in immune disorders provides support for their role in AMD.
There are two main macrophage phenotypes: M1 (classically activated) and M2 (alternatively activated). M1 macrophages are pro-inflammatory, microbicidal, and anti-tumoral. M2 macrophages are anti-inflammatory, pro-tumoral, immunoregulatory, and pro-angiogenic.,,
The population of macrophages differs in the eyes of healthy subjects compared to AMD eyes. The eyes of patients with GA showed significantly elevated M1 macrophages levels, and higher M1:M2 ratios in the macula. An association between classic M1 macrophage activation and the development of AMD in the eye has been strongly suggested.,
Human retinal microglial cells identified by CD18 expression, a microglial marker, express CX3CR1. Microglial cells are the only cells in the retina that express CX3CR1. In AMD, activated microglia cells accumulate in the affected areas of the macula., Some have proposed microglia as a potential contributor to inflammation and immunity in the pathogenesis of AMD. In addition, accumulation of subretinal microglial cells associated with migratory defect may result in the formation of drusen, CNV, and retinal degeneration.
The CS is an integral part of the innate immune system and synthesized by the hepatocytes and macrophages. They are found in the circulating blood. CS is involved in tissue inflammation (via the anaphylatoxins complement component 3a and complement component 5a), cell opsonization, and cytolysis. The classical, alternative, and lectin pathways result in the formation of the cytolytic membrane attack complex (MAC) capable of generating perforations in the cell membrane, thereby promoting cell lysis and the elimination of unnecessary cells.
Gene polymorphism for coding complement regulatory proteins and complement effectors show a strong association with the development of AMD. Significant associations have been reported between AMD and known genetic polymorphisms of CFH, C2, and C3, with CFH showing the strongest association. Under physiological conditions, complement activation is effectively controlled by the coordinated action of soluble and membrane-associated complement regulatory molecules (CRMs). The main components of the CS, including C3, C5, and the MAC complex, are normally present in the capillary vessels of the choroid and the vitreous of human eyes.,,,
Complement activation is augmented in retinal tissue with age. RPE/choroid complexes from aged mice showed expression of different CS in vivo. Basal CS activation in cultured cells increases with advancing age. Synthesis of endogenous CRMs such as CFH , and CFB  is augmented by basal CS activation. The membrane-bound CRMs such as CD46, CD55, and CD59 are upregulated by inflammatory cytokines such as interferon-gamma, TNF-α, and IL-1β, and by repetitive nonlethal exposure to oxidative stress. This phenomenon is important as a protective mechanism in the natural aging of the retina and in retinal age-related diseases. CD59a was more abundant in the murine eyes than in nonocular tissues, implying that CD59a might play a protective role in complement-mediated injury.In vivo andin vitro upregulation of complement inhibitors observed in retinal tissue may be the biological response to the augmented immune responses seen in aging.
The same mediators known for the protective role of CS are also responsible for the pathological effects of CS. Unregulated CS activation may damage host tissue via an active complement cascade. CRMs provide protection against complement through expression and secretion to the retina. Choroid and RPE regulate the CS activity in the eye, and these retinal elements play an important role in the pathogenesis of AMD.
Pattern recognition receptors
The PRRs include families of toll-like receptors, NOD-like receptors (NLRs), C-type lectin receptors, RIG-I-like receptors, and AIM-2-like receptors. These receptors play a key role in human immunity. First, they directly recognize antigen determinants of nearly all classes of pathogens (pathogen-associated molecular patterns) and promote their elimination by triggering innate and adaptive immune response. Second, they recognize endogenous ligands released during cell stress (damage-associated molecular patterns), and therefore can activate the immune response in the absence of an infectious agent. In addition, PRRs are known to possess a number of other vital functions, regulating the processes of apoptosis, DNA repair, autophagy, and angiogenesis.
NOD-like receptors: The NLRP3 inflammasome
A subset of the NLRs contains a pyrin domain at the amino terminus, in addition to the nucleotide-binding and oligomerization (NACHT) domain and carboxy-terminal leucine-rich repeat domain found in other NLRs. These are known as NLRPs. The inflammasome consists of an NLRP, an adaptor protein called PYCARD/ASC, and caspase-1. An inflammasome is an intracellular, multiprotein complex and its molecular composition is stimulus dependent. Inflammasome activation is a key component of innate immunity, and its overactivation has been linked to many human immune diseases.,,
Recently, NLRP3 is the center of interest for AMD research. NLRP3 activation results in Apoptosis associated Speck-like protein containing a Caspase recruitment domain (ASC) recruitment and mediates the proximity-induced procaspase-1 autoactivation. Then NLRP3 inflammasome turns into a cytokine-processing platform for cleaving pro-IL-1β/pro-IL-18 into mature peptides and releasing them into extracellular space (Gao 2015). The rich proteinaceous composition of drusen is made of complement regulators, amyloid-β (Aβ), and oxidation by-products.,, These components are ideal for interactions with the NLRP3 inflammasome.,, The secreted inflammasome effector cytokines, IL-1β and IL-18, exert cytotoxic effects on RPE cells. These effects may explain Aβ-inducedin vitro RPE cell death.
RPE cells phagocytose the oxidized tips of outer segments of photoreceptors for the recycling of 11-cis retinal as part of the visual cycle. With age, the recycling capacity of RPE cells decreases significantly. As a result lipofuscin, a lipid peroxidation by-product accumulates in the RPE., Lipofuscin accumulation in RPE leads to lysosome damage and NLRP3 inflammasome formation. Other lipid peroxidation end products, 4-hydroxynonenal and carboxyethylpyrrole, also contribute to NLRP3 inflammasome activation.
AMD is a complex disease that is influenced by genetic variations. IL-1β and IL-18 are elevated in dry AMD eyes with homozygous CFH Y402H risk variant. Previous studies have reported that the repetitive element-derived Alu RNA transcripts are inducers for RPE degeneration in GA patients. Loss of DICER1 expression, due to oxidative stress in the RPE, is responsible for the abnormal Alu repeats accumulation in GA patients. RPE degeneration can be blocked by the inhibition of inflammasome components or IL-18.
It has been proposed that inflammasome activation and subsequent IL-1β and IL-18 production result in elevated levels of IL-17 secretion and autoimmunity.
Activation of inflammasome pathway by the damaged RPE cells may further lead to RPE atrophy in GA.
Pyroptosis in age-related macular degeneration
The term pyroptosis is an alternative cell death pathway which is linked to inflammation. It is dependent on activation of caspase-1, a key component of NLRP3 inflammasome. Inflammatory cytokines including IL-1β and IL-18 are secreted during the process. In the form of pyroptosis cell death, pores form in the cell membrane and rapid lysis occurs releasing cytosolic contents including cytokines into the extracellular space. Pyroptosis occurs quickly and leads to inflammation. Involvement of NLRP3 inflammasome in AMD suggests pyroptosis instead of apoptosis as a cell death pathway.
Autography in age-related macular degeneration
Autophagy is the cell death mechanism in which mitochondria sequester and expel xenobiotic material into the cytoplasm. The mitochondria directly donate their membrane during the formation of autophagosomic vesicles and turn into lysosomes. Continued exposure causes mitochondrial depletion, cellular dedifferentiation, and the eventual death of the cell. Cytokines such as IL-1β and IL-17 are inducers of autophagy and may cause cell death via autophagy  and may induce AMD through autophagy.
Thus the innate immune system seems closely related to the pathogenesis of AMD. The caspase-1-mediated pyroptosis, with autophagy, cause damage to retinal tissue and cell death in AMD.
New drugs targeting the inflammatory cytokines, macrophages, CS, or inflammasomes may play a role in the preventing the progression of AMD.
| Clinical Trials|| |
The clinical trials from this review are summarized in [Table 1]. The targeted pathophysiological mechanisms for some of the trials are presented in [Figure 2].
|Table 1: Summary of recent years clinical trials performed for dry age-related macular degeneration|
Click here to view
|Figure 2: Flow chart of pathophysiology steps targeted in different recent clinical trials|
Click here to view
Retinal pigment epithelium and photoreceptor preservation
One method of treating dry AMD is to improve choroidal circulation and hence preserving photoreceptors and the RPE. A European multicenter (France, Belgium, and Spain), randomized, double-blind, placebo-controlled clinical trial investigated the effect of 70 mg trimetazidine daily on the occurrence of CNV or GA in AMD. Trimetazidine is used to treat angina pectoris as it improves myocardial glucose utilization by inhibiting fatty acid metabolism and has been proven to prevent ischemia/reperfusion-induced cardiomyocyte apoptosis. However, trimetazidine did not slow the conversion of dry AMD to wet AMD, and there was no statistically significant difference in the progression of GA.
Therapies currently in clinical trials include vasodilators such as alprostadil, MC-1101, moxaverine, and sildenafil. The administration of vasodilators may improve choroidal blood flow that generally decreases due to age, probably due to a decrease in choriocapillaris diameter and density. This may delay the progression of nonexudative as well as exudative manifestations of late AMD. Moreover, decreased choroidal blood flow is correlated positively with fundus findings associated with an increased risk of CNV such as drusen and pigmentary changes.
Alprostadil, also known as prostaglandin E1 (PGE1), is being investigated for its vasodilatory effect. PGE1 is produced endogenously to relax vascular smooth muscle and hence cause vasodilation. The presumed rationale is based on the belief that improved circulation would slow the progression of AMD. In this German, multicenter, randomized, placebo-controlled study, patients were treated with intravenous infusion of either 60 µg alprostadil or placebo over 3 weeks and best-corrected visual acuity (BCVA) was assessed immediately, 3 months and 6 months after treatment. Alprostadil infusion was superior to placebo treatment by a mean of 0.94 lines after 3 months and 1.51 lines after 6 months. Further clinical studies are needed particularly as the early termination of the study (technical changes in study design had to be carried out) resulted in analysis of only 33 participants. Long-term follow-up of the safety and therapeutic effect of PGE1 is also warranted especially as a case of macular edema following intracorporeal injection of alprostadil has recently been reported.
A Phase Ib trial found that topical instillation of MC-1101 was not only safe and well tolerated, but it also reached the macula, relaxed the epithelial lining of the vasculature, dilated choroidal blood vessels by stimulating nitric oxide production, and increased choroidal blood circulation. The increased ocular blood flow in the choroidal vessels prevents the rupture of Bruch membrane. MC-1101 is also anti-inflammatory and an antioxidant. A randomized, double-masked Phase II/III double-masked, single center study is currently underway examining one eye of 60 individuals with mild to moderate dry AMD randomly assigned to receive either topical 1% MC-1101 twice a day or a vehicle control over 2 years. MC-1101 has the United States Food and Drug Administration (FDA) “Fast Track” status and the estimated study completion date is April 2016. The Phase I study showed mild, transitory ocular hyperemia was the most common treatment-related adverse event; however, this was expected given MC-1101's mechanism of action. The drop is administered with a novel delivery system that employs unit-dose, micro-pump “blisters” that are inserted into a small handheld pump sprayer to deliver a preservative-free uniform spray dose to the ocular surface.
Intravenous administration of 150 mg moxaverine (a nonselective phosphodiesterase inhibitor) has been demonstrated to increase choroidal blood flow in healthy young subjects compared to placebo (Resch et al. 2009, Pemp et al. 2012)., Moxaverine seems to achieve this via smooth muscle relaxation and subsequent peripheral vasodilatation  and by an improvement of blood rheology.
Schmidl et al.'s data, however, showed that orally administered moxaverine does not increase ocular blood flow. The reason for these contradictory results is uncertain, but may be related to the low bioavailability after oral administration. Further studies are necessary to investigate whether long-term treatment with intravenous moxaverine is clinically efficacious for patients with dry AMD.
A study at Duke Eye Centre was undertaken to investigate the effect of 100 mg oral dose of sildenafil citrate on choroidal thickness in eyes with AMD. Choroidal thinning has been postulated to be a factor in the pathogenesis of AMD, and therefore it was believed that sildenafil (known to increase choroidal thickness in young healthy patients) may possibly reduce AMD progression. Unfortunately, this study was terminated in April 2015 due to inadequate support to complete recruitment/data analysis. Metelitsina et al.'s  double-blinded, randomized, placebo-controlled, crossover study demonstrated that sildenafil citrate did not cause any statistically significant changes in the foveolar choroidal circulation of AMD patients. This was a limited study group of 15 subjects, however further illustrating the fact that the possible role of sildenafil citrate in AMD therapy is therefore questionable at the moment.
Fenretinide is a retinol analog that competitively binds to the retinol-binding protein in the circulation preventing the uptake of retinol by the RPE, thus downregulating photoreceptor metabolism. A Phase II multicenter, randomized, double-masked, placebo-controlled study of the safety and efficacy of fenretinide in the treatment of GA has been completed. The efficacy of 100 mg and 300 mg daily fenretinide in decreasing lesion growth was examined over 2 years. In the study of 246 patients, fenretinide treatment produced dose-dependent reversible reductions in serum retinol-binding protein-retinol which correlated with reduced lesion growth rates. The study also identified a second mechanism of fenretinide which is the reduced incidence of CNV (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose-dependent and is consistent with anti-angiogenic and anti-inflammatory properties of fenretinide, which have been observed in other pathologies such as neuroblastoma.
Downregulation of photoreceptor activity is also being investigated using emixustat hydrochloride (ACU-4429). ACU-4429, a small nonretinoid molecule, is a modulator of the isomerase (RPE65) required for the conversion of all-trans-retinol to 11-cis-retinal in the RPE. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors and decreases the accumulation of retinal toxic by-products such as A2E.
Seventy-two subjects in the US (54 emixustat and 18 placebo) were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. After 45 min dark adaptation, electroretinographic findings confirmed that emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner as is consistent with its mechanism of action. Suppression peaked by day 14 and was reversible within 7 days to 14 days after drug cessation. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved within 7–14 days after study drug cessation. Long-term therapy needs to be evaluated, especially the reversibility of adverse events.
5-HT1A agonists are neuroprotective in animal models of CNS ischemia  and MPTP-toxicity models of Parkinson. AL-8309B (Tandospirone) is a selective serotonin 1A receptor agonist that has been shown to protect both RPE and photoreceptors cells of albino rats from severe blue light-induced photo-oxidative stress. A completed controlled, double-masked, randomized, multicenter phase III clinical trial studied the effect of AL-8309B ophthalmic solution 1.0% and 1.75% on the growth of GA lesions in AMD patients. This study was the GA Treatment Evaluation trial. Unfortunately, fundus autofluorescence imaging showed an increase in mean lesion size in both the AL-8309B and vehicle treatment groups. Growth rates were also disappointingly similar in all treatment groups.
Ciliary neurotrophic factor-501
Ciliary neurotrophic factor (CNTF) is a cytokine member of the IL-6 family and a potent neuroprotective agent in multiple retinal degeneration animal models across a wide range of species (Wen et al., 2013). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, its mechanism of action remains poorly understood. Rhee et al. propose that exogenous CNTF initially targets Müller glia, and consequently induces cytokines acting through gp130 in photoreceptors to enhance cone and rod survival. Intravitreal-encapsulated CNTF sustained-release platform (CNTF/NT-501) that produces CNTF for a year or longer was developed by Neurotech Pharmaceuticals (RI, USA). It is an intraocular encapsulated cell technology (ECT) implant. A randomized Phase II trial evaluated the effect of an NT-501 implant in patients with retinitis pigmentosa and GA over a period of up to 2 years. CNTF was consistently released over a 2-year period. CNTF treatment resulted in a dose-dependent increase in retinal thickness and apparent stabilization of visual acuity in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. No benefit in terms of the progression of the lesion was demonstrated. These investigators concluded that the CNTF–ECT implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline. Kauper et al. showed that both the implant and the implant procedure were well-tolerated. CNTF, anti-CNTF antibodies, and antibodies to the encapsulated cells were not detected in the serum of patients.
Brimonidine is the second neuroprotective molecule under development. It is an alpha-2 adrenergic receptor agonist, which has been shown to be neuroprotective in animal models. The mechanism of action has not been elucidated. Multiple mechanisms have been proposed including upregulating the endogenous production of trophic factors in retinal ganglion cells, promotion of intracellular cell-survival signaling pathways, stabilization of mitochondrial transmembrane potential under oxidative stress, and diminution of glial cell activation and the immunoreactivity of retinal glial fibrillary acidic protein. A Phase II study used a sustained delivery system with biodegradable polymer matrix similar to the dexamethasone intravitreal implant (Ozurdex) model. Patients received either 200 μg or 400 μg of drug or a sham treatment. The study has been completed but results have not been published to date.
An innovative strategy for the preservation of photoreceptors and the RPE uses a therapeutic strategy for the treatment of Alzheimer's disease. Amyloid deposits (Aβ) accumulate in the drusen of AMD patients. This toxic by-product is targetted by RN6G - an intravenously administered, humanized monoclonal antibody that binds with high affinity to the Aβ peptides, Aβ40, and Aβ42. Systemic RN6G decreased the amount of ocular amyloid β in a mouse model of AMD. A Phase II multicenter, randomized, multidose study was completed in March 2015, however, the results have not been published to date.
Similar to intravenous RN6G, GSK933776 is a humanized monoclonal antibody targeting the toxic by-product amyloid β. It is delivered to the eye by an intravitreal injection. A Phase I study has been completed in patients with advanced AMD. A Phase II, multicenter, randomized, double-masked, placebo-controlled study, evaluating 6 monthly doses of 3 mg/kg, 6 mg/kg, and 15 mg/kg, on the growth of GA is currently underway.
Prevent oxidative stress injury
Age-related eye disease study formulation
Even though new antioxidants such as crocetin, curcumin, vitamins B6, B9, and B12, and resveratrol are being assessed, the Age-Related Eye Disease Study (AREDS) remains the gold standard for validating the importance of dietary supplementation in dry AMD. The AREDS2 study (published in 2013) examined in its primary randomization, adding carotenoid vitamins (lutein and zeaxanthin), as well as omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to the original AREDS formula. Lutein and zeaxanthin have a 40-carbon basal structure, which include conjugated double bonds (alternating double and single bonds). Chemical structures with conjugated bonds have the property of absorbing light in the visible range; lutein and zeaxanthin absorb blue visible light (400–500 nm). Carotenoids that are substituted with hydroxyl(–OH) functional groups are known as xanthophylls. Lutein and zeaxanthin are xanthophylls, and their hydroxyl groups enable passage through both blood-ocular and blood-brain barriers (Roberts and Dennison, Journal of Ophthalmology, in press http://www.hindawi.com/journals/joph/aip/687173/).
The original AREDS formula consisted of vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), zinc (80 mg), and copper (2 mg). However, carotenoids such as β-carotene contain only carbon and hydrogen atoms and do not cross the blood-brain or ocular barriers (Roberts and Dennison, Journal of Ophthalmology, in press http://www.hindawi.com/journals/joph/aip/687173/). Thus, secondary randomization included the original AREDS1 medication, the AREDS1 formulation without beta-carotene, the AREDS1 formulation with reduced zinc or the AREDS1 formulation without beta-carotene and low zinc. The AREDS 2 trial investigated the risk of progression to advanced AMD. The study demonstrated that the addition of lutein and zeaxanthin, DHA and EPA, or both to the AREDS formulation had no positive effect on the progression to advanced AMD. Subgroup analysis however revealed that patients who had a dietary deficiency of lutein and zeaxanthin benefited from these additional nutrients. There was no statistically significant difference between low- and high-dose zinc supplements which are particularly relevant due to the gastrointestinal and genitourinary side effects associated with zinc consumption. When comparing patients who took the AREDS supplement containing lutein and zeaxanthin with those who took beta-carotene, there was an 18% reduction in the development of advanced AMD. This multicenter, Phase III, randomized controlled clinical trial with 4186 participants showed that patients who took the supplement over 5 years had a 25% lower chance of progressing to advanced AMD than those who took placebo. Interestingly, the study showed that former smokers receiving the beta-carotene version of the AREDS formula had an increased risk of developing lung cancer. Thus, lutein and zeaxanthin may be a preferred beta-carotene substitute, in general, and especially so for smokers and ex-smokers.
The saffron extract (Crocus sativus L.) is a natural carotenoid dicarboxylic acid which seems to inhibit caspase activity. Experiments with albino rat models demonstrated that saffron may protect photoreceptor from retinal stress, preserving both morphology and function and probably acting as a regulator of apoptosis, in addition to its antioxidant and anti-inflammatory properties. In addition to being an antioxidant, results show that short-term saffron supplementation (for 3 months) improves retinal flicker sensitivity in early AMD. The clinical significance of this finding is yet to be assessed.
Curcumin may be another novel strategy to reduce lipid peroxidation and formation of reactive oxygen species. Zhu et al. used a pulsed H2O2 exposure aging model to investigate the effects of curcumin on aging RPE cells. Curcumin improved cell viability, decreased apoptosis, and decrease oxidative stress. In addition, curcumin had a significant influence on expression of apoptosis-associated proteins (Bax, Bcl-2, and caspase-3) and oxidative stress biomarkers (malondialdehyde, superoxide dismutase, and glutathione).
Vitamins B6, B9, and B12
Both cross-sectional  and case-control  studies have revealed a direct association between blood homocysteine concentrations and risk of AMD, suggesting that homocysteine may be a modifiable risk factor for AMD. The results for AMD from the Women's Antioxidant and Folic Acid Cardiovascular Study  showed that there was a statistically significant (35–40%) decreased the risk of AMD in participants who were given daily supplements of pyridoxine (vitamin B6), folic acid (vitamin B9), and cyanocobalamin (vitamin B12).
Resveratrol is a polyphenol phytoalexin present in many fruits and plants but is especially abundant in grape skin and seeds. Nagineni et al. demonstrated the dose-dependent (10–50 µM) inhibitory actions of resveratrol on inflammatory cytokine, TGF-β, and hypoxia-induced VEGF-A and VEGF-C secretion by human RPE cells prepared from aged human donor eyes.
The Phase II COMPLETE study was the first prospective, randomized, placebo-controlled investigation of complement inhibition for the treatment of AMD. Genetic polymorphisms and overactivity of the alternative complement pathway have been associated with the development of GA. Yehoshua et al. demonstrated the effect of intravenous eculizumab, an inhibitor of complement component (C5), on the growth of GA in patients with AMD. Eculizumab was well tolerated without adverse events; however, at 26 weeks, it did not decrease the growth rate of GA significantly or improve visual acuity. The authors argued that this result may have been because the cohort studied was small (30 eyes of 30 patients were enrolled) or because the drug needs to be delivered intravitreally to reach optimal levels at the retina or RPE. However, even Garcia Filho et al. in 2014 published that systemic complement inhibition with eculizumab did not significantly reduce drusen volume.
Ongoing clinical trials using other intravitreal drugs that target C5 and factor D (fD) will determine whether complement inhibition for the treatment of GA is a viable treatment strategy for AMD.
A Phase I Study of intravitreal ARC1905 (Anti-C5 Aptamer) in subjects with dry AMD has been completed (November 2012), but not yet published.
Anti-fD (FCFD4514S, lampalizumab, AFD) is a humanized IgG Fab fragment directed against fD, a rate-limiting serine protease in the alternative complement pathway (AP). AFD is a unique complement pathway inhibitor because it targets an amplification step in the complement cascade. The Phase II study assessing AFD is currently ongoing but not recruiting participants. Phase I study data indicated single-dose intravitreal FCFD4514S administrations were safe, well tolerated, and not associated with any study drug-related ocular or systemic adverse events. Loyet et al. have published data that casts some uncertainty about the upcoming results from the clinical trial. AFD was found to inhibit the systemic alternative complement pathway activity only when the molar concentration of AFD exceeded the molar concentration of fD. This observation was noted in cynomolgus monkeys at serum AFD levels that were 8-fold greater than the maximum serum concentration observed following a single 10 mg intravitreal dose in a clinical investigation in patients with GA. Therefore, it seems unlikely that the current intravitreal doses will produce a significant effect on systemic AP activity.
LFG316 is a human monoclonal C5 antibody. The Phase II clinical study determining the effect of 20 mg/0.2 ml in GA has been completed (June 2015), but results have not been published to date.
Glatiramer acetate (copaxone)
Glatiramer acetate is a small peptide that suppresses T cells, downregulates inflammation, and appears to reduce amyloid-induced retinal microglial cytotoxicity allowing a neuroprotective phenotype of microglia to form. It is currently used in the treatment of multiple sclerosis (FDA approved). Less drusen were noted in a small cohort of 8 Alzheimer's patients on glatiramer. However, fewer drusen in this cohort were not associated with improved vision. Subcutaneous 20 mg glatiramer acetate (NCT00541333) was administered weekly to patients with dry AMD for 12 weeks; there was a 19.2% reduction in drusen (compared with 6.5% in sham, P = 0.13). Drusen that were convex in shape had low internal reflectivity and high reflectivity were more susceptible to glatiramer acetate. Phase II and Phase III are inactive.
Fluocinolone acetonide (iluvien)
Fluocinolone acetonide (Alimera) is currently approved in Europe for diabetic macular edema. A Phase II randomized and double-masked trial was conducted for bilateral GA due to AMD treated with two doses of 0.2 and 0.5 µg/day intravitreal fluocinolone acetonide inserts. This study has been terminated and results have not been published to date.
Sirolimus binds with FK-binding protein 12 to inhibit mechanistic target of rapamycin. It is currently used in the prevention of coronary artery restenosis after balloon angioplasty. In Phase I/II trial, eight patients with bilateral GA received 440 mg subconjunctival sirolimus every 3 months and were followed for 24 months. At all study points, treated eyes had worse visual acuity than fellow control eyes. There was no statistically significant difference in lesion size, drusen area, central retinal thickness, or macular sensitivity. Intravitreal sirolimus was also demonstrated to not have any anatomical or functional ocular benefit.
Statins are hydroxymethylglutaryl coenzyme A reductase inhibitors known to have anti-inflammatory  and anti-angiogenic properties  in addition to their lipoprotein reducing ability. Barbosa et al. showed that statin use had a statistically significant effect in reducing AMD incidence in participants aged 68 years and older, however, not in patients aged 40–67 years. The authors proposed that this might be due to the fact that the benefit of statins in AMD is observed after long-term use. The association of statin intake and AMD remains controversial as demonstrated by a 2012 Cochrane database review. Gehlbach et al. included two random controlled trials (144 total participants from Italy and Australia) and showed that simvastatin did not seem to influence AMD prevention or delay progression. However, it could be argued that the data analyzed were not of high quality due to the short duration of treatment.
Heparin-induced extracorporeal lipoprotein precipitation
This therapy has previously been shown to reduce serum lipoproteins and fibrinogen by 50–60% through the application of heparin and lowering the pH value. Heparin-induced extracorporeal lipoprotein precipitation also reduces the levels of intercellular adhesion molecule adhesion molecules (involved in the development and progression of atherosclerosis) and improves coronary vasodilation capacity. A study of 22 participants undergoing eight treatments over 12 weeks has been completed; however, published results are not currently available.
Borrelli et al.'s study suggests that ozonated autohemotherapy could be a safe and effective therapeutic option for dry AMD patients. In this trial, 70 patients underwent ozone therapy whereas the 70 controls only received multivitamin supplements. At 6 months, none of the eyes treated with ozone had deterioration in BCVA more than 2 lines whereas 16% of the control group eyes had more than 2 lines loss, 25% had more than 3 lines loss (P< 0.05). At 1 year, none of the treated eyes had a loss of more than 2 or 3 lines in BCVA compared to more than 2 line loss of 40% and more than 3 line loss of 38% in the control group patients (P< 0.05). The plasma oxidative stress was significantly decreased after treatment confirming the role of antioxidant enzymes in the increase and the reduction of the oxidative stress.
Ozonated autohemotherapy is believed to trigger certain defense mechanisms against ischemic and neurotoxic injury, thus preventing photoreceptor death. In their review article (2013), Borrelli and Bocci proposed that this therapy works via the following mechanisms:
- Improvement of blood rheology
- Improvement of the glycolytic pathways on erythrocytes. The increased concentration of adenosine triphosphate levels may facilitate a micro release at hypoxic sites
- Activation of the hexose-monophosphate shunt on erythrocytes with increased levels of 2,3-DPG particularly if the patient has had a low level. This change increases oxygen availability to hypoxic tissues due to a shift to the right of the HbO2 dissociation curve
- Vasodilation due to enhanced release of nitric oxide and prostacyclin
- Release of growth factors from platelets
- Upregulation of antioxidant enzymes, phase 2-proteins, and heme-oxygenase-1 with release of CO and bilirubin.
Stem cell therapy
Induced pluripotent stem cell-derived human RPE have increasingly gained attention in biomedicine as they have been shown to rescue the retina in animal models of retinal degeneration involving RPE mutations. While some studies practice the technique of integrating cell replacement strategies in the eye to functionally replace RPE, others use cell injections that produce their effects by influencing the nature of thein vivo inflammatory environment or by releasing neuroprotective cytokines. Transplantation of rod precursors has shown improved vision in mice that lack rod function., At the frontline at the moment is the simultaneous transplantation of photoreceptors and RPE cells (Carr et al., 2013).
Although little is known about the etiology of AMD, it is widely acknowledged that genetics plays an important role, for example, CFH or age-related maculopathy susceptibility 2 (ARMS2) (Priya et al., 2012; Gorin et al., 2012)., AMD is a challenging disease to study from a genetic viewpoint because its development and progression are multifactorial, and it is a heterogeneous disease, suggesting that there may be different disease mechanisms involved. Hence, different genes may cause the various clinical subtypes. Future developments could lead using genetic analysis to aid clinicians in tailoring personalized treatments. Gene therapy for targeting autophagic pathways, in particular, is an exciting future possibility, especially as gene transfer of master autophagy regulator TFEB in transgenic mice, has been shown to result in a significant reduction in hepatotoxic ATZ levels in alpha-1-anti-trypsin deficiency. Currently, genetics has helped us in the risk prediction of disease development or progression. Treatments based on such facts are more suited for prevention rather than treatment of manifest disease. As a consequence, future research in AMD needs to be significantly focused on approaches relevant to the patients and their medical needs.
Implantable miniature telescope
Most clinical trials on AMD focus on preventing the development of AMD development or reducing progression. Therapeutic options for patients with bilateral central scotomas due to end-stage AMD are very restricted.
Boyer et al. carried out the first prospective, open-label, multicenter clinical trial, with fellow eye controls, evaluating the long-term (60 months) results of an implantable miniature telescope (IMT) in patients with bilateral, end-stage AMD (NCT00976235). Cataracts were extracted and replaced by an intraocular lens which provided 3 times larger magnification. This Phase III study showed a significant preservation of improvement in best-corrected distance visual acuity (BCDVA). Mean BCDVA improvement from baseline to 60 months was 2.41 ± 2.69 lines in all patients. Younger patients (65 years to <75 years) retained more vision than their older ( ≥75 years) counterparts and had fewer complications. The most common significant surgery-related ocular complications in the younger age group were iritis >30 days postoperatively (10%) and persistent corneal edema (4.3%). In their older counterparts, a decrease in BCDVA in the implanted eye or IMT removal (7.9%), corneal edema >30 days postoperatively (7.1%), and persistent corneal edema (4.7%) were more common. Four patients required corneal transplants. On IMT explanation, a conventional intraocular lens was placed.
Telescope contact lenses
This is a new option and some details are provided through http://www.sciencedaily.com/releases/2015/02/150213145049.htm, however no clinical trials have been performed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Friedman DS, O'Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, et al.
Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-72.
Coleman HR, Chan CC, Ferris FL 3rd
, Chew EY. Age-related macular degeneration. Lancet 2008;372:1835-45.
Chen Y, Bedell M, Zhang K. Age-related macular degeneration: Genetic and environmental factors of disease. Mol Interv 2010;10:271-81.
Alten F, Eter N. Current knowledge on reticular pseudodrusen in age-related macular degeneration. Br J Ophthalmol 2015;99:717-22.
Tarttelin EE, Gregory-Evans CY, Bird AC, Weleber RG, Klein ML, Blackburn J, et al.
Molecular genetic heterogeneity in autosomal dominant drusen. J Med Genet 2001;38:381-4.
Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, et al.
Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001;108:697-704.
Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;276:1141-6.
Kabasawa S, Mori K, Horie-Inoue K, Gehlbach PL, Inoue S, Awata T, et al.
Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population. Ophthalmology 2011;118:1082-8.
Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: Association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol 2003;121:1728-37.
Gao J, Liu RT, Cao S, Cui JZ, Wang A, To E, et al.
NLRP3 inflammasome: Activation and regulation in age-related macular degeneration. Mediators Inflamm 2015;2015:690243.
Chan CC, Ardeljan D. Molecular pathology of macrophages and interleukin-17 in age-related macular degeneration. Adv Exp Med Biol 2014;801:193-8.
Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, Cohen C, et al.
Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 2002;8:119-26.
Laudisi F, Spreafico R, Evrard M, Hughes TR, Mandriani B, Kandasamy M, et al.
Cutting edge: The NLRP3 inflammasome links complement-mediated inflammation and IL-1ß release. J Immunol 2013;191:1006-10.
Ardeljan D, Wang Y, Park S, Shen D, Chu XK, Yu CR, et al.
Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: Implications for age-related macular degeneration. PLoS One 2014;9:e95900.
Yehoshua Z, Rosenfeld PJ, Albini TA. Current clinical trials in dry AMD and the definition of appropriate clinical outcome measures. Semin Ophthalmol 2011;26:167-80.
Penfold PL, Killingsworth MC, Sarks SH. Senile macular degeneration: The involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol 1985;223:69-76.
Erwig LP, Henson PM. Immunological consequences of apoptotic cell phagocytosis. Am J Pathol 2007;171:2-8.
Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity 2005;23:344-6.
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013;229:176-85.
Biswas SK, Chittezhath M, Shalova IN, Lim JY. Macrophage polarization and plasticity in health and disease. Immunol Res 2012;53:11-24.
Cao X, Shen D, Patel MM, Tuo J, Johnson TM, Olsen TW, et al.
Macrophage polarization in the maculae of age-related macular degeneration: A pilot study. Pathol Int 2011;61:528-35.
Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, et al.
Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194-8.
Hollyfield JG, Perez VL, Salomon RG. A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol 2010;41:290-8.
Gupta N, Brown KE, Milam AH. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 2003;76:463-71.
Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, et al.
CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 2007;117:2920-8.
Gasque P. Complement: A unique innate immune sensor for danger signals. Mol Immunol 2004;41:1089-98.
Janeway CA Jr., Travers P, Walport M, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology: The Immune System in Health and Disease. 5th
ed. New York, USA: Garland Science; 2001.
Tuo J, Grob S, Zhang K, Chan CC. Genetics of immunological and inflammatory components in age-related macular degeneration. Ocul Immunol Inflamm 2012;20:27-36.
Chen Y, Zeng J, Zhao C, Wang K, Trood E, Buehler J, et al.
Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol 2011;129:344-51.
Kawa MP, Machalinska A, Roginska D, Machalinski B. Complement system in pathogenesis of AMD: Dual player in degeneration and protection of retinal tissue. J Immunol Res 2014;2014:483960.
Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, et al.
Drusen proteome analysis: An approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A 2002;99:14682-7.
Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835-46.
Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH. A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70:441-9.
Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001;73:887-96.
Chen H, Liu B, Lukas TJ, Neufeld AH. The aged retinal pigment epithelium/choroid: A potential substratum for the pathogenesis of age-related macular degeneration. PLoS One 2008;3:e2339.
Chen M, Muckersie E, Robertson M, Forrester JV, Xu H. Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 2008;87:543-50.
Chen M, Forrester JV, Xu H. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 2007;84:635-45.
Kim YH, He S, Kase S, Kitamura M, Ryan SJ, Hinton DR. Regulated secretion of complement factor H by RPE and its role in RPE migration. Graefes Arch Clin Exp Ophthalmol 2009;247:651-9.
Yang P, Tyrrell J, Han I, Jaffe GJ. Expression and modulation of RPE cell membrane complement regulatory proteins. Invest Ophthalmol Vis Sci 2009;50:3473-81.
Kutikhin AG, Yuzhalin AE. Editorial: Pattern recognition receptors and cancer. Front Immunol 2015;6:481.
Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821-32.
Menu P, Vince JE. The NLRP3 inflammasome in health and disease: The good, the bad and the ugly. Clin Exp Immunol 2011;166:1-15.
Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 2011;29:707-35.
Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 2009;10:241-7.
Hageman GS, Luthert PJ, Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-32.
Dentchev T, Milam AH, Lee VM, Trojanowski JQ, Dunaief JL. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol Vis 2003;9:184-90.
Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, et al.
DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 2012;149:847-59.
Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D'Amore PA, et al.
NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: Implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 2013;54:110-20.
Anderson OA, Finkelstein A, Shima DT. A2E induces IL-1ß production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One 2013;8:e67263.
Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K. Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells – Implications for age-related macular degeneration (AMD). Immunol Lett 2012;147:29-33.
Cao S, Ko A, Partanen M, Pakzad-Vaezi K, Merkur AB, Albiani DA, et al.
Relationship between systemic cytokines and complement factor H Y402H polymorphism in patients with dry age-related macular degeneration. Am J Ophthalmol 2013;156:1176-83.
Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, et al.
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011;471:325-30.
Mills KH, Dungan LS, Jones SA, Harris J. The role of inflammasome-derived IL-1 in driving IL-17 responses. J Leukoc Biol 2013;93:489-97.
Cookson BT, Brennan MA. Pro-inflammatory programmed cell death. Trends Microbiol 2001;9:113-4.
Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417-26.
Fink SL, Cookson BT. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 2006;8:1812-25.
Cook KL, Soto-Pantoja DR, Abu-Asab M, Clarke PA, Roberts DD, Clarke R. Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy. Cell Biosci 2014;4:16.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al.
Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 2009;16:3-11.
Ardeljan CP, Ardeljan D, Abu-Asab M, Chan CC. Inflammation and cell death in age-related macular degeneration: An immunopathological and ultrastructural model. J Clin Med 2014;3:1542-60.
Cohen SY, Bourgeois H, Corbe C, Chaine G, Espinasse-Berrod MA, Garcia-Sanchez J, et al.
Randomized clinical trial France DMLA2: Effect of trimetazidine on exudative and nonexudative age-relatedmacular degeneration. Retina 2012;32:834-43.
Grunwald JE, Hariprasad SM, DuPont J. Effect of aging on foveolar choroidal circulation. Arch Ophthalmol 1998;116:150-4.
Grunwald JE, Metelitsina TI, Dupont JC, Ying GS, Maguire MG. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 2005;46:1033-8.
Augustin AJ, Diehm C, Grieger F, Bentz J. Alprostadil infusion in patients with dry age related macular degeneration: A randomized controlled clinical trial. Expert Opin Investig Drugs 2013;22:803-12.
Asahi MG, Chou C, Gallemore RP. Acute macular edema following intracorporeal prostaglandin injection for erectile dysfunction. Int Med Case Rep J 2015;8:141-4.
Resch H, Weigert G, Karl K, Pemp B, Garhofer G, Schmetterer L. Effect of systemic moxaverine on ocular blood flow in humans. Acta Ophthalmol 2009;87:731-5.
Pemp B, Garhofer G, Lasta M, Schmidl D, Wolzt M, Schmetterer L. The effects of moxaverine on ocular blood flow in patients with age-related macular degeneration or primary open angle glaucoma and in healthy control subjects. Acta Ophthalmol 2012;90:139-45.
Berg G, Andersson RG, Ryden G. Effects of different phosphodiesterase-inhibiting drugs on human pregnant myometrium: Anin vitro
study. Arch Int Pharmacodyn Ther 1987;290:288-92.
Schmidl D, Pemp B, Lasta M, Boltz A, Kaya S, Palkovits S, et al.
Effects of orally administered moxaverine on ocular blood flow in healthy subjects. Graefes Arch Clin Exp Ophthalmol 2013;251:515-20.
Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. Effect of Viagra on the foveolar choroidal circulation of AMD patients. Exp Eye Res 2005;81:159-64.
Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 2013;33:498-507.
Di Paolo D, Pastorino F, Zuccari G, Caffa I, Loi M, Marimpietri D, et al.
Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma. J Control Release 2013;170:445-51.
Dugel PU, Novack RL, Csaky KG, Richmond PP, Birch DG, Kubota R. Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina 2015;35:1173-83.
Saruhashi Y, Matsusue Y, Hukuda S. Effects of serotonin 1A agonist on acute spinal cord injury. Spinal Cord 2002;40:519-23.
Bezard E, Gerlach I, Moratalla R, Gross CE, Jork R. 5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease. Neurobiol Dis 2006;23:77-86.
Collier RJ, Wang Y, Smith SS, Martin E, Ornberg R, Rhoades K, et al.
Complement deposition and microglial activation in the outer retina in light-induced retinopathy: Inhibition by a 5-HT1A agonist. Invest Ophthalmol Vis Sci 2011;52:8108-16.
Jaffe GJ, Schmitz-Valckenberg S, Boyer D, Heier J, Wolf-Schnurrbusch U, Staurenghi G, et al.
Randomized trial to evaluate tandospirone in geographic atrophy secondary to age-related macular degeneration: The GATE study. Am J Ophthalmol 2015;160:1226-34.
Wen R, Tao W, Li Y, Sieving PA. CNTF and retina. Prog Retin Eye Res 2012;31:136-51.
Rhee KD, Nusinowitz S, Chao K, Yu F, Bok D, Yang XJ. CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells. Proc Natl Acad Sci U S A 2013;110:E4520-9.
Zhang K, Hopkins JJ, Heier JS, Birch DG, Halperin LS, Albini TA, et al.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 2011;108:6241-5.
Kauper K, McGovern C, Sherman S, Heatherton P, Rapoza R, Stabila P, et al.
Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest Ophthalmol Vis Sci 2012;53:7484-91.
Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol 2003;48 Suppl 1:S47-51.
Kupperman BD. Drug Delivery Implants for Geographic Atrophy. Retina Today; May, 2012.
Ding J, Lin J, Mace BE, Herrmann R, Sullivan P, Bowes Rickman C. Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: Anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res 2008;48:339-45.
Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm 2015;95(Pt B):158-72.
Age-Related Eye Disease Study Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-related eye disease study 2 (AREDS2) randomized clinical trial. JAMA 2013;309:2005-15.
Maccarone R, Di Marco S, Bisti S. Saffron supplement maintains morphology and function after exposure to damaging light in mammalian retina. Invest Ophthalmol Vis Sci 2008;49:1254-61.
Bisti S, Maccarone R, Falsini B. Saffron and retina: Neuroprotection and pharmacokinetics. Vis Neurosci 2014;31:355-61.
Falsini B, Piccardi M, Minnella A, Savastano C, Capoluongo E, Fadda A, et al.
Influence of saffron supplementation on retinal flicker sensitivity in early age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:6118-24.
Mandal MN, Patlolla JM, Zheng L, Agbaga MP, Tran JT, Wicker L, et al.
Curcumin protects retinal cells from light-and oxidant stress-induced cell death. Free Radic Biol Med 2009;46:672-9.
Zhu W, Wu Y, Meng YF, Wang JY, Xu M, Tao JJ, et al.
Effect of curcumin on aging retinal pigment epithelial cells. Drug Des Devel Ther 2015;9:5337-44.
Rochtchina E, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum Vitamin B12, folate, and age-related macular degeneration: The Blue Mountains Eye Study. Am J Ophthalmol 2007;143:344-6.
Kamburoglu G, Gumus K, Kadayifcilar S, Eldem B. Plasma homocysteine, Vitamin B12 and folate levels in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2006;244:565-9.
Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: The women's antioxidant and folic acid cardiovascular study. Arch Intern Med 2009;169:335-41.
Nagineni CN, Raju R, Nagineni KK, Kommineni VK, Cherukuri A, Kutty RK, et al.
Resveratrol suppresses expression of VEGF by human retinal pigment epithelial cells: Potential nutraceutical for age-related macular degeneration. Aging Dis 2014;5:88-100.
Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, Gregori G, Penha FM, Moshfeghi AA, et al.
Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: The COMPLETE study. Ophthalmology 2014;121:693-701.
Garcia Filho CA, Yehoshua Z, Gregori G, Nunes RP, Penha FM, Moshfeghi AA, et al.
Change in drusen volume as a novel clinical trial endpoint for the study of complement inhibition in age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina 2014;45:18-31.
Do DV, Pieramici DJ, van Lookeren Campagne M, Beres T, Friesenhahn M, Zhang Y, et al.
Aphase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy. Retina 2014;34:313-20.
Loyet KM, Good J, Davancaze T, Sturgeon L, Wang X, Yang J, et al.
Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration. J Pharmacol Exp Ther 2014;351:527-37.
Landa G, Butovsky O, Shoshani J, Schwartz M, Pollack A. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration. Curr Eye Res 2008;33:1011-3.
Landa G, Rosen RB, Patel A, Lima VC, Tai KW, Perez VR, et al.
Qualitative spectral OCT/SLO analysis of drusen change in dry age-related macular degeneration patients treated with Copaxone. J Ocul Pharmacol Ther 2011;27:77-82.
Medina A, Suarez de Lezo J, Pan M, Delgado A, Segura J, Pavlovic D, et al.
Sirolimus-eluting stents for treatment of in-stent restenosis: Immediate and late results. Tex Heart Inst J 2005;32:11-5.
Wong WT, Dresner S, Forooghian F, Glaser T, Doss L, Zhou M, et al.
Treatment of geographic atrophy with subconjunctival sirolimus: Results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013;54:2941-50.
Chuo JY, Wiens M, Etminan M, Maberley DA. Use of lipid-lowering agents for the prevention of age-related macular degeneration: A meta-analysis of observational studies. Ophthalmic Epidemiol 2007;14:367-74.
Sagara N, Kawaji T, Takano A, Inomata Y, Inatani M, Fukushima M, et al.
Effect of pitavastatin on experimental choroidal neovascularization in rats. Exp Eye Res 2007;84:1074-80.
Barbosa DT, Mendes TS, Cíntron-Colon HR, Wang SY, Bhisitkul RB, Singh K, et al.
Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): Results from the national health and nutrition examination survey 2005-2008. Eye (Lond) 2014;28:472-80.
Gehlbach P, Li T, Hatef E. Statins for age-related macular degeneration. Cochrane Database Syst Rev 2012;3:CD006927.
Mellwig KP. Heparin-induced extracorporeal low-density lipoprotein precipitation. Ther Apher Dial 2003;7:365-9.
Borrelli E, Diadori A, Zalaffi A, Bocci V. Effects of major ozonated autohemotherapy in the treatment of dry age related macular degeneration: A randomized controlled clinical study. Int J Ophthalmol 2012;5:708-13.
Borrelli E, Bocci V. Visual improvement following ozonetherapy in dry age related macular degeneration; a review. Med Hypothesis Discov Innov Ophthalmol 2013;2:47-51.
Carr AJ, Vugler AA, Hikita ST, Lawrence JM, Gias C, Chen LL, et al
. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One 2009;4:e8152.
Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, et al.
Restoration of vision after transplantation of photoreceptors. Nature 2012;485:99-103.
Singh MS, Charbel Issa P, Butler R, Martin C, Lipinski DM, Sekaran S, et al.
Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci U S A 2013;110:1101-6.
Carr AJ, Smart MJ, Ramsden CM, Powner MB, da Cruz L, Coffey PJ. Development of human embryonic stem cell therapies for age-related macular degeneration. Trends Neurosci 2013;36:385-95.
Gorin MB. Genetic insights into age-related macular degeneration: Controversies addressing risk, causality, and therapeutics. Mol Aspects Med 2012;33:467-86.
Pastore N, Blomenkamp K, Annunziata F, Piccolo P, Mithbaokar P, Maria Sepe R, et al.
Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol Med 2013;5:397-412.
Boyer D, Freund KB, Regillo C, Levy MH, Garg S. Long-term (60-month) results for the implantable miniature telescope: Efficacy and safety outcomes stratified by age in patients with end-stage age-related macular degeneration. Clin Ophthalmol 2015;9:1099-107.
[Figure 1], [Figure 2]