|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 Jan 20];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|
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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|
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|Figure 2: Flow chart of pathophysiology steps targeted in different recent clinical trials|
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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.
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