Review Article Future Therapies of Wet Age-Related Macular ...downloads.hindawi.com/journals/joph/2015/138070.pdf · in patients with age-related macular degeneration (EMER-ALD),

Review ArticleFuture Therapies of Wet Age-Related Macular Degeneration

Makoto Ishikawa Daisuke Jin Yu Sawada Sanae Abe and Takeshi Yoshitomi

Department of Ophthalmology Akita Graduate University School of Medicine Akita 010-8543 Japan

Correspondence should be addressed to Makoto Ishikawa makomedakita-uacjp

Received 22 December 2014 Accepted 10 February 2015

Academic Editor Lawrence S Morse

Copyright copy 2015 Makoto Ishikawa et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population and the prevalence of thedisease increases exponentially with every decade after the age of 50 years While VEGF inhibitors are promising drugs for treatingpatients with ocular neovascularization there are limitations to their potential for improving vision in AMD patients Thus futuretherapies are required to have the potential to improve visual outcomes This paper will summarize the future strategies andtherapeutic targets that are aimed at enhancing the efficacy and duration of effect of antiangiogenic strategies

1 Introduction

Age-related macular degeneration (AMD) is a leading causeof blindness that affects the macular region of elderly indi-viduals [1] The early phase of AMD is characterized by RPEchanges and subretinal deposits (drusen) between the retinalpigmented epithelium (RPE) and Bruchrsquos membrane [2] Thedisease can progress to either choroidal neovascularization(CNV) a rapidly deteriorating late form of AMD character-ized by new blood vessels that invade themacula (wet AMD)or to geographic atrophy (dryAMD) a slower late onset formthat causes degeneration of the RPE in the macula [3]

It has been known that vascular endothelial growth factor(VEGF) is the most important angiogenic regulator of CNV[4] and a prominent promoter of vascular permeability inAMD [5 6] For this reason VEGF is a key target in treatingAMD Current treatment of wet AMD involves the inhibitionof VEGF via intravitreal injection of VEGF inhibitors (beva-cizumab pegaptanib ranibizumab or aflibercept) [7]

While VEGF inhibitors are promising drugs for treatingpatients with ocular neovascularization there are limitationsfor ameliorating vision in wet AMD patients [8] Anti-VEGFtherapy also requires monthly or bimonthly injections andassessments to determine whether patients have respondedto the treatment [8]These injections and clinical assessmentsmay impose an enormous drain on patients as well asophthalmologists [8] Therefore it is required to develop

options that have the potential not only to reduce patientvisits and injections but also to improve visual outcomesby increasing drug effectiveness and lengthening treatmentdurability [8]

While the VEGF pathways have proven to be a successfultarget in AMD treatment there aremany other new therapiesand approaches in the pipeline which hold promise forimproving the treatment of wet AMD [7] As our understand-ing of themolecularmechanisms involved inAMD increasesmultiple new treatments are emerging In this review wedescribe the present knowledge concerning the therapeutictargets of AMD and investigational drugs and treatmentslisted in Table 1

2 PDGF Inhibition

Platelet-derived growth factor (PDGF) stimulates angiogen-esis as well as pericyte recruitment and maturation [9] Per-icytes play an important role in protection of endothelialcells against VEGF inhibition [10 11] Consistently inhibitionof PDGF increases endothelial cell sensitivity to anti-VEGFagents [10 12]

E10030 (Ophthotech Corporation Princeton NJ USA)is an aptamer directed against PDGF and is currentlyenrolling in parallel phase 3 clinical trials in combina-tion with anti-VEGF injections (ClinicalTrialsgov identifier

Hindawi Publishing CorporationJournal of OphthalmologyVolume 2015 Article ID 138070 10 pageshttpdxdoiorg1011552015138070

2 Journal of Ophthalmology

Table 1 Summary of neovascular AMD therapeutic agents mechanisms route and phase of development

Agent Mechanism Treatment Phase

E10030 Platelet-derived growth factor (PDGF)inhibitor iv 3

Sirolimus Mammalian target of rapamycin(mTOR) inhibitor

ivsc 2

Infliximab Anti-tumor necrosis factor alpha(TNF-120572) antibody iv 1

POT-4 Complement component 3 (C3)inhibitor iv 2

JSM6427 Integrin receptor antagonist iv 1Volociximab Anti-120572v1205731 integrin monocle antibody iv 1ALG-1001 Integrin receptor antagonist iv 2a

ATG003 Nicotinic acetylcholine receptor(nAchR) antagonist Eye drop 2

AdPEDF11 Transgene for cDNA of human PEDF iv 1Methotrexate Antifolate drug iv mdashTriple combination therapy(verteporfin-ranibizumab-dexamethasone)

Targeting multiple components ofchoroidal neovascularization

iv(ranibizumab dexamethasone)

after VPDT2

iv intravitreal injection sc subconjunctival injectionVPDT verteporfin photodynamic therapy

NCT01940900) E10030 decreases pericyte density in neovas-cular vessels and therefore improves the effect of anti-VEGFagents [12]

A phase 1 study of patients (119899 = 22) evaluated intravi-treal E10030 in combination with ranibizumab (a phase 1safety tolerability and pharmacokinetic profile of intravi-treous injections of E10030 (anti-PDGF pegylated aptamer)in subjects with neovascular age-related macular degener-ation ClinicalTrialsgov identifier NCT00569140) In thecombination group 59 of patients experienced at least athree-line gain in visual acuity by 12 weeks (a phase 1 safetytolerability and pharmacokinetic profile of intravitreousinjections of E10030 (anti-PDGF pegylated aptamer) insubjects with neovascular age-related macular degener-ation ClinicalTrialsgov identifier NCT00569140 Clini-calTrialsgov online httpwwwclinicaltrialsgovct2showNCT00569140 accessed December 27 2009)

A phase 2 clinical trial evaluated the efficacy and safetyof E10030 administered in combination with an anti-VEGFagent for the treatment of patients newly diagnosed with wetAMD The trial enrolled 449 patients at approximately 69centers inNorthAmerica SouthAmerica Europe and Israeland E10030 (03mg or 15mg) administered in combinationwith ranibizumab injection (05mg) demonstrated statis-tically significant improvement compared to ranibizumabmonotherapy based on the primary endpoint ofmean changein visual acuity from baseline at 24 weeks The proportionsof subjects gaining 15 or more ETDRS letters from baselineat the week 24 visit are 391 versus 340 in patientsreceiving the combination therapy (15mg of E10030 and05mg ranibizumab) and ranibizumab monotherapy respec-tively E10030 exhibited a favorable safety profile and no

serious adverse effects were observed for E10030 combinationtherapy as compared to ranibizumab monotherapy

3 Anti-Immune orAnti-Inflammatory Pathways

Recently comparative transcriptome analysis of AMD andnormal humandonor eyes has yielded important insights intoAMD including the molecular pathways underlying AMDrsquosonset and progression [13] Newman et al [13] reported cell-mediated immune responses as the central feature of allAMD phenotypes Therefore addressing the role of immuneresponse in the pathogenesis of ocular neovascularizationmay be a promising avenue for identifying targets for AMDtreatments

31 mTOR Mammalian target of rapamycin (mTOR) is anevolutionarily conserved serinethreonine kinase that playsa central role in integrating environmental cues in the formof growth factors amino acids and energy [14] In the studyof the immune system mTOR is emerging as a criticalregulator of immune function because of its role in sensingand integrating cues from the immune microenvironment[14]

Sirolimus (previously known as rapamycin Santen Phar-maceutical Inc Osaka Kapan and MacuSight Inc UnionCity CA) was originally developed as a macrolide antifungalagent but was found to possess potent immunosuppressiveand antiproliferative properties Sirolimus blocks the T-lymphocyte activation and smooth muscle and endothelialcell proliferation that occurs in response to antigenic and

Journal of Ophthalmology 3

cytokine (interleukins IL-2 IL-4 and IL-15) stimulationthrough either calcium-dependent or calcium-independentpathways Sirolimus arrests cell cycle progression by directinteraction with two intracellular proteins (immunophilinFK binding protein 12 (FKBP-12) and the mammalian targetof rapamycin (mTOR) a multifunctional serine-threoninekinase) [15] In cells sirolimus binds to FKBP-12 and theresulting sirolimus-FKBP-12 complex then binds to andinhibits mTOR [15] Sirolimus is used to prevent rejectionafter organ transplantation particularly after renal transplan-tation [15] Sirolimus markedly inhibits response of vascularendothelial cells to stimulation by VEGF [16] and inhibitshypoxia-inducible factor-1120572 a major upstream regulator ofVEGF [17] In a murine AMD model systemic adminis-tration of sirolimus inhibited both choroidal and retinalneovascularization [18 19]

A phase 1 study of 30 patients found that intravitreallyand subconjunctivally injected sirolimus was safe and welltolerated in doses tested (phase 12 study of an ocular sir-olimus (rapamycin) formulation in patients with age-related macular degeneration ClinicalTrialsgov identifierNCT00712491 ClinicalTrialsgov online httpwwwclinical-trialsgovct2showNCT00712491) A single intravitrealadministration of sirolimus (352 120583g) was associated withimprovement in visual acuity Additionally patients alsoexperienced anatomical improvements as demonstrated bya reduction in retinal thickness Preliminary findings sug-gested that subconjunctival administration (sirolimus1320 120583g) was as effective as intravitreal sirolimus injectionMacuSight Inc (Union City CA) announces positive pre-liminary results from phase 1 study of sirolimus in wetage-relatedmacular degeneration (httpwwwmedicalnews-todaycomarticles98491php accessed December 26 2008)Although intravitreal injection is the standard route ofadministration for current anti-VEGF therapies it isuncomfortable for many patients and are accompanied bythe risk of infection in a small percentage of patients Incontrast subconjunctival injections are designed to offerphysicians and patients a less invasive and more convenientprocedure

A phase 2 trial examined subconjunctival sirolimus(440 120583g or 1320 120583g) in combination with intravitreal rani-bizumab (500120583g) (phase 2 study of an ocular sirolimus(rapamycin) formulation in combination with ranibizumabin patients with age-related macular degeneration (EMER-ALD) ClinicalTrialsgov identifier NCT00766337)

A phase 12 study is underway and is examining theeffect of intravitreal sirolimus in the treatment of bilateralgeographic atrophy associated with AMD (ClinicalTri-alsgov identifier NCT01445548 ClinicalTrialsgov onlinehttpwwwclinicaltrialsgovct2showNCT01445548)

Results from earlier phase 1 and phase 2 studies showedthat the drug was safe and well tolerated There was noevidence of increased intraocular pressure inflammatoryresponse to treatment or indication of progression ofcataracts Patients showed improvements in visual acuity andimprovements in retinal thickness

32 TNF-120572 Tumor necrosis factor alpha (TNF-120572) is the pro-totypic ligand of theTNF superfamily It is a keymolecule thatplays a central role in inflammation apoptosis and immunesystem The anti-TNF-120572 monoclonal antibody infliximab(Remicade Centocor Inc Horsham PA USA) is used forvarious inflammatory diseases such as rheumatoid arthritisinflammatory bowel disease psoriasis and noninfectiousuveitis Regression of CNV and improvement of visual acuitywere reported in three wet AMD patients treated withintravenous infliximab for inflammatory arthritis [20 21] Ithas been reported that intravitreal infliximab also inhibitedlaser-induced CNV in rats [22] Subsequent experimentsrevealed that intravitreally administered infliximab is safelyincreased up to 2mg in the rabbit eye [23] Such doses canbe used in the design of future clinical trials assessing theeffects of infliximab for selected patients with immune-mediated ocular conditions [23] It has been also reportedthat intravitreal infliximabwas administered to three patientswith wet AMD resulting in improved visual acuity andcentral foveal thickness on OCT [24]

A phase 1 study is now underway and is evaluating int-ravitreal infliximab for wet AMD as well as for refractorydiabetic macular edema (intravitreal infliximab for diabe-tic macular edema (DME) and choroidal neovascularization(CNV) (ITVR) (ClinicalTrialsgov identifier NCT00695682ClinicalTrialsgov online httpwwwclinicaltrialsgovct2showNCT00695682))

33 Complement Component 3 Complement component 3often simply called C3 is a protein of the immune system Itplays a central role in the complement system and contributesto innate immunity Complement component 3 (C3) isdetected in the vicinity of the drusen [25 26] Genetic studiesrevealed highly significant statistical associations betweenAMD and variants of C3 gene [27ndash30] C3 induces VEGFexpression in vivo and in vitro and C3 gene polymorphismincreases the risk of AMD [30] Thus inhibition of C3suppresses complement cascade activation that could leadto local inflammation tissue damage and upregulation ofVEGF [31]

Thus inhibition of immune pathways may play a thera-peutic role in wet AMD POT-4 (Potentia PharmaceuticalsLouisville KY USA) binds and inhibits C3 [32] POT-4 is asynthetic peptide of 13 amino acids and ldquogel-likerdquo productwhen injected into the vitreous The effect is long-lasting (3to 6 months) A phase 1 study will provide safety and tol-erability information on POT-4 injected into the eyes ofpatients with wet AMD (Potentia pharmaceuticalsrsquo POT-4drug candidate for age-relatedmacular degeneration success-fully completes phase 1 clinical trial httpwwwmedical-newstodaycomarticles148725php) POT-4 also demon-strated therapeutic efficacy in a few end-stage wet AMDpatients (safety of intravitreal POT-4 therapy for patientswithneovascular age-related macular degeneration (AMD)(ASaP) ClinicalTrialsgov identifier NCT00473928 httpwwwclinicaltrialsgovct2showNCT00473928) A phase 2study to further define the safety efficacy and pharmacok-inetic profile of POT-4 is planning


Taken together innovation of immunotherapy that canprevent inflammatory damage to retinal tissue may inhibitdrusen formation during the early stages of AMD and afforda therapeutic to delay vision loss

4 Integrin Receptor Antagonist

Integrins are transmembranous proteins that mediate theattachment between a cell and its surrounding ECM Theligands of integrins are defined as fibronectin vitronectincollagen and laminin [33] Integrins are composed of 120572 and120573 subunits that heterodimerize to produce more than 20different receptors capable of mediating a variety of cellresponses such as spreading and migration control of geneexpression growth and differentiation [34ndash39]

Integrin 120572v1205735 localized at the apical surface of RPE bindsto ligands in the interphotoreceptor matrix (IPM) [40] andparticipates in the interactions between photoreceptors andthe RPE [41] In 1205735 integrin-deficient mice which specificallylack 120572v1205735 integrins retinal adhesion and phagocytosis ofphotoreceptor outer segments are compromised With agelack of 120572v1205735 leads to declined retinal photoresponses andaccumulation of autofluorescent storage bodies in the RPE[40]

In pathologic condition such as proliferative vitreoret-inopathy altered patterns of integrin expressions are associ-atedwithRPE activationmigration andproliferation [42] InAMD pathological changes reduced integrin molecules andthese changes may induce dissociation between the IPM andsurrounding cells [43] These changes would be predicted todecrease the supply of oxygen nutrients and growth factorsto the cells from the choroidal or retinal vessels and inhibitthe phagocytosis of photoreceptor outer segments [44]

It has been revealed that 120572v1205731 [45] 120572v1205733 [46] and120572v1205735 integrins [45 46] were expressed in neovascular oculartissue from patients with wet AMD Hammes et al [47]showed that subcutaneous injection of cyclic RGDfV peptide(antagonist of 120572v1205733 and 120572v1205735) remarkably prevented retinalneovascularization in a mouse model of hypoxia inducedproliferative retinopathyThese results indicate the possibilitythat 120572v1205733 and 120572v1205735 integrins might be a therapeutic targetfor AMD [48 49] Additionally the effectiveness of 120572v1205731and 120572v1205735 integrin antagonists (JNJ-26076713) against ocularneovascularization has been well documented [50] Thereare two therapeutic candidates to antagonize 120572v1205731 integrinJSM6427 and volociximab for the treatment of AMD

41 JSM6427 JSM6427 is a small molecule inhibitor of 120572v1205731integrin which has been shown in preclinical models toinhibit retinal and choroidal neovascularization [51] Phase Iclinical trial of JSM6427 for exudative AMD has beenalready completed (a phase 1 safety study of single andrepeated doses of JSM6427 (intravitreal injection) to treatAMD httpclinicaltrialsgovct2showNCT00536016) Int-ravitreal administration of one dose of JSM6427 increasedmean best corrected visual acuity in all patients

42 Volociximab Volociximab (Ophthotech CorporationPrinceton NY USA) is a chimeral monoclonal antibody spe-cifically blocking the binding of fibronectin to the 120572v1205731 inte-grin A phase 1 study evaluated the safety of intravitrealvolociximab combined with ranibizumab for neovascularAMD (a phase 1 ascending and parallel group trial toestablish the safety tolerability and pharmacokinetics profileof volociximab (alpha 5 beta 1 integrin antagonist) in subjectswith exudative age-related macular degeneration Clinical-Trialsgov identifierNCT00782093 ClinicalTrialsgov onlinehttpwwwclinicaltrialsgovct2showNCT00782093) Vol-ociximabwas used in combinationwith ranibizumab becausethe volociximab was lacking an antipermeability effect Pre-liminary results from 10 subjects receiving two doses ofvolociximab in combination with ranibizumab revealed avisual acuity improvement of 108 letters at nine weeksHowever these results do not separate the independent con-tributions from ranibizumab and volociximab [32] Planningof a phase 2 study is underway

43 ALG-1001 ALG-1001 (Allegro Ophthalmics San JuanCapistrano CA USA) is a synthetic oligopeptide that medi-ates 12057251205731 120572v1205733 and 120572v1205735 integrins Its efficacy lasted for 90days following one intravitreal injection in diabetic maculaedema In phase 1b clinical trial of ALG-1001 in neovascularAMD fifteen participants who received 3 monthly injectionsof ALG-1001 monotherapy had an improvement of meanbest corrected visual acuity more than 5 letters along with a30 decrease in central macular thickness [52] Since safetyand well-tolerability have been observed in integrin peptidetherapy attention is now being turned to determining thebest dosage and dosing regimen of ALG-1001 [53] Phase2a clinical studies of ALG-1001 are now going (a safetyand efficacy study of ALG-1001 in human subjects withwet age-related macular degeneration phase 2 ClinicalTri-alsgov identifier NCT00782093 ClinicalTrialsgov onlinehttpwwwclinicaltrialsgovct2showNCT01749891)

Upregulation of integrin receptors is a downstream eventto VEGF upregulation in the angiogenic cascade of AMD[54]Therefore it seems possible that combination of integrinpeptide and anti-VEGF therapy may enhance the therapeuticeffects against choroidal neovascularization Taken togetherintegrin peptide therapy is an emerging new class of wetAMD treatment

5 PEDF

PEDF was originally described by Tombran-Tink and John-son [55] It is a cell survival factor secreted by the RPE andwidely expressed in central and peripheral nervous system[54ndash56] PEDF is also known as an endogenous inhibitor ofangiogenesis in the eye [57] By contrast VEGF is one ofthe most potent angiogenic stimulators [58] Inappropriateexpression levels of PEDF andVEGF are associated with neo-vascularization [59 60] Steinle et al [61] characterized age-related changes in PEDF and VEGF in rat retina Increases inVEGF and its receptor VEGFR2 and simultaneous decreasein PEDF were found in aged rats These results suggest


that normal aging retina is at increased risk for neovascularchanges [61] A critical balance appears to exist betweenPEDF and VEGF with PEDF counteracting the angiogenicpotential of VEGF [61] A decrease in PEDF may disruptthis balance and create a permissive environment for theformation of CNV in AMD Lin et al [62] also indicate thepossibilities that PEDF gene polymorphisms may contributeto AMD

51 ATG003 Cigarette smoking is the strongest environ-mental risk factor for wet AMD [63 64] Recently it hasbeen reported that PEDF protein expression was decreasedin RPE from smoker patients with AMD compared withcontrols [63] The same authors also reported that nicotine apotent angiogenic agent increased VEGFPEDF ratio in theRPE through nicotinic acetylcholine receptor (nAchR) [65]These results indicate that increasedVEGFPEDF ratiomightinduce CNV formation in smoker patients

In this context a unique therapeutic eye drop for AMDtreatment ATG003 has been developed ATG003 (CoMen-tis formerly Athenagen South San Francisco CA USA) is atopical mecamylamine and antagonizes nAchR pathway thatmediates angiogenesis It is the first noninvasive eye droptherapy for AMD and phase 2 clinical trial has recently beencompleted (safety and efficacy of ATG003 in patients withwetage-relatedmacular degeneration (AMD) httpwwwclinic-altrialsgovct2showNCT00414206order=1) (safety and eff-icacy of ATG003 in patients with AMD receiving anti-VEGFhttpwwwclinicaltrialsgovct2showNCT00607750) An-other phase 2 trial is evaluating the safety and efficacy ofATG003 drops in 60 patients receiving maintenance intra-vitreal injections of ranibizumab or bevacizumab All pat-ients will be treated for up to 48 weeks This trial is cur-rently ongoing (safety and efficacy of ATG003 in patientswith AMD receiving anti-VEGF ClinicalTrialsgov identi-fier NCT00607750 ClinicalTrialsgov online httpwwwclinicaltrialsgovct2showNCT00607750)

52 AdPEDF11 The RPE secretes both VEGF and PEDF inpolarized fashion in opposing direction Namely secretionof PEDF is primarily apical to support the retinal neuronsand photoreceptors and that for VEGF is primarily basal formaintenance of choriocallilaris and choroidal vessels [66 67]Sonoda et al [66] suggested that loss of polarity of RPEin advanced AMD results in marked loss of neurotrophicand vascular support for the retina potentially leading tophotoreceptor loss and blindness

Dawson et al [68] indicated the possibility that PEDFmay be of therapeutic use especially in retinopathies wherepathological neovascularization compromises vision andleads to blindness Recently it has been reported that PEDFlevels in aqueous humor or vitreous are decreased in patientswith proliferative diabetic retinopathy (PDR) which suggeststhat a loss of PEDF in the human eye may contribute tothe development and progression of PDR [69] Yoshida etal [70] previously suggested that PEDF might be used as atherapeutic target for PDR Furthermore animal studies alsoconfirmed the therapeutic effect of PEDF administration for

retinal neovascularization in a model of diabetic retinopathyoxygen-induced retinopathy [71 72] and AMD [73]

It has been shown that an adenoviral vector containingcomplementary DNA encoding human PEDF known asAdGVPEDF11D (GenVec Inc Gaithersburg MD USA)allows expression of large amount of PEDF in the target tissueand inhibits ocular neovascularization inmurine AMDmod-els [74] Intravitreal injection of AdGVPEDF11D containingthe transgene for cDNA of human PEDF results in the localproduction of PEDF A phase 1 single dose trial enrolled 28patients with severe neovascular AMD [75] The percentageof patients who had no change or improvement in lesion sizeat 6 months was 71 in the high-dose group versus 50 inthe low-dose group A clinical study suggested the possibilitythat antiangiogenic activity may last for several months (upto 6 months) after a single intravitreous injection as half ofthe treated lesions did not change in size from baseline [75]

Although anti-VEGF therapy (intravitreal injection ofranibizumab pegaptanib aflibercept and bevacizumab) isregarded as the more effective treatment for AMD now [76]the potential therapeutics of PEDFmay be positive indicationfor future treatment of AMD

6 MMP and TIMP

MMPs are a family of zinc-containing proteolytic enzymesthat are responsible for degrading ECM components andplay an important role in the physiological and pathologicalremodeling of tissues [77] MMPs are also thought to playa major role in cell proliferation differentiation angiogen-esis apoptosis and immune defense [78] MMPs and theirinhibitors TIMPs colocalize in the human IPM [79] andlikely play a role in physiological reconstruction and turnoverof the IPM Among the MMP isozymes MMP-9 is essentialfor the development of CNV in AMD [80]

Fiotti et al [81] found a relationship between polymor-phisms inMMP-9 and neovascularization in AMD Recentlyit has been reported that MMP-9 Rs3918242 (CrarrT) singlenucleotide polymorphism is found to play a significantrole in the development of AMD and the effect was morepronounced at the age of less than 65 years [82]

The circulating MMPs and TIMPs have been suggestedto participate in vascular remodeling and angiogenesis [83]However it is still controversial whether circulating MMPsare directly linked to pathogenesis of the AMD Chau et al[84] firstly reported a link between raised plasma MMP-9levels and AMD By contrast Zeng et al [85] reported a linkbetween increased levels of circulating gelatinases (MMP-2and MMP-9) and polypoidal choroidal vasculopathy anabnormal choroidal vasculopathy distinct from typical CNV[86] but not AMD

In AMD lesions it was believed that endothelial cells areactivated and release MMP that destroys Bruchrsquos membrane[87] Conversely it has been reported that total levels of activeMMP-2 and MMP-9 were significantly reduced in Bruchrsquosmembrane-choroid preparations from AMD patients [88]Downregulation of MMP-2 and MMP-9 may lead to theadvanced pathological changes that can progress to AMD


Consistently Ahir et al [89] have demonstrated that adminis-tration of activatedMMP-2 andMMP-9 can improve the fluidpermeability of Bruchrsquos membraneTherefore reactivation ofthe MMP pathway may be effective therapeutics in AMDpatients

The so-called ldquonanosecondrdquo pulse laser uses pulse dura-tions in the nanosecond range and restricts these heat tran-sients to lt30 120583m [90] These short-pulse lasers specificallytarget RPE cells without damage to photoreceptors or Bruchrsquosmembrane therefore it is suggested that they could allowtherapeutic access to the entiremacular region [90] RecentlyZhang et al [91] reported that the nanosecond laser pulsemodality induces increasing of the RPE-mediated releaseof active MMP enzymes Additionally the result of one-year clinical trial using ultrashort-pulse laser applicationhas been reported It is interesting that a single unilateralapplication of the ultrashort-pulse laser to the macula ofAMD patients produced bilateral improvements in maculaappearance and function This finding may be due to theresult that the unilateral laser photocoagulation inducesbilaterally MMP pathway activation by releasing circulatingfactors Taken together targeting theMMP activationmay beuseful approach to the treatment of AMD

7 MTX

Recent innovations in anti-VEGF have dramaticallyimproved the prognosis of wet AMD patients [92 93] whilesome remain refractory to anti-VEGF therapy Methotrexate(MTX)is an antifolate drug and is used in high doses totreat cancer Primary intraocular lymphoma is treated withintravitreal MTX [94] Low doses of MTX have also beenshown to be a potent anti-inflammatory agent and are usedsystemically for the treatment of rheumatoid arthritis [95]or noninfectious uveitis [96] There are several proposedmechanisms for low-dose MTX in interrupting the angiog-enesis cascade at various levels [97ndash100]

Kurup et al [101] reported that two wet AMD patientswere refractory to anti-VEGF treatment but showed someimprovement by intravitreal MTX injection (400mg) Onepatient showed improved visual acuity and both patientsshowed decreased serous retinal detachment and decreasedperifoveal leakage 2 weeks after injection Although thesecase reports indicate the potential benefits of MTX as anadjunct treatment for wet AMD patients who are resistantto the traditional anti-VEGF therapy large-scale and long-term clinical trials are necessary to evaluate the effectivenessof intravitreal MTX

8 Combination Therapy

Although the current standard of therapy is intravitreal injec-tions of VEGF inhibitors combination therapy with anti-VEGF therapy and various treatment modalities for exud-ative AMD offers another option to reduce treatment fre-quency In order to further address the multifactorial path-ogenesis of exudative AMD investigators have begun toexamine the combination of corticosteroids verteporfin

photodynamic therapy (VPDT) and anti-VEGF agents (Tri-ple Therapy) [102ndash106] The RADICAL (Reduced FluenceVisudyne-Anti-VEGF Dexamethasone in Combination forAMD Lesions) study is a phase 2 multicenter randomizedsingle-masked study of 162 patients with CNV second-ary to wet AMD (httpsclinicaltrialsgovct2showresultsNCT00492284) The trial is studying the following therapies

81 14 Fluence Triple Therapy Quarter fluence verteporfin(180mWcm2 for 83 seconds to deliver 15 Jcm2) is followedwithin two hours by intravitreal ranibizumab (05mg) andthen intravitreal dexamethasone (05mg)

82 12 Fluence Triple Therapy Half fluence verteporfin(300mWcm2 for 83 seconds to deliver 25 Jcm2) is followedwithin two hours by intravitreal ranibizumab (05mg) andthen intravitreal dexamethasone (05mg)

83 12 Fluence Double Therapy Half fluence verteporfin(300mWcm2 for 83 seconds to deliver 25 Jcm2) is followedwithin two hours by intravitreal ranibizumab (05mg)

84 Ranibizumab Monotherapy (05mg) Three verteporfin-ranibizumab combination therapies (groups 1ndash3) were eval-uated against ranibizumab monotherapy (httpwwwqltinccomnewsCenter2010100622htm) Of the three combina-tion therapies groups with verteporfin-ranibizumab the 12fluence triple therapy group had the fewest retreatmentvisits compared with ranibizumab monotherapy Through24 months patients in the 12 fluence triple therapy had amean of 42 retreatment visits compared with 89 for patientswho received ranibizumab monotherapy (119875 lt 0001) How-ever mean visual acuity change from baseline in the 12fluence triple therapy was not statistically different from theranibizumab monotherapy group (119875 = 071) The incidencesof ocular adverse events were reported for 30ndash38 of patientsin the combination therapy groups and 27 of patients inthe ranibizumab monotherapy group respectively The adv-erse events in combination therapy were transient visual dis-turbances associated with verteporfin therapy

Taken together the two-year result from the RADICALstudy shows not only reduction in retreatment visits but alsoacceptable vision outcome and safety profile compared withranibizumab monotherapy

9 Conclusions

AMD therapy has changed dramatically over the last decadeAs our understanding of the molecular mechanisms involvedin AMD increases multiple new treatments are emergingThe understanding of AMD pathogenesis could provideinnovative therapeutic approaches to AMD

Conflict of Interests

The authors declare no conflict of interests


Acknowledgment

This work was supported in part by JSPS KAKENHI Grantno 24592666 to MI

References

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[2] M L Klein and P J Francis ldquoGenetics of age-related maculardegenerationrdquo Ophthalmology Clinics of North America vol 16no 4 pp 567ndash574 2003

[3] D T Kasuga Y Chen and K Zhang Genetics of Age-RelatedMacular Degeneration A C Ho and C D Regillo Eds Spri-nger Science+Business Media New York NY USA 2011

[4] D W Leung G Cachianes W-J Kuang D V Goeddel andN Ferrara ldquoVascular endothelial growth factor is a secretedangiogenic mitogenrdquo Science vol 246 no 4935 pp 1306ndash13091989

[5] P J Keck S D Hauser G Krivi et al ldquoVascular permeabilityfactor an endothelial cellmitogen related to PDGFrdquo Science vol246 no 4935 pp 1309ndash1312 1989

[6] D R Senger D T Connolly L van deWater J Feder and H FDvorak ldquoPurification and NH2-terminal amino acid sequenceof guinea pig tumor-secreted vascular permeability factorrdquoCancer Research vol 50 no 6 pp 1774ndash1778 1990

[7] A G Smith and P K Kaiser ldquoEmerging treatments for wetage-relatedmacular degenerationrdquo Expert Opinion on EmergingDrugs vol 19 no 1 pp 157ndash164 2014

[8] P K Kaiser ldquoEmerging therapies for neovascular age-relatedmacular degeneration drugs in the pipelinerdquo Ophthalmologyvol 120 no 5 supplement pp S11ndashS15 2013

[9] M Hellstrom H Gerhardt M Kalen et al ldquoLack of pericytesleads to endothelial hyperplasia and abnormal vascular mor-phogenesisrdquoThe Journal of Cell Biology vol 152 no 3 pp 543ndash553 2001

[10] C Hellberg A Ostman and C-H Heldin ldquoPDGF and vesselmaturationrdquoRecent Results in Cancer Research vol 180 pp 103ndash114 2010

[11] L E Benjamin I Hemo and E Keshet ldquoA plasticity windowfor blood vessel remodelling is defined by pericyte coverage ofthe preformed endothelial network and is regulated by PDGF-Band VEGFrdquo Development vol 125 no 9 pp 1591ndash1598 1998

[12] G Bergers S Song N Meyer-Morse E Bergsland and DHanahan ldquoBenefits of targeting both pericytes and endothelialcells in the tumor vasculature with kinase inhibitorsrdquo TheJournal of Clinical Investigation vol 111 no 9 pp 1287ndash12952003

[13] A M Newman N B Gallo L S Hancox et al ldquoSystems-levelanalysis of age-related macular degeneration reveals globalbiomarkers and phenotype-specific functional networksrdquoGenome Medicine vol 4 no 2 article no 16 2012

[14] J D Powell K N Pollizzi E B Heikamp and M R HortonldquoRegulation of immune responses by mTORrdquoAnnual Review ofImmunology vol 30 pp 39ndash68 2012

[15] N Hay and N Sonenberg ldquoUpstream and downstream ofmTORrdquo Genes and Development vol 18 no 16 pp 1926ndash19452004

[16] M Guba P von Breitenbuch M Steinbauer et al ldquoRapamycininhibits primary andmetastatic tumor growth by antiangiogen-esis involvement of vascular endothelial growth factorrdquo NatureMedicine vol 8 no 2 pp 128ndash135 2002

[17] W Wang W-D Jia G-L Xu et al ldquoAntitumoral activityof rapamycin mediated through inhibition of HIF-1alpha andVEGF in hepatocellular carcinomardquo Digestive Diseases andSciences vol 54 no 10 pp 2128ndash2136 2009

[18] N S Dejneka A M Kuroki J Fosnot W Tang M JTolentino and J Bennett ldquoSystemic rapamycin inhibits retinaland choroidal neovascularization in micerdquo Molecular Visionvol 10 pp 964ndash972 2004

[19] G A Peyman R Fiscella and M Conway ldquoCombinationangiostatic therapies current statusrdquoRetina vol 29 supplement6 pp S18ndashS20 2009

[20] J M Reichert ldquoAntibodies to watch in 2015rdquoMAbs vol 7 no 1pp 1ndash8 2014

[21] H OhH Takagi C Takagi et al ldquoThe potential angiogenic roleof macrophages in the formation of choroidal neovascularmembranesrdquo Investigative Ophthalmology and Visual Sciencevol 40 no 9 pp 1891ndash1898 1999

[22] J L Olson R J Courtney and N Mandava ldquoIntravitreal inflix-imab and choroidal neovascularization in an animal modelrdquoArchives of Ophthalmology vol 125 no 9 pp 1221ndash1224 2007

[23] P G Theodossiadis V S Liarakos P P Sfikakis et al ldquoIntrav-itreal administration of the anti-TNF monoclonal antibodyinfliximab in the rabbitrdquo Graefersquos Archive for Clinical andExperimental Ophthalmology vol 247 no 2 pp 273ndash281 2009

[24] P GTheodossiadis V S Liarakos P P Sfikakis I A VergadosandG PTheodossiadis ldquoIntravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degenerationrdquo American Journal of Ophthal-mology vol 147 no 5 pp 825e1ndash830e1 2009

[25] L V Johnson W P Leitner M K Staples and D H AndersonldquoComplement activation and inflammatory processes in drusenformation and age related macular degenerationrdquo ExperimentalEye Research vol 73 no 6 pp 887ndash896 2001

[26] D H Anderson M J Radeke N B Gallo et al ldquoThe pivotalrole of the complement system in aging and age-relatedmaculardegeneration hypothesis re-visitedrdquo Progress in Retinal and EyeResearch vol 29 no 2 pp 95ndash112 2010

[27] D D G Despriet C M van Duijn B A Oostra et al ldquoCom-plement component C3 and risk of age-related macular degen-erationrdquoOphthalmology vol 116 no 3 pp 474e2ndash480e2 2009

[28] J B Maller J A Fagerness R C Reynolds B M Neale MJ Daly and J M Seddon ldquoVariation in complement factor 3is associated with risk of age-related macular degenerationrdquoNature Genetics vol 39 no 10 pp 1200ndash1201 2007

[29] K H Park B L Fridley E Ryu N Tosakulwong and A OEdwards ldquoComplement component 3 (C3) haplotypes and riskof advanced age-related macular degenerationrdquo InvestigativeOphthalmology amp Visual Science vol 50 no 7 pp 3386ndash33932009

[30] J R W Yates T Sepp B K Matharu et al ldquoComplement C3variant and the risk of age-related macular degenerationrdquo TheNew England Journal of Medicine vol 357 no 6 pp 553ndash5612007

[31] Z Ni and P Hui ldquoEmerging pharmacologic therapies for wetage-related macular degenerationrdquo Ophthalmologica vol 223no 6 pp 401ndash410 2009


[32] C P Shah and J S Heier ldquoThe future of neovascular age-relatedmacular degenerationrdquo in Age-Related Macular DegenerationDiagnosis and Treatment A C Ho and C D Regillo Eds pp135ndash174 Springer New York NY USA 2011

[33] R O Hynes ldquoThe extracellular matrix not just pretty fibrilsrdquoScience vol 326 no 5957 pp 1216ndash1219 2009

[34] E Ruoslahti ldquoIntegrinsrdquo The Journal of Clinical Investigationvol 87 no 1 pp 1ndash5 1991

[35] T A Springer ldquoAdhesion receptors of the immune systemrdquoNature vol 346 no 6283 pp 425ndash434 1990

[36] E D Hay ldquoRole of cell-matrix contacts in cell migration andepithelial-mesenchymal transformationrdquo Cell Differentiationand Development vol 32 no 3 pp 367ndash375 1990

[37] R O Hynes ldquoIntegrins versatility modulation and signalingin cell adhesionrdquo Cell vol 69 no 1 pp 11ndash25 1992

[38] E A Clark and J S Brugge ldquoIntegrins and sign transductionpathways the road takenrdquo Science vol 268 no 5208 pp 233ndash239 1995

[39] M A Schwartz M D Schaller andM H Ginsberg ldquoIntegrinsemerging paradigms of signal transductionrdquo Annual Review ofCell and Developmental Biology vol 11 pp 549ndash599 1995

[40] E F Nandrot Y Kim S E Brodie X Huang D Sheppard andS C Finnemann ldquoLoss of synchronized retinal phagocytosisand age-related blindness in mice lacking 120572v1205735 integrinrdquo TheJournal of ExperimentalMedicine vol 200 no 12 pp 1539ndash15452004

[41] M Mallavarapu and S C Finnemann ldquoNeural retina andMerTK-independent apical polarity of alphavbeta5 integrinreceptors in the retinal pigment epitheliumrdquo Advances inExperimental Medicine and Biology vol 664 pp 123ndash131 2010

[42] S C Finnemann V L Bonilha A D Marmorstein and ERodriguez-Boulan ldquoPhagocytosis of rod outer segments by reti-nal pigment epithelial cells requires 120572v1205735 integrin for bindingbut not for internalizationrdquoProceedings of theNational Academyof Sciences of the United States of America vol 94 no 24 pp12932ndash12937 1997

[43] M R Al-Ubaidi M I Naash and S M Conley ldquoA perspectiveon the role of the extracellular matrix in progressive retinaldegenerative disordersrdquo Investigative Ophthalmology amp VisualScience vol 54 no 13 pp 8119ndash8124 2013

[44] G R Jackson C Owsley and C A Curcio ldquoPhotoreceptordegeneration and dysfunction in aging and age-related mac-ulopathyrdquo Ageing Research Reviews vol 1 no 3 pp 381ndash3962002

[45] M Friedlander C L Theesfeld M Sugita et al ldquoInvolvementof integrins 120572v1205733 and 120572v1205735 in ocular neovascular diseasesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 93 no 18 pp 9764ndash9769 1996

[46] J Luna T Tobe S A Mousa T M Reilly and P A Campo-chiaro ldquoAntagonists of integrin alpha v beta 3 inhibit retinalneovascularization in a murine modelrdquo Laboratory Investiga-tion vol 75 no 4 pp 563ndash573 1996

[47] H P Hammes M Brownlee A Jonczyk et al ldquoSubcutaneousinjection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularizationrdquo NatureMedicine vol 2 pp 529ndash533 1996

[48] T Yasukawa SHoffmannW Eichler U Friedrichs Y-SWangand P Wiedemann ldquoInhibition of experimental choroidalneovascularization in rats by an alpha(v)-integrin antagonistrdquoCurrent Eye Research vol 28 no 5 pp 359ndash366 2004

[49] Y Fu M L Ponce M Thill P Yuan S W Nam and K GCsaky ldquoAngiogenesis inhibition and choroidal neovasculariza-tion suppression by sustained delivery of an integrin antagonistEMD478761rdquo Investigative Ophthalmology and Visual Sciencevol 48 no 11 pp 5184ndash5190 2007

[50] R J Santulli W A Kinney S Ghosh et al ldquoStudies with anorally bioavailable 120572V integrin antagonist in animal modelsof ocular vasculopathy retinal neovascularization in miceand retinal vascular permeability in diabetic ratsrdquo Journal ofPharmacology andExperimentalTherapeutics vol 324 no 3 pp894ndash901 2008

[51] A-K B Maier N Kociok G Zahn et al ldquoModulation of hyp-oxia-induced neovascularization by JSM6427 an integrinalpha5beta 1 inhibiting moleculerdquo Current Eye Research vol 32no 9 pp 801ndash812 2007

[52] H Quiroz-Mercado ldquoIntegrin peptide therapy in choroidal andretinal neovascularizationrdquo Retina Today 2013

[53] L A Dipietro ldquoAngiogenesis and scar formation in healingwoundsrdquo Current Opinion in Rheumatology vol 25 no 1 pp87ndash91 2013

[54] S A Mousa W Lorelli and P A Campochiaro ldquoRole of hypo-xia and extracellular matrix-integrin binding in themodulationof angiogenic growth factors secretion by retinal pigmentedepithelial cellsrdquo Journal of Cellular Biochemistry vol 74 no 1pp 135ndash143 1999

[55] J Tombran-Tink and L V Johnson ldquoNeuronal differentiation ofretinoblastoma cells induced bymediumconditioned by humanRPE cellsrdquo Investigative Ophthalmology and Visual Science vol30 no 8 pp 1700ndash1707 1989

[56] J Tombran-Tink S M Shivaram G J Chader L V Johnsonand D Bok ldquoExpression secretion and age-related downreg-ulation of pigment epithelium-derived factor a serpin withneurotrophic activityrdquo The Journal of Neuroscience vol 15 no7 pp 4992ndash5003 1995

[57] N M Holekamp N Bouck and O Volpert ldquoPigmentepithelium-derived factor is deficient in the vitreous of patientswith choroidal neovascularization due to age-related maculardegenerationrdquoAmerican Journal of Ophthalmology vol 134 no2 pp 220ndash227 2002

[58] M J Cross and L Claesson-Welsh ldquoFGF and VEGF functionin angiogenesis signalling pathways biological responses andtherapeutic inhibitionrdquo Trends in Pharmacological Sciences vol22 no 4 pp 201ndash207 2001

[59] A M Kolomeyer I K Sugino and M A Zarbin ldquoCharacter-ization of conditioned media collected from aged versus younghuman eye cupsrdquo Investigative Ophthalmology and Visual Sci-ence vol 52 no 8 pp 5963ndash5972 2011

[60] M Anna S Krzysztof M-P Katarzyna D Violetta and KDanuta ldquoPEDF and VEGF plasma level alterations in patientswith dry form of age-related macular degenerationmdasha possiblelink to the development of the diseaserdquo Klinika Oczna vol 114no 2 pp 115ndash120 2012

[61] J J Steinle S Sharma and V C Chin ldquoNormal aging involvesaltered expression of growth factors in the rat choroidrdquo Journalsof Gerontology Series A Biological Sciences andMedical Sciencesvol 63 no 2 pp 135ndash140 2008

[62] J M Lin L Wan Y Y Tsai et al ldquoPigment epithelium-derivedfactor gene Met72Thr polymorphism is associated withincreased risk of wet age-related macular degenerationrdquoThe American Journal of Ophthalmology vol 145 no 4 pp716e2ndash721e2 2008


[63] W G Christen R J Glynn J E Manson U A Ajani and J EBuring ldquoA prospective study of cigarette smoking and risk ofage-related macular degeneration in menrdquo The Journal of theAmerican Medical Association vol 276 no 14 pp 1147ndash11511996

[64] JM SeddonWCWillett F E Speizer and S EHankinson ldquoAprospective study of cigarette smoking and age-related maculardegeneration in womenrdquo The Journal of the American MedicalAssociation vol 276 no 14 pp 1141ndash1146 1996

[65] M Pons and M E Marin-Castano ldquoNicotine increases theVEGFPEDF ratio in retinal pigment epithelium a possiblemechanism for CNV in passive smokers with AMDrdquo Investiga-tive Ophthalmology and Visual Science vol 52 no 6 pp 3842ndash3853 2011

[66] S Sonoda P G Sreekumar S Kase et al ldquoAttainment of polaritypromotes growth factor secretion by retinal pig-ment epithelialcells relevance to age-relatedmacular degenerationrdquoAging vol2 no 1 pp 28ndash42 2010

[67] KM Ford andPADrsquoAmore ldquoMolecular regulation of vascularendothelial growth factor expression in the retinal pigmentepitheliumrdquoMolecular Vision vol 18 pp 519ndash527 2012

[68] D W Dawson O V Volpert P Gillis et al ldquoPigment epithe-lium-derived factor a potent inhibitor of angiogenesisrdquo Sciencevol 285 no 5425 pp 245ndash248 1999

[69] B Zheng T Li H Chen X Xu and Z Zheng ldquoCorrelationbetween ficolin-3 and vascular endothelial growth factor-to-pigment epithelium-derived factor ratio in the vitreous of eyeswith proliferative diabetic retinopathyrdquo American Journal ofOphthalmology vol 152 no 6 pp 1039ndash1043 2011

[70] Y Yoshida S-I Yamagishi TMatsui et al ldquoPositive correlationof pigment epithelium-derived factor and total antioxidantcapacity in aqueous humour of patients with uveitis and prolif-erative diabetic retinopathyrdquo British Journal of Ophthalmologyvol 91 no 9 pp 1133ndash1134 2007

[71] V Haurigot P Villacampa A Ribera et al ldquoLong-term retinalPEDF overexpression prevents neovascularization in a murineadult model of retinopathyrdquo PLoS ONE vol 7 no 7 Article IDe41511 2012

[72] J-X Ma R Longeras K Farjo and M Ihnat ldquoA PEDF-derived peptide inhibits retinal neovascularization and blocksmobilization of bone marrow-derived endothelial progenitorcellsrdquo Experimental Diabetes Research vol 2012 Article ID518426 11 pages 2012

[73] Y Wang P Subramanian D Shen J Tuo S P Becerra and C-C Chan ldquoPigment epithelium-derived factor reduces apoptosisand pro-inflammatory cytokine gene expression in a murinemodel of focal retinal degenerationrdquo ASN Neuro vol 5 no 5Article ID e00126 2013

[74] K Mori P Gehlbach A Ando D McVey L Wei and P ACampochiaro ldquoRegression of ocular neovascularization inresponse to increased expression of pigment epithelium-derived factorrdquo Investigative Ophthalmology and Visual Sciencevol 43 no 7 pp 2428ndash2434 2002

[75] P A Campochiaro Q D Nguyen S M Shah et al ldquoAdenoviralvector-delivered pigment epithelium-derived factor for neovas-cular age-related macular degeneration results of a phase Iclinical trialrdquo Human Gene Therapy vol 17 no 2 pp 167ndash1762006

[76] L K Cheung andA Eaton ldquoAge-relatedmacular degenerationrdquoPharmacotherapy vol 33 no 8 pp 838ndash855 2013

[77] V Lesauskaite G Sinkunaite R Benetis et al ldquoMatrix met-alloproteinase-3 gene polymorphism and dilatative pathology

of ascending thoracic aortardquo Medicina vol 44 no 5 pp 386ndash391 2008

[78] Y Itoh and H Nagase ldquoMatrix metalloproteinases in cancerrdquoEssays in Biochemistry vol 38 pp 21ndash36 2002

[79] J J Plantner A Smine and T A Quinn ldquoMatrix metallopro-teinases and metalloproteinase inhibitors in human interpho-toreceptor matrix and vitreousrdquo Current Eye Research vol 17no 2 pp 132ndash140 1998

[80] J Westermarck and V-M Kahari ldquoRegulation of matrix metal-loproteinase expression in tumor invasionrdquoThe FASEB Journalvol 13 no 8 pp 781ndash792 1999

[81] N Fiotti M Pedio M B Parodi et al ldquoMMP-9 microsatellitepolymorphism and susceptibility to exudative form of age-related macular degenerationrdquo Genetics in Medicine vol 7 no4 pp 272ndash277 2005

[82] R Liutkeviciene V Lesauskaite G Sinkunaite-Marsalkiene etal ldquoThe role of matrix metalloproteinases polymorphisms inage-related macular degenerationrdquo Ophthalmic Genetics 2013

[83] J D Raffetto and R A Khalil ldquoMatrix metalloproteinases andtheir inhibitors in vascular remodeling and vascular diseaserdquoBiochemical Pharmacology vol 75 no 2 pp 346ndash359 2008

[84] K Y Chau S SivaprasadN Patel T ADonaldson P J Luthertand N V Chong ldquoPlasma levels of matrix metalloproteinase-2and -9 (MMP-2 and MMP-9) in age-related macular degenera-tionrdquo Eye vol 22 no 6 pp 855ndash859 2008

[85] R Zeng F Wen X Zhang and Y Su ldquoSerum levels of matrixmetalloproteinase 2 and matrix metalloproteinase 9 elevatedin polypoidal choroidal vasculopathy but not in age-relatedmacular degenerationrdquo Molecular Vision vol 19 pp 729ndash7362013

[86] L A Yannuzzi A Ciardella R F Spaide M Rabb K BaileyFreund and D A Orlock ldquoThe expanding clinical spectrumof idiopathic polypoidal choroidal vasculopathyrdquo Archives ofOphthalmology vol 115 no 4 pp 478ndash485 1997

[87] J J Plantner C Jiang and A Smine ldquoIncrease in interphotore-ceptormatrix gelatinaseA (MMP-2) associatedwith age-relatedmacular degenerationrdquo Experimental Eye Research vol 67 no6 pp 637ndash645 1998

[88] A A Hussain Y Lee J-J Zhang and J Marshall ldquoDisturbedmatrix metalloproteinase activity of Bruchrsquos membrane in age-relatedmacular degenerationrdquo Investigative Ophthalmology andVisual Science vol 52 no 7 pp 4459ndash4466 2011

[89] A Ahir L Guo A A Hussain and J Marshall ldquoExpression ofmetalloproteinases from human retinal pigment epithelial cellsand their effects on the hydraulic conductivity of Bruchrsquosmembranerdquo Investigative Ophthalmology and Visual Sciencevol 43 no 2 pp 458ndash465 2002

[90] J Roider F Hillenkamp T Flotte and R Birngruber ldquoMicro-photocoagulation selective effects of repetitive short laserpulsesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 90 no 18 pp 8643ndash8647 1993

[91] J J Zhang Y Sun A A Hussain and J Marshall ldquoLaser-mediated activation of human retinal pigment epithelial cellsand concomitant release of matrix metalloproteinasesrdquo Inves-tigative ophthalmology and visual science vol 53 no 6 pp2928ndash2937 2012

[92] D M Brown P K Kaiser M Michels et al ldquoRanibizumab ver-sus verteporfin for neovascular age-related macular degenera-tionrdquoThe New England Journal of Medicine vol 355 no 14 pp1432ndash1444 2006


[93] P J Rosenfeld D M Brown J S Heier et al ldquoRanibizumabfor neovascular age-related macular degenerationrdquo The NewEngland Journal ofMedicine vol 355 no 14 pp 1419ndash1431 2006

[94] J Peer F H Hochberg and C S Foster ldquoClinical reviewtreatment of vitreoretinal lymphomardquo Ocular Immunology ampInflammation vol 17 no 5 pp 299ndash306 2009

[95] M E Weinblatt J S Coblyn D A Fox et al ldquoEfficacy of low-dose methotrexate in rheumatoid arthritisrdquo The New EnglandJournal of Medicine vol 312 no 13 pp 818ndash822 1985

[96] C M Samson N Waheed S Baltatzis and C S Foster ldquoMet-hotrexate therapy for chronic noninfectious uveitis analysis ofa case series of 160 patientsrdquo Ophthalmology vol 108 no 6 pp1134ndash1139 2001

[97] A M Joussen F E Kruse H-E Volcker and B KirchhofldquoTopical application of methotrexate for inhibition of cornealangiogenesisrdquo Graefersquos Archive for Clinical and ExperimentalOphthalmology vol 237 no 11 pp 920ndash927 1999

[98] MCMontesinosM Takedachi L FThompson T FWilder PFernandez and B N Cronstein ldquoThe antiinflammatory mech-anism of methotrexate depends on extracellular conversionof adenine nucleotides to adenosine by ecto-51015840-nucleotidasefindings in a study of ecto-51015840-nucleotidase gene-deficient micerdquoArthritis and Rheumatism vol 56 no 5 pp 1440ndash1445 2007

[99] D C Phillips K J Woollard and H R Griffiths ldquoThe anti-inflammatory actions of methotrexate are critically dependentupon the production of reactive oxygen speciesrdquo British Journalof Pharmacology vol 138 no 3 pp 501ndash511 2003

[100] B N Cronstein ldquoLow-dose methotrexate a mainstay in thetreatment of rheumatoid arthritisrdquo Pharmacological Reviewsvol 57 no 2 pp 163ndash172 2005

[101] S K Kurup C Gee and CM Greven ldquoIntravitreal methotrex-ate in therapeutically resistant exudative age-related maculardegenerationrdquo Acta Ophthalmologica vol 88 no 4 pp e145ndashe146 2010

[102] A J Augustin S Puls and I Offermann ldquoTriple therapy forchoroidal neovascularization due to age-relatedmacular degen-eration verteporfin PDT bevacizumab and dexamethasonerdquoRetina vol 27 no 2 pp 133ndash140 2007

[103] P P Yip C F Woo H H Y Tang and C K Ho ldquoTriple ther-apy for neovascular age-related macular degeneration usingsingle-session photodynamic therapy combined with intravit-real bevacizumab and triamcinolonerdquo British Journal of Oph-thalmology vol 93 no 6 pp 754ndash758 2009

[104] D Ehmann and R Garcıa ldquoTriple therapy for neovascularage-related macular degeneration (verteporfin photodynamictherapy intravitreal dexamethasone and intravitreal beva-cizumab)rdquo Canadian Journal of Ophthalmology vol 45 no 1pp 36ndash40 2010

[105] S J Bakri S M Couch C A McCannel and A O EdwardsldquoSame-day triple therapy with photodynamic therapy intrav-itreal dexamethasone and bevacizumab in wet age-relatedmacular degenerationrdquo Retina vol 29 no 5 pp 573ndash578 2009

[106] HAhmadieh R TaeiM Soheilian et al ldquoSingle-session photo-dynamic therapy combined with intravitreal bevacizumab andtriamcinolone for neovascular age-related macular degenera-tionrdquo BMC Ophthalmology vol 7 article 10 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Summary of neovascular AMD therapeutic agents mechanisms route and phase of development

Agent Mechanism Treatment Phase

E10030 Platelet-derived growth factor (PDGF)inhibitor iv 3

Sirolimus Mammalian target of rapamycin(mTOR) inhibitor

ivsc 2

Infliximab Anti-tumor necrosis factor alpha(TNF-120572) antibody iv 1

POT-4 Complement component 3 (C3)inhibitor iv 2

JSM6427 Integrin receptor antagonist iv 1Volociximab Anti-120572v1205731 integrin monocle antibody iv 1ALG-1001 Integrin receptor antagonist iv 2a

ATG003 Nicotinic acetylcholine receptor(nAchR) antagonist Eye drop 2

AdPEDF11 Transgene for cDNA of human PEDF iv 1Methotrexate Antifolate drug iv mdashTriple combination therapy(verteporfin-ranibizumab-dexamethasone)

Targeting multiple components ofchoroidal neovascularization

iv(ranibizumab dexamethasone)

after VPDT2

iv intravitreal injection sc subconjunctival injectionVPDT verteporfin photodynamic therapy

NCT01940900) E10030 decreases pericyte density in neovas-cular vessels and therefore improves the effect of anti-VEGFagents [12]

A phase 1 study of patients (119899 = 22) evaluated intravi-treal E10030 in combination with ranibizumab (a phase 1safety tolerability and pharmacokinetic profile of intravi-treous injections of E10030 (anti-PDGF pegylated aptamer)in subjects with neovascular age-related macular degener-ation ClinicalTrialsgov identifier NCT00569140) In thecombination group 59 of patients experienced at least athree-line gain in visual acuity by 12 weeks (a phase 1 safetytolerability and pharmacokinetic profile of intravitreousinjections of E10030 (anti-PDGF pegylated aptamer) insubjects with neovascular age-related macular degener-ation ClinicalTrialsgov identifier NCT00569140 Clini-calTrialsgov online httpwwwclinicaltrialsgovct2showNCT00569140 accessed December 27 2009)

A phase 2 clinical trial evaluated the efficacy and safetyof E10030 administered in combination with an anti-VEGFagent for the treatment of patients newly diagnosed with wetAMD The trial enrolled 449 patients at approximately 69centers inNorthAmerica SouthAmerica Europe and Israeland E10030 (03mg or 15mg) administered in combinationwith ranibizumab injection (05mg) demonstrated statis-tically significant improvement compared to ranibizumabmonotherapy based on the primary endpoint ofmean changein visual acuity from baseline at 24 weeks The proportionsof subjects gaining 15 or more ETDRS letters from baselineat the week 24 visit are 391 versus 340 in patientsreceiving the combination therapy (15mg of E10030 and05mg ranibizumab) and ranibizumab monotherapy respec-tively E10030 exhibited a favorable safety profile and no

serious adverse effects were observed for E10030 combinationtherapy as compared to ranibizumab monotherapy

3 Anti-Immune orAnti-Inflammatory Pathways

Recently comparative transcriptome analysis of AMD andnormal humandonor eyes has yielded important insights intoAMD including the molecular pathways underlying AMDrsquosonset and progression [13] Newman et al [13] reported cell-mediated immune responses as the central feature of allAMD phenotypes Therefore addressing the role of immuneresponse in the pathogenesis of ocular neovascularizationmay be a promising avenue for identifying targets for AMDtreatments

31 mTOR Mammalian target of rapamycin (mTOR) is anevolutionarily conserved serinethreonine kinase that playsa central role in integrating environmental cues in the formof growth factors amino acids and energy [14] In the studyof the immune system mTOR is emerging as a criticalregulator of immune function because of its role in sensingand integrating cues from the immune microenvironment[14]

Sirolimus (previously known as rapamycin Santen Phar-maceutical Inc Osaka Kapan and MacuSight Inc UnionCity CA) was originally developed as a macrolide antifungalagent but was found to possess potent immunosuppressiveand antiproliferative properties Sirolimus blocks the T-lymphocyte activation and smooth muscle and endothelialcell proliferation that occurs in response to antigenic and






















5 PEDF











6 MMP and TIMP








7 MTX











9 Conclusions





Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































5 PEDF











6 MMP and TIMP








7 MTX











9 Conclusions





Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























5 PEDF











6 MMP and TIMP








7 MTX











9 Conclusions





Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























6 MMP and TIMP








7 MTX











9 Conclusions





Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















7 MTX











9 Conclusions





Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Acknowledgment


References




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Future Therapies of Wet Age-Related Macular ...downloads.hindawi.com/journals/joph/2015/138070.pdf · in patients with age-related macular degeneration (EMER-ALD),