Drug discovery in glaucoma and the role of animal models

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DDMOD-376; No of Pages 8laer MDrug Discovery Today: Disease Models Vol. xxx, No. xx 2014 Sansdiscoveries which relate to potential new therapeuticavenues.IntroductionThe discovery of therapeutic drug targets relies heavily onanimal models which represent a valuable tool for under-standing both the progression and cause of human disease.However, glaucoma is not one single disease entity andrather, comprises a heterogeneous group of disorders; thismakes drug discovery difficult. The brainstem, the visualcortex and the visual pathway are impacted in the diseaseand this results in progressive blindness due to chronic opticnerve damage and a loss of RGCs [1]. Worldwide, glaucoma isa leading cause of irreversible blindness and visual fielddefects and it is estimated that the disease will affect over80 million people by 2020 [2]. Similar to other neurodegen-erative disorders, glaucoma correlates with age and asimprovements in healthcare denote an increased lifespanGlaucoma a complex disorderHuman glaucoma is generally classified into three major sub-groups: Primary Open Angle Glaucoma (POAG), PrimaryAngle Closure Glaucoma (PACG), and Primary CongenitalGlaucoma (PCG) and in most populations, POAG is the mostcommon form of the disease [3]. Currently, three causativegenes (Myocilin, Optineurin and WDR36) have been identi-fied for POAG although more than 20 genetic loci have beenreported [4]. Despite there being different forms of the dis-ease, progressive visual impairment (and eventual blindness)caused by atrophy of the optic nerve and axonal damagerepresents a final common pathway of tissue damage in alltypes of glaucoma.As mentioned, the most common form of glaucoma isopen-angle which is a multi-factorial optic neuropathydefined by open anterior chamber angles, elevated intra-ocular pressure (IOP), progressive optic nerve fiber loss andvisual field defects [5]. It is the chronic elevation of IOP inglaucoma which leads to the death of RGCs and IOP is, in fact,a major risk factor for the disease [6]. As such, a primary focusfor intervention is lowering IOP. So what causes IOP elevation*Corresponding author.: S. McNally (mcnallsa@tcd.ie), (mcnally_sara@hotmail.com)1740-6757/$ 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddmod.2013.12.002 e1DRUG DISCOVERYTODAYDISEASEMODELSDrug discovery in grole of animal modeSara McNally*, Colm J. OBrienCatherine McAuley Clinical Research Centre, Institute of Ophthalmology, MatGlaucoma is a neurodegenerative disorder charac-terised by damage to inner layers of the retina andthe optic nerve (ON). The slow degeneration of retinalganglion cells (RGCs) and their axons results in aprogressive loss of vision. To date, a wide variety ofanimal models have been used to study glaucoma dis-ease mechanisms and these include monkey, dog, androdent models. However, there remains no idealmodel for studying glaucoma disease and this is largelydue to its complexity. Here, we review common animalmodels in use for glaucoma research and highlightEditors-in-ChiefJan Tornell AstraZeneca, SwedenAndrew McCulloch University of California,Models for eye disorderPlease cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma anducoma and thelsisericordiae Hospital, 21 Nelson Street, Dublin, IrelandSection editors:Ian Jackson Medical and Developmental Genetics,University of Edinburgh Western General Hospital,Edinburgh, UK.Marcela Votruba School of Optometry & Vision Sciences,Cardiff University, Cardiff, UK.for our population, a larger economic burden will result froman increasing number of people at risk of developing visualimpairment.Diego, USA the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/Drug Discovery Today: Disease Models | Models for eye disorders Vol. xxx, No. xx 2014DDMOD-376; No of Pages 8in glaucoma disease? A reduction in the outflow of aqueoushumor (AH) (which is produced by the cilliary body andmoves into the anterior chamber before leaving the eye)generally gives rise to an IOP increase. Exit of AH can occureither via the conventional pathway (trabecular meshwork(TM)/Schlemms canal) or via the non-conventional (uveoscl-eral) pathway [7]. As such IOP homeostasis depends on thebalance between AH production in the ciliary body and itsdrainage [8,9].Glaucoma patients with chronic high IOP who are leftuntreated develop aberrations in the retinal inner layersand the optic nerve head (ONH) which clinically manifestsas visual field loss [5]. Given that IOP is the only proventreatable risk factor for glaucoma disease, IOP-reduction stra-tegies remain the major approach for patient management.However, owing to the complexity of glaucoma disease (andadding to the difficulty of treatment) many patients continueto suffer visual field defects despite IOP management. Addi-tionally, some patients develop normal tension glaucoma(NTG); highlighting that IOP-independent mechanisms forthe development and progression of optic neuropathy exist[10].What drugs are currently in use for treatment ofdisease?The current mode of treating glaucoma comprises an IOPreduction strategy involving laser therapy, surgical operationor pharmacology (typically treatment with eye drops). Evenfor glaucoma patients suffering from impaired vision andhaving low IOP (normal tension or low-tension glaucoma),therapies which regulate IOP are advised [1114]. Both open-angle and closed angle patients are initially managed withIOP-lowering therapies which act by decreasing the rate of AHinflow and/or increasing outflow. There are five major classesof drugs administered as eye-drops that are approved forlowering IOP in glaucoma patients (these are reviewed in[15]). b-Adrenergic receptor blockers (timolol, betaxol, car-teolol, levobunolol) decrease inflow by regulating AH forma-tion [16]. Cholinergic drugs (pilocarpine, carbachol) increaseTM outflow through ciliary muscle contraction [17]. a-Adre-nergic receptor agonists (apraclonidine, brimonidine)decrease inflow by inactivating adenylel cyclase [18]. Prosta-glandins (PGF2a analogues: latanaprost, travoprost, bima-trost, tafluprost) increase outflow by increasing matrixmetalloproteinase expression [19] and carbonic anyhydraseinhibitors (dorzolamide, brinzolamide, acetazolamide,methazolamide) decrease AH formation [20].Animal models for glaucoma diseaseAs previously mentioned, increased IOP is a major risk factorfor glaucoma onset and progression. It is evident that therelevant animal models for glaucoma would comprise RGCand ON damage brought about by chronic or transient ocularPlease cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma ande2 www.drugdiscoverytoday.comhypertension. The best glaucoma animal models require thatfrequent IOP measurements be done and easy assessment ofretinal neuronal damage should be possible. However, thefield describes a lack of validated animal models for glaucomaneuroprotection and this negatively impacts drug develop-ment. Glaucoma rodent models used to investigate pressure-independent factors are reviewed in [21].The relevance, usefulness and validity of any animal modelmust, in part, be based on its similarity to the human diseasein question but there is large variation in glaucoma researchin terms of reliance on different model species. For example,rodent models possess similarity to human ocular anatomyand other factors such as affordability, genetic manipulation,availability and short life span all form the basis of decisionmaking in terms of experimental design [22].And yet, currently incurable diseases are plighted, in part,by the use of research models which fail to mimic the humandisorder completely. Separately, glaucoma damage at time ofclinical diagnosis precludes the study of disease onset and thisposes a problem. However, the development of animal mod-els has been necessary for the study of the pathophysiology ofhuman glaucoma. Good animal models are also essential forpharmacological studies and should be characterised by lowcost, reproducibility, easy disease induction and limited sideeffects to neighbouring tissue. For an up-to date review ofcurrent animal models for PACG, PCG and other forms ofglaucoma, see [23].The literature classifies glaucoma models as naturallyoccurring or induced/experimental models. Naturallyoccurring models of glaucoma arise spontaneously and thecaveat with these is the difficulty in regulating disease onsetand subsequently, obtaining a homogenous experimentalgroup. In contrast, induced glaucoma models provide thecorrect conditions for controlled experiments and thereforeallow the examination of disease onset and pathologicalprogression. However, induction of glaucoma disease canbe somewhat unpredictable and whilst experimental modelsare important for testing responses to pharmacologic agents,genetic models developed to address specific hypothesesgenerate further insight into pathophysiology of glaucomaand potentially lead to the discovery of new drug targets.Table 1 highlights the major (and historic) animal modelsthat exist in both the natural and spontaneous classifications,and segregates models according to species. Because of theircontribution to knowledge about hypertension and sponta-neous or induced glaucoma, animal models have facilitatedthe development of therapeutic strategies [24]. As Table 1shows, in glaucoma, a wide variety of animal models ofdifferent species have been used to study the disease[24,25]. These include large animals such as monkeys [26],dogs [27,28], pigs [29], and small animals such as rodents [21].However, no ideal animal model for glaucoma exists andTable 2 lists the advantages and disadvantages associated the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/Vol. xxx, No. xx 2014 Drug Discovery Today: Disease Models | Models for eye disordersDDMOD-376; No of Pages 8Please cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma and the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/Table 1. Natural and induced models of glaucomaSpecies Naturally occurring glaucoma models Induced glaucoma modelsMouse - DBA/2J mouse; develops progressive increase of IOP; death ofganglion cells [62]- Increase in IOP appears at 8 months, pressure remains chronicallyhigh until death; model of spontaneous, chronic, high IOP; suitablefor studying cause of pathology- Transgenic mouse strain expressing the Tyr423His myocilin pointmutation corresponding to the human MYOC Tyr427His mutationdeveloped to study POAG [63,64]; loss of RGCs in peripheral retina,axonal degeneration on ON, moderate and persistent elevation ofIOP- Transgenic mouse; a1 collagen type 1 mutation. POAG model. openangles, progressive ON axonal loss, gradual elevation of IOP [65,66]Rabbit - 1960s; albino New Zealand rabbits, open-angle glaucoma, alterationin trabecular meshwork development [67]- Reduction in structural support of the trabeculae could be the causeof elevated IOP- Corticosteroid model; topical steroid application, increase in IOP inalbino rabbits [68]; mimics human chronic open angle glaucomaDog - Inherited POAG in lab beagles [69]; autosomal recessive, bilateralelevation of IOP, reduction in AH outflow- Closed angle glaucoma in Beagles, Cockers, and Basset hounds- Cocker race develops glaucoma from an early age; Beagles andBassets the process is progressive and expressed between 6-12months of age [70]- Autosomal recessive phenotype in Beagles, present a pre-glaucomastage- Glaucoma treated pharmacologically (pilocarpine, epinephrine,acetozolamide, dichlorphenamide)Non-humanprimates- First described in quay/Cayo Santiago Macque/Macaca monkeys inPuerto Rico; maternal inheritance, 40% prevalence of elevated IOP;loss of retina ganglion cells, excavation of the optic nerve andelectrophysiological evidence of damages in the retina peripheralfield [71]- Earliest models of induced glaucoma- Alpha chymotrypsin model (Lessell and Kuwabara, 1969); atrophy inciliary body. Blockage of anterior chamber by drug-induced lysates.Elevated IOP- Experimental monkey model of POAG. Argon laser photocoagulation[72]. First laser model of glaucoma. Argon laser-induced scar forma-tion of trabecular meshwork (Gaasterland and Kupfer, 1974); tem-porary increase in IOP caused by fibrin mesh obstructing thetrabecular meshwork. IOP elevation in 70% of animals. ON cupping,loss of RGCs, thinning of nerve fiber layer- Model of chronic IOP elevation developed using latex microspheresinto anterior chamber, inexpensive [40]- Model of chronic IOP elevation developed using autologous fixed redblood cells/ghost blood cells injected into anterior chamber; cantvisualise fundus [38,39]- Model of acute elevation of IOP [41]Rats - 1995; cauterisation of epi-scleral veins, induce chronically high IOP[up to 6 months, 25% rat life]. Trabecula protected [31]; pressure-reducing and neuron-protecting drugs tested in this model. Lessinvasive than laser photo-coagulation- Long-lived glaucomatous rats present optic disc changes similar tothose in late stage human glaucoma [73]- Rat glaucoma model, induced by topical application of dexametha-sone; to study myocilin expression. Shows elevated IOP [74]- Hypertonic saline solution injection to episcleral vein [32]; increaseIOP by reducing AH drainage- Injection of magnetic microspheres; directed by handheld magnet [75]Zebra-fish - wdr36 mutant; used to characterise wdr36 function but does notshow typical glaucoma phenotype [76]- bug eye mutant; RGC death and high IOP [77,78]; model used toidentify mutation in low-density lipoprotein receptor-related protein2 (Lrp2) which is important for myopia and other glaucoma riskfactors [79]www.drugdiscoverytoday.com e3Drug Discovery Today: Disease Models | Models for eye disorders Vol. xxx, No. xx 2014DDMOD-376; No of Pages 8Please cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma and the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/Table 2. Comparison of animal species used in glaucoma modelsModel species Pros ConsMouse - Few ethical restrictions- Sample numbers for study can be large- Eyes are easy to obtain- Easy to house and handle- Genetic manipulation- High degree of conservation between mice and humangenomes- Inexpensive- Availability of specific models may be limited- Very small size of ocular globe; hard to access clinically- Absence of lamina cribrosa in the ONRat - Easy to maintain in the lab- Enable genetic manipulation- Can be used in large numbers- Main progress in the study of glaucoma was driven bydevelopment of rat models- Economic- Small ethical issues- increased IOP easily induced- Chronic high IOP progressively damages RGCs (as in humans)[80]- The rat shares similar anatomical and developmental char-acteristics of the anterior chamber, especially in the aqueousoutflow pathway, with the human [8184]- Anatomical similarities with primates regarding anteriorsegment blood supply and aqueous humor drainage [85]- Size of its eye limits its useNon-human primates - Close phylogeny and high homology of the monkey withhumans; retinal and ON anatomy almost identical- Broadly used for improving clinical indicators of initial opticnerve damages in glaucoma- Resemblance between human and primate glaucoma [36]- Very expensive- Limited availability- Difficult to handle, special housing facilities- Ethical and economical factors- Fixed midriasis occurs; ciliar nerve damage- Large fluctuations in IOP- Several laser sessions needed to obtain continuous high IOP- Severe inflammation in ocular globe; trabecular alterationsPigs and mini-pigs - Epi-scleral cauterisation system- Vascular and retinal studies possible as the eyes are largerthan rodent models [29].- Pig eye/retina shares many similarities with the human [29]- Diagnostic tools can be applied- Mini pigs are easy to handle and grow slowly- Visualisation of lamina cribrosa in mini pig is more difficultthan in humans 4 to central venous ring [86]Dogs - Spontaneous inheritance of the disease without congenitalabnormalities- Availability of genome sequence- Relatively large eyes- Can be aggressive and difficult to handle- Availability may be limited- Intrascleral plexas rather than a Schlemms canalRabbits - Inadequate model for studying alterations in the retina or itsvascularisation in glaucoma- Absence of lamina cribrosa- Partial myelinisation (by oligodendrocytes) of optic axonswithin the retina- Prominent vasculous sac- Steroid model; IOP measurements are difficult to standardiseas rabbit eye dries variably depending on stressZebra-fish - Short generation time- Well supported genomic infrastructure- Can be maintained in a small space- Attractive model for genetic manipulatione4 www.drugdiscoverytoday.comVol. xxx, No. xx 2014 Drug Discovery Today: Disease Models | Models for eye disordersDDMOD-376; No of Pages 8with various animal species for their inclusion as an experi-mental model.Rudzinski and Saragovi review rat glaucoma models cur-rently used in research and categorise each model based onthe (pre-trabecular, trabecular and post-trabecular) mechan-ism of increased IOP [30]. Episcleral cauterisation models areused widely in the literature owing to their feasibility and lackof complications compared to other in vivo models. For theexamination of alterations in IOP, one of the most exten-sively used animal models is the chronic moderately elevatedIOP rat. This model is based on the obstruction of the veinsresponsible for drainage, either by cauterisation of episcleralveins [31] or by micro-injection of hypertonic solution [32].Also, pharmacological studies of pressure-lowering and neu-roprotective agents employ the chronic IOP elevation ratmodel based of Sharmas episcleral vein cauterisation [31],and this is generally done preceding studies in larger animalsand human clinical trials. Aims to investigate the causes ofincreased IOP from anatomic and functional alterations inthe eye and the optic nerve rely heavily on non-humanprimate (monkey) models [3337]. Additionally, models ofchronic IOP elevation have been designed using autologousfixed red blood cells [38,39] and latex microspheres in experi-mental monkeys [40]. The mechanism of optic nerve damagehas also been studied in a separate model which developsacute IOP elevation [41]. Interestingly, the identification ofADAMTS10 as a candidate gene for POAG arose from agenome wide SNP array study to map disease genes in acanine model of POAG (autosomal recessive) [42].Drug discovery from animal models areas to watchThe development of new pharmacological interventionscomes from studies of the molecular mechanisms of pathologyand the mechanisms which lead to RGC death, both of whichrely on animal models. Drug discovery for glaucoma is bothenhanced and impeded by unique features of the human eye.In situ visualisation of the optic nerve and retina is possiblewith non-invasive diagnostic techniques (e.g. optical coher-ence tomography). Because of the clinical accessibility of thehuman eye tissues, drug delivery methods such as local injec-tions or eye drops can be employed. Systemic toxic effects areminimised in cases of local delivery and exposure to a ther-apeutic agent and this enhances drug therapeutic index. How-ever, in spite of the advantage of clinical accessibility, otherchallenges exist in relation to ocular barriers of the human eye.For example, drug efficacy can be reduced and drug transportimpeded by ocular barriers (tear dilution, blood flow, lympha-tic clearance, blood-ocular barriers) [43]. Because of thesefactors and to the complexity of the disease itself, glaucomadrug discovery is a relatively slow process. In fact, no newclasses of glaucoma drugs have arisen since Latanoprost, aprostaglandin which was launched a decade ago and is nowPlease cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma andconsidered first-line treatment. We now highlight areas ofinterest for potential emerging therapies.Novel IOP-lowering drugsInhibition of actin polymerisation via the action of Latrun-culins (marine sponge macrolides) is a possible mode of IOP-reduction which is under current study [44]. A novel mechan-ism of action of actin cytoskeleton disruption has beenreported for Latrunculins where trabecular meshwork out-flow is increased in the eyes of male and female adult cyno-molgus monkeys and post-mortem patient eyes [45].Unfortunately, clinical trials to date have only yielded mar-ginal success and this is possibly due, in part, to their poorsolubility. It is hoped that improvements in drug efficacy mayfollow changes in the delivery system [46].Cannabinoid receptor agonistsIntriguingly, historic evidence from observations in the1970s highlight a transient IOP reduction in response tosmoking marijuana and has prompted interest in the useof cannabinoid receptor agonists for glaucoma disease [47].It has subsequently been shown that topical application of acannabinoid receptor agonist lowers IOP in a non-humanprimate induced model of glaucoma (unilateral induction viaargon or diode laser photocoagulation of the mid-trabecularmeshwork) [48]. This study employed an agonist selective forcannabinoid receptor 1 using normotensive and glaucoma-tous adult female Macaca cynamolgus monkeys and IOP wasreduced by a reduction in AH flow.Neuroprotective agentsAs highlighted, current treatment methods for glaucomafocus on IOP reduction and fail to combat associated retino-pathy and optic neuropathy. It is clear that there is a require-ment for neuroprotective treatment of glaucoma. A commonend point in glaucoma and retinal diseases is the death ofretinal neurons. As such, neuroprotective therapies are anunmet medical need for glaucoma patients but have been afocus of animal model research for some time. For examples,agonists of the 5-hydroxy-tryptamine 1A receptor (5-HT1A)are documented to have neuroprotective qualities. AL-8309Bis a topical selective agonist of 5-HT1A which has been used instudies using male Wistar and male LongEvans rats as a modelof central nervous system injury [49,50]. AL-8309B representsa promising next generation therapy as results show neuro-protective effects against excitotoxic neuronal damage. Inaddition, a separate model of excitotoxic neuronal and lightdamage using male Sprague-Dawley rats demonstrated areduction in neuronal death upon treatment with AL-8309B [51].Reduced IOP is reported for agonists of the a-adrenergicreceptor and experimental animal models also reveal RGCprotection but convincing data has yet to emerge from the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/www.drugdiscoverytoday.com e5Drug Discovery Today: Disease Models | Models for eye disorders Vol. xxx, No. xx 2014DDMOD-376; No of Pages 8patient studies [52]. One a2-adrenergic receptor agonist,brimonidine tartrate, which was originally created for IOPreduction, has proven promising as a neuroprotective agentin rodent models. Induction of retinal degeneration by lightdamage in male Sprague-Dawley rats reveals that brimoni-dine is protective for photoreceptors and enhances the pro-duction of neurotrophic factors [53]. An experimental rodentmodel of ocular hypertension (argon laser photocoagulationused for IOP elevation in male Wistar rats) documents pro-tection of RGCs in response to systemic administration ofbrimonidine [54]. Topical brimonidine is FDA approved forglaucomatous IOP reduction and its preservation of visualfield loss has been studied.A role for melatonin in the treatment and management ofglaucoma is slowly emerging. Melatonin in the eye is apromising agent which has local antioxidant effects due tothe inhibition of nitric oxide synthase and this makes it acandidate as a neuroprotective factor [5557]. Animal modelsused for the study of melatonin action on IOP are reviewed in[58]. Studies using a normotensive white rabbit model haveshown that the melatonin derivative, agomelatine, is a hypo-tensive compound which could also hold promise for glau-coma treatment [59]. While agomelatine has proven IOP-lowering ability (equal to that of melatonin), it is also aneuroprotective agent [60].Comparisons can be drawn between chronic neurodegen-erative disorders and glaucoma and this can shed light onfactors responsible for disease progression [61]. For example,Alzheimers disease and glaucoma can both be characterisedby dysregulation of neurotrophic growth factors, caspaseactivation and both diseases can be managed via NMDA(N-methyl-D aspartate) receptor antagonists, neurotrophinsor immune regulators. One NMDA receptor antagonist, mem-antine, has come to the fore in studies of non-human primateexperimental models. RGCs can become over-loaded withintracellular calcium if there is sustained activation of theNMDA signalling pathway, and this results in cell death byapoptotic means. In an experimental primate model ofinduced unilateral glaucoma, RGCs of non-human primatesare conferred protection (as are relay neurons of the lateralgeniculate body) in response to oral administration of mem-antine [1]. To date, the efficacy of memantine in glaucomahas failed at Phase III of clinical trials as patients at high risk ofdeveloping glaucoma see no reduction in visual field loss.ConclusionProgress in glaucoma treatment has been associated with thedevelopment of animal models and disease prevention andneurological protection are prime areas of focus [24]. Onemajor impediment to breakthrough in human studies is thatdamage present at diagnosis precludes the study of humandisease development from onset. Comparative animal studiestherefore, are necessary and have broadened understandingPlease cite this article in press as: McNally S, OBrien CJ. 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Limbal microvasculature of the rat eye. InvestOphthalmol Vis Sci 1995;36:7516.[86] Galdos M, et al. Morphology of retinal vessels in the optic disk in aGottingen minipig experimental glaucoma model. Vet Ophthalmol2012;15(Suppl. 1):3646.Drug Discovery Today: Disease Models | Models for eye disorders Vol. xxx, No. xx 2014DDMOD-376; No of Pages 8Please cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma ande8 www.drugdiscoverytoday.com the role of animal models, Drug Discov Today: Dis Model (2014), http://dx.doi.org/Drug discovery in glaucoma and the role of animal modelsIntroductionGlaucoma - a complex disorderWhat drugs are currently in use for treatment of disease?Animal models for glaucoma diseaseDrug discovery from animal models - areas to watchNovel IOP-lowering drugsCannabinoid receptor agonistsNeuroprotective agentsConclusionConflict of interestReferences

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