Drug discovery in glaucoma and the role of animal models

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  • DDMOD-376; No of Pages 8

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    Drug Discovery Today: Disease Models Vol. xxx, No. xx 2014

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    sdiscoveries which relate to potential new therapeutic

    avenues.

    Introduction

    The discovery of therapeutic drug targets relies heavily on

    animal 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 and

    rather, comprises a heterogeneous group of disorders; this

    makes drug discovery difficult. The brainstem, the visual

    cortex and the visual pathway are impacted in the disease

    and this results in progressive blindness due to chronic optic

    nerve damage and a loss of RGCs [1]. Worldwide, glaucoma is

    a leading cause of irreversible blindness and visual field

    defects and it is estimated that the disease will affect over

    80 million people by 2020 [2]. Similar to other neurodegen-

    erative disorders, glaucoma correlates with age and as

    improvements in healthcare denote an increased lifespan

    Glaucoma a complex disorder

    Human glaucoma is generally classified into three major sub-

    groups: Primary Open Angle Glaucoma (POAG), Primary

    Angle Closure Glaucoma (PACG), and Primary Congenital

    Glaucoma (PCG) and in most populations, POAG is the most

    common form of the disease [3]. Currently, three causative

    genes (Myocilin, Optineurin and WDR36) have been identi-

    fied for POAG although more than 20 genetic loci have been

    reported [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 damage

    represents a final common pathway of tissue damage in all

    types of glaucoma.

    As mentioned, the most common form of glaucoma is

    open-angle which is a multi-factorial optic neuropathy

    defined by open anterior chamber angles, elevated intra-

    ocular pressure (IOP), progressive optic nerve fiber loss and

    visual field defects [5]. It is the chronic elevation of IOP in

    glaucoma which leads to the death of RGCs and IOP is, in fact,

    a major risk factor for the disease [6]. As such, a primary focus

    for 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 DISCOVERY

    TODAY

    DISEASEMODELS

    Drug discovery in grole of animal modeSara McNally*, Colm J. OBrienCatherine McAuley Clinical Research Centre, Institute of Ophthalmology, Mat

    Glaucoma is a neurodegenerative disorder charac-

    terised by damage to inner layers of the retina and

    the optic nerve (ON). The slow degeneration of retinal

    ganglion cells (RGCs) and their axons results in a

    progressive loss of vision. To date, a wide variety of

    animal models have been used to study glaucoma dis-

    ease mechanisms and these include monkey, dog, and

    rodent models. However, there remains no ideal

    model for studying glaucoma disease and this is largely

    due to its complexity. Here, we review common animal

    models in use for glaucoma research and highlight

    Editors-in-Chief

    Jan Tornell AstraZeneca, Sweden

    Andrew McCulloch University of California,

    Models for eye disorderPlease cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma anducoma and thels

    isericordiae Hospital, 21 Nelson Street, Dublin, Ireland

    Section 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 from

    an increasing number of people at risk of developing visual

    impairment.

    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 2014

    DDMOD-376; No of Pages 8in glaucoma disease? A reduction in the outflow of aqueous

    humor (AH) (which is produced by the cilliary body and

    moves into the anterior chamber before leaving the eye)

    generally gives rise to an IOP increase. Exit of AH can occur

    either via the conventional pathway (trabecular meshwork

    (TM)/Schlemms canal) or via the non-conventional (uveoscl-

    eral) pathway [7]. As such IOP homeostasis depends on the

    balance between AH production in the ciliary body and its

    drainage [8,9].

    Glaucoma patients with chronic high IOP who are left

    untreated develop aberrations in the retinal inner layers

    and the optic nerve head (ONH) which clinically manifests

    as visual field loss [5]. Given that IOP is the only proven

    treatable risk factor for glaucoma disease, IOP-reduction stra-

    tegies remain the major approach for patient management.

    However, owing to the complexity of glaucoma disease (and

    adding to the difficulty of treatment) many patients continue

    to suffer visual field defects despite IOP management. Addi-

    tionally, some patients develop normal tension glaucoma

    (NTG); highlighting that IOP-independent mechanisms for

    the development and progression of optic neuropathy exist

    [10].

    What drugs are currently in use for treatment of

    disease?

    The current mode of treating glaucoma comprises an IOP

    reduction strategy involving laser therapy, surgical operation

    or pharmacology (typically treatment with eye drops). Even

    for glaucoma patients suffering from impaired vision and

    having 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 with

    IOP-lowering therapies which act by decreasing the rate of AH

    inflow and/or increasing outflow. There are five major classes

    of drugs administered as eye-drops that are approved for

    lowering 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) increase

    TM 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 matrix

    metalloproteinase expression [19] and carbonic anyhydrase

    inhibitors (dorzolamide, brinzolamide, acetazolamide,

    methazolamide) decrease AH formation [20].

    Animal models for glaucoma disease

    As previously mentioned, increased IOP is a major risk factor

    for glaucoma onset and progression. It is evident that the

    relevant animal models for glaucoma would comprise RGCand ON damage brought about by chronic or transient ocular

    Please cite this article in press as: McNally S, OBrien CJ. Drug discovery in glaucoma and

    e2 www.drugdiscoverytoday.comhypertension. The best glaucoma animal models require that

    frequent IOP measurements be done and easy assessment of

    retinal neuronal damage should be possible. However, the

    field describes a lack of validated animal models for glaucoma

    neuroprotection 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 model

    must, in part, be based on its similarity to the human disease

    in question but there is large variation in glaucoma research

    in terms of reliance on different model species. For example,

    rodent models possess similarity to human ocular anatomy

    and other factors such as affordability, genetic manipulation,

    availability and short life span all form the basis of decision

    making 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 human

    disorder completely. Separately, glaucoma damage at time of

    clinical diagnosis precludes the study of disease onset and this

    poses a problem. However, the development of animal mod-

    els has been necessary for the study of the pathophysiology of

    human glaucoma. Good animal models are also essential for

    pharmacological studies and should be characterised by low

    cost, reproducibility, easy disease induction and limited side

    effects to neighbouring tissue. For an up-to date review of

    current animal models for PACG, PCG and other forms of

    glaucoma, see [23].

    The literature classifies glaucoma models as naturally

    occurring or induced/experimental models. Naturally

    occurring models of glaucoma arise spontaneously and the

    caveat with these is the difficulty in regulating disease onset

    and subsequently, obtaining a homogenous experimental

    group. In contrast, induced glaucoma models provide the

    correct conditions for controlled experiments and therefore

    allow the examination of disease onset and pathological

    progression. However, induction of glaucoma disease can

    be somewhat unpredictable and whilst experimental models

    are important for testing responses to pharmacologic agents,

    genetic model