Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development
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Pharm Res (2019) 36: 58 https://doi.org/10.1007/s11095-019-2588-5 EXPERT REVIEW Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development Mihir Shah1 & Sara Cabrera-Ghayouri 1 & Lori-Ann Christie 1 & Katherine S. Held 1 & Veena Viswanath1 Received: 30 August 2018 /Accepted: 8 February 2019 /Published online: 25 February 2019 # The Author(s) 2019 ABSTRACT Preclinical models of human diseases are criti- ABBREVIATIONS cal to our understanding of disease etiology, pathology, and AAA Alpha-aminoadipic acid progression and enable the development of effective treat- AMD Age-related macular degeneration ments. An ideal model of human disease should capture ana- Ang1 Angiopoietin-1 tomical features and pathophysiological mechanisms, mimic Ang2 Angiopoietin-2 the progression pattern, and should be amenable to evaluating AqH Aqueous humor translational endpoints and treatment approaches. Preclinical BCVA Best corrected visual acuity animal models have been developed for a variety of human C5 Complement factor 5 ophthalmological diseases to mirror disease mechanisms, CFD Complement factor D location of the affected region in the eye and severity. CNV Choroidal neovascularization These models offer clues to aid in our fundamental CSME Clinically-significant macular edema understanding of disease pathogenesis and enable pro- DED Dry eye disease gression of new therapies to clinical development by DME Diabetic macular edema providing an opportunity to gain proof of concept DR Diabetic retinopathy (POC). Here, we review preclinical animal models asso- DRSS Diabetic Retinopathy Severity Scale ciated with development of new therapies for diseases of ECM Extracellular matrix the ocular surface, glaucoma, presbyopia, and retinal ERG Electroretinography diseases, including diabetic retinopathy and age-related GA Geographic Atrophy macular degeneration (AMD). We have focused on sum- IOP Intraocular pressure marizing the models critical to new drug development IRMAs Intra-retinal microvascular abnormalities and described the translational features of the models IVT Intravitreal that contributed to our understanding of disease patho- KCS Keratoconjunctivitis sicca genesis and establishment of preclinical POC. MGD Meibomian gland dysfunction nAMD Neovascular age-related macular degeneration NDA New drug application KEY WORDS Age-related macular degeneration . diabetic NHP Non-human primates retinopathy . dry eye disease . glaucoma . ocular allergy NPDR Non-proliferative diabetic retinopathy OCT Optical coherence tomography OIR Oxygen-induced retinopathy ONL Outer nuclear layer PACG Primary angle-closure Guest Editors: Hovhannes J Gukasyan, Shumet Hailu, and Thomas Karami PDGF Platelet derived growth factor PDR Proliferative diabetic retinopathy * Veena Viswanath [email protected] POAG Primary open angle POC Proof of concept 1 Biological Research, Allergan plc, 2525 Dupont Drive RGCs Retinal ganglion cells Irvine, California 92612, USA RPE Retinal pigment epithelium 58 Page 2 of 34 Pharm Res (2019) 36: 58 SD Sprague Dawley Ocular Surface Diseases STZ Streptozotocin VEGF Vascular endothelial growth factor The ocular surface is a complex tissue system harmonized to VE-PTP Vascular endothelial-protein tyrosine phosphatase achieve a stable tear film and contribute to visual acuity. The lacrimal and meibomian glands, mucin producing goblet cells, and nervous systems are key components of a lacrimal func- INTRODUCTION tional unit which contribute to maintaining a stable tear film (1). Furthermore, epithelial cells and underlying lymphoid as- The pathologies of the eye are usually divided into different sociated tissues provide a mucosal barrier to prevent irritants categories based on the affected region: ocular surface, ante- and pathogens from entering the body. The ocular surface is rior and posterior diseases. Multiple diseases such as cataract, vulnerable to environmental insults and when components of age-related macular degeneration (AMD), glaucoma, presby- this tissue are compromised mild to severe disease can ensue. opia, dry eye disease (DED), ocular allergy and others can lead The most prevalent ocular surface disorders encompass dry to visual impairments and blindness. Ocular pathologies are eye disease (DED), blepharitis, meibomian gland dysfunction also observed as a common finding in multiple systemic dis- (MGD), and ocular allergy. Patients may experience ocular eases including autoimmune diseases like rheumatoid arthri- dryness, itch, photosensitivity and foreign body sensations, tis, Sjogren’s Syndrome (SS), rosacea, Graves Diseases, graft which in many cases are shared symptoms of several ocular versus host disease and chronic diseases such as diabetes and surface disorders (2). Disease progression necessitates pharma- hypertension. Development of therapeutic strategies for ocu- ceutical intervention such as anti-inflammatory drugs for lar diseases requires a thorough understanding of etiology, DED and ocular allergy, and antibiotics for blepharitis. molecular and anatomical pathogenic mechanisms and natu- While many patients respond to pharmaceutical treatments, ral history of the disease. Mimicking human diseases in animal there remains a large population that is non-responsive or models in species such as mice, rats, guinea pigs, rabbits, dogs, cannot tolerate the side effects associated with these therapies. and primates has been critical to our understanding of several To enable effective therapies a variety of in vivo models that human ocular diseases and for the development of novel mimic multi-tissue heterogeneous pathologies have been de- drugs, drug delivery strategies and advancement of oph- veloped. Highlighted in this portion of the review are animal thalmological diagnostic technologies. This review pro- models of ocular allergy, dry eye syndrome (aqueous deficient vides a focused summary of models key to the develop- and evaporative), and ocular pain that have been utilized in ment of novel therapies for the most common ocular drug development. We will not address preclinical models of diseases (ocular allergy, DED, glaucoma, presbyopia, di- ocular infections or wound healing in the eye as they have abetic retinopathy (DR), and AMD). The application of been reviewed elsewhere (3,4). these models in ocular pharmacology and translational potential to human disease are also discussed. Our in- Ocular Inflammation: Ocular Allergy and Dry Eye Disease tention is not to provide a complete listing of all pre- clinical models for these ophthalmic diseases. Instead, Inflammation plays a key role in the pathology of multiple we focus on the key in vivo models that were used to diseases of the ocular surface including DED, SS and ocular establish preclinical POC prior to entry into the clinic, allergy, thus desirable drug candidates include anti- with emphasis on drugs that have demonstrated clinical inflammatory or immune modulatory molecules. A variety efficacy. Collation of drugs and their preclinical POC of preclinical ocular models have been used to validate the models was done by reviewing information provided in anti-inflammatory property of drugs, as one model may not regulatory documents (eg. New Drug Applications, represent all aspects of the pathology. Discussed below are the NDA), conference abstracts, patent publications, compa- preclinical models used in drug development for ocular allergy ny press releases, Clarivate Analytics’ Integrity and DED. Multiple models of SS have been reported in the Experimental Models Knowledge Area and published literature which have been previously reviewed and will not be literature. Although many of these animal models mimic addressed in the present review (5,6). aspects of ocular diseases, none of them capture the full complexity of human disease. Therefore, multiple Ocular Allergy. Ocular allergy (allergic conjunctivitis) is a hy- models of the same disease are typically needed to re- persensitivity disorder that affects the conjunctiva, lids and/or capitulate different aspects of human pathology. Finally, cornea, with prevalence as high as 20% in the U.S. (7). Several we outline several gaps in current preclinical models subtypes have been described including: Seasonal, the prom- and endpoints that should be considered in the future inent subtype that results in mild disease, perennial allergic development of novel therapeutics to address unmet pa- conjunctivitis, and the less common severe vernal and atopic tient needs. keratoconjunctivitis disorders (VKC and AKC). Robust Pharm Res (2019) 36: 58 Page 3 of 34 58 clinical signs and symptoms such as tearing, chemosis, mucous In contrast to models that mainly capture mast cell discharge and itch are shared among the subtypes, while se- degranulatory responses, antigen-challenge models provide a vere allergy may involve keratitis and corneal ulcer (8). Ocular better opportunity to evaluate factors associated with chronic allergic reactions are initiated with IgE-mediated responses disease. Induction of antigen-challenge begins with a sensiti- that result in mast cell degranulation of factors that drive the zation period initiated with peripheral immunization, typical- hallmark signs and symptoms. This early-phase response ly with a protein, ovalbumin, or an environmental antigen, peaks within 1 h, and can lead to a late-phase response involv- ragweed. This is followed by topical antigen challenge that ing the influx of eosinophils and neutrophils 4–6hlater(9). induces chemosis, tearing, mucus