Drug discovery in ophthalmology: past success, present challenges, and future opportunities

Abstract

BackgroundDrug discovery has undergone major transformations in the last century, progressing from the recognition and refinement of natural products with therapeutic benefit, to the systematic screening of molecular libraries on whole organisms or cell lines and more recently to a more target-based approach driven by greater knowledge of the physiological and pathological pathways involved. Despite this evolution increasing challenges within the drug discovery industry are causing escalating rates of failure of development pipelines.DiscussionWe review the challenges facing the drug discovery industry, and discuss what attempts are being made to increase the productivity of drug development, including a refocusing on the study of the basic biology of the disease, and an embracing of the concept of ‘translational research’. We consider what ophthalmic drug discovery can learn from the sector in general and discuss strategies to overcome the present limitations. This includes advances in the understanding of the pathogenesis of disease; improvements in animal models of human disease; improvements in ophthalmic drug delivery and attempts at patient stratification within clinical trials.SummaryAs we look to the future, we argue that investment in ophthalmic drug development must continue to cover the whole translational spectrum (from ‘bench to bedside and back again’) with recognition that both biological discovery and clinical understanding will drive drug discovery, providing safe and effective therapies for ocular disease.

New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies

“…6), and Proper expression of surface mucins by the corneal epithelium is important not only for ocular defense against invading microbes, but also for accurate adhesion of microparticles and nanomaterials used in the modern ophthalmic drugs. 7 We have compared gene expression of surface mucins (MUC1, MUC4, and MUC16) in the 3D corneal tissue model and excised human corneal epithelium and demonstrated that all mucins were similarly expressed in both reconstructed 3D corneal tissues and excised human corneal epithelium, with MUC16 having the highest level of expression and MUC4 the lowest (Kaluzhny Y, unpublished data, 2018).…”

“…7 Analysis of topical ophthalmic drug absorption is one of the main steps in the identification of compounds with favorable pharmacokinetic properties since the physical and structural barriers of the cornea, which are vitally important for eye protection, present major challenges for delivery and bioavailability. Although in vivo animal studies can be used, anatomic and physiological differences make species extrapolation unreliable.…”

“…6 The ocular drug bioavailability of topically applied formulations is typically below 5%. 7,8 The low bioavailability is due to multiple factors, including fast clearing of the drug from the surface of the eye, drug solubility, and protective mechanisms and barriers of the cornea. 2,9 The apical layer of the corneal epithelium forms tight junctions and presents the main ratelimiting step to the majority of topically applied lipophilic drugs.…”

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

“…[1] Ideal candidates for improved drug delivery treatments are those ocular diseases that drastically affect patients’ quality of life including dry eye disease (DED), age-related macular degeneration (AMD), and uveitis. [2–4] These three common ocular diseases affect different regions of the eye and have immuno-mechanistic characteristics in their disease pathogenesis.…”

Integrated Approaches to Drug Discovery for Oxidative Stress‐Related Retinal Diseases

“…Various therapies have been developed for retinal diseases [10] with some success, most notably the prostaglandin analogs for glaucoma [11] and antivascular endothelial growth factor (anti-VEGF) agents for AMD [12] and diabetic retinopathy [13]. However, there has been a chronic lack of innovation in drug discovery for retinal diseases [14], as there has been for other diseases [15]. For example, therapies targeting OS in retinal diseases have failed to show efficacy in clinical trials; examples are an antioxidant supplement mixture [16] and a hydroxylamine with antioxidant properties [17].…”