Introduction to Special Issue on Ocular Pathology and Drug Development

Abstract

Dysfunction of the visual system remains a leading cause of human disability worldwide. Preclinical studies are a key component of efforts to develop drugs and devices to ameliorate visual impairment. Although new opportunities for the delivery of targeted ocular therapeutics have been created, clinical success has been confounded by unique challenges of drug development for the eye. This Special Issue brings together a broad range of articles that augment our current understanding of the visual system and highlight methods for assessing ocular toxicity and some of the current challenges in ocular drug development. Topics addressed include the anatomy, developmental anatomy, and/or immunobiology of the visual system and associated lymphoid tissues; animal models; methods for assessing ocular toxicity; spontaneous background and procedure-related microscopic findings and common artifacts in histologic sections of ocular tissues; and novel ocular drug delivery systems.

Dysfunction of the visual system remains a leading cause of human disability worldwide. ¹ In the United States, the leading causes of blindness and low vision are primarily age-related eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy, cataract, and glaucoma. ² Efforts to develop drugs and devices to ameliorate visual impairment continue to expand and have resulted in important advances in clinical therapies. ³ Preclinical studies remain a key component of these efforts.

A considerable body of literature exists for the ocular toxicity of small molecules, which can often be traced to cellular pathways that result in predictable functional or anatomical changes. Advances in technology and molecular science have resulted in novel therapeutics that often have ocular toxicity that is not well understood. Although new opportunities for the delivery of targeted ocular therapeutics have been created, clinical success has been confounded by unique challenges of drug development for the eye, including the complex structure and organization of multiple tissue matrices specifically designed to function in concert for transparency and visual acuity, and the deviated immune status of the internal ocular environment. ⁴

This Special Issue brings together a broad range of articles that augment our current understanding of the visual system and highlight methods for assessing ocular toxicity and some of the current challenges in ocular drug development. Topics addressed by these articles include the anatomy, developmental anatomy, and/or immunobiology of the visual system and associated lymphoid tissues; animal models; methods (predominantly terminal) for assessing ocular toxicity; spontaneous background and procedure-related microscopic findings and common artifacts in histologic sections of ocular tissues; and novel ocular drug delivery systems.

One of our goals for this issue was to highlight the challenges associated with novel methods of ocular drug delivery. Although topical administration remains the most commonly used route of drug delivery to the eye, the intravitreal route has become the preeminent approach to deliver drugs to the retina. Millions of intravitreal injections are performed each year, ^3,5 primarily to treat wet AMD with compounds that inhibit retinal neovascularization. One of the major current challenges in ocular drug development is to identify strategies to prolong the action of such compounds in order to reduce the frequency of intravitreal injections. Seven papers in this issue illustrate a variety of approaches to achieving this goal and the associated challenges and include strategies that vary from adjusting formulation pH or concentration, to conjugation of the active compound to various large molecules, to refillable intraocular implants.

Finally, the critical role played by the anatomic pathologist and the anatomic pathology report in ocular drug development are elucidated in a capstone manuscript by Dr Brian Short. This manuscript reviews selected aspects of study design for ocular toxicity studies, ocular histology procedures that meet regulatory expectations, and the generation of a report that correlates microscopic findings with key ophthalmic findings to facilitate the production of a high-quality, integrated ocular toxicology report.