Ophthalmic Disease Mechanisms And Drug Discovery

Kang Zhang

• Publisher: WSPC
• Year: 2016
• eBook ISBN: 9789814663083
• Topic: Biological Sciences
• Subtopic: Science General
• Index: Biological Sciences

This invaluable book presents a concise discussion on the most important topics of ophthalmology — mechanism of ophthalmic diseases, imaging techniques used for diagnosis, novel therapies and drug delivery systems. It also covers current knowled

Chapter 1: Pathology and Mechanism of Eye Diseases

Katherine J. Wert^†, Heike Kroeger^‡, Frances Wu^‡,
Stephen H. Tsang^§, and Jonathan H. Lin^‡,**

^†The Whitehead Institute for Biomedical Research,
Cambridge, MA 02142

^‡Departments of Pathology and Ophthalmology,
University of California San Diego, La Jolla, CA 92093

^§Departments of Ophthalmology, Pathology, and Cell Biology,
Columbia University College of Physicians and Surgeons,
New York, NY 10032

**VA San Diego Healthcare System, San Diego, CA 92161

1.Introduction

Retinal degenerative diseases are the leading cause of irreversible blindness in Western nations, and the loss of sight affects over 3.4 million people in the United States alone.¹ These diseases have high genetic and allelic heterogeneity, and therefore our understanding of the pathophysiology of these conditions is limited. However, progress in molecular genetics has determined specific factors that play significant roles in the pathogenesis of retinal degeneration. This chapter is focused on understanding the pathology of the human eye, the molecular genetics identified in degenerative diseases of the eye, and the current known mechanisms for these diseases.

2.The Eye

The human eye is a complex organ that consists of many different cell types. The eye transmits information to be processed by the brain on the color, form, and light intensity of objects. The human eye can be divided into two main parts: the anterior and the posterior segments.²

2.1.Anterior eye

In the anterior portion, the sclera and cornea act as outer protective layers of the eye. Also anterior in the eye is the uveal tract, composed of the iris, ciliary body, and anterior choroid. The components of the uveal tract mainly function under the control of the autonomic nervous system. The uveal tract allows for the exchange of nutrition and gases into the posterior portion of the eye. The ciliary body and the iris are directly supplied by the uveal vessels, while these vessels indirectly support the sclera, lens, and outer retina via diffusible nutrients. The uveal tract contains numerous melanocytes that reduce the light reflected within the eye and absorb light transmitted through the sclera, in order to improve the retinal image.² Moreover, the ciliary body produces an aqueous humor and regulates the contour of the translucent lens, thereby controlling the focus of the eye. The iris provides the eye pigmentation, as well as pupil dilation and constriction to allow for varying levels of retinal illumination. The choroid is a vascular layer that supplies the outer retina and the retinal pigment epithelium (RPE), both parts of the posterior eye as described in the next section.

2.2.Posterior eye

The posterior eye consists of the RPE and the neurosensory retina.^3,4 The RPE creates a selective permeability barrier between the outer choriocapillaris vasculature of the eye and the inner sensory retina, and this is known as the outer blood-retinal barrier.⁴ It is comprised of a pigmented monolayer of RPE cells. The RPE monolayer consists of cells cuboidal in shape in the periphery of the eye, to columnar in shape nearing the macular region of the eye. The barrier function of the RPE allows for the provision of nutrients, such as vitamin A metabolites, as well as the clearing of photoreceptor outer segment (POS) debris daily from the overlying photoreceptor cell layer.^5–9 Between each RPE cell there are tight junctions and ion transporters, which create electrical potential differences between the apical and basal surfaces of the cell as well as intercellular communications. Using this electrical potential, the RPE cells regulate the composition, such as pH, of the photoreceptor extracellular matrix and protect the visual function of the retina. Additionally, the RPE cells contain microvilli on the apical surface, which help phagocytose the POS debris as well as transport enzymes from the basal to apical surface to contact the inner retinal layers.

2.2.1.The retina

The retina is composed of different types of neurons that each form distinct synapses with one another.⁴ The retina transduces the optical properties of an image into neural signals, which are then transmitted through the retinal cell layers to the visual cortex of the brain. The outermost layer of neurons, overlying the RPE monolayer, is the photoreceptor cell layer. These photoreceptor cells create a mosaic pattern of light and darkness that reflect the optical properties of the image, which cause repetitive discharges to the bipolar cells. The bipolar cells then synapse to the ganglion cells, whose axons comprise the nerve fiber layer and the optic nerve. The ganglion cells then discharge the mosaic pattern of light and darkness to the brain, to comprise the visual image.

In addition to these three cell types, there are the horizontal, amacrine, and Müller glial cells. The horizontal cells synapse with the bipolar neurons and photoreceptor cells, while the amacrine cells synapse between the bipolar cells and the ganglion cells. The Müller glial cells span the width of the entire retina, from the inner limiting membrane to the outer limiting membrane where the Müller glial cells form junctions with the photoreceptor cells. The complex neurocircuitry of the retina relies on the signaling mosaicism of the light-sensitive photoreceptor cells, as will be described further in the next sections.

2.2.2.The photoreceptor cells

The photoreceptor cells are the light-sensing neurons directly overlying the RPE. There are two types of photoreceptor cells in the retina: the rods and the cones. The majority of the photoreceptor cells, approximately 97%, are comprised of the rods, while the remaining 3% consist of the cones. Both the rod and cone photoreceptor cells have specific roles for the amount and type of light required for their signaling synaptic response. The rod cells respond to single photons of light, and are therefore highly sensitive and react in low-light, nighttime visual settings. The rod cells have a response of up to 10,000 photons per second, known as mesopic vision, a response range of three orders of magnitude before saturation.¹⁰ At the point of rod cell saturation, the cone cells begin to sense photons of light. The cone cells act as photopic vision, responding up to 10 billion photons per second and providing daytime sight for the human eye. In addition, there are three forms of cone cells in the human eye, the S-, M-, and L-cones, which respond to specific wavelengths of light and provide for color vision.

The human eye is enriched in specific regions for each of these photo-receptor cell types, which provide the visual signals that are sensed daily in an individual’s life. The central region of the retina, known as the macula, is enriched with cone cells. This allows for bright light and color vision in the central visual field, while the rod photoreceptor cells enrich the peripheral visual field.^10,11 Of note, pathological diseases affecting vision will either cause a loss of function of the rod or the cone photoreceptor cells, or both. Depending on which cell type is affected, the patient will exhibit a loss of nighttime vision and the peripheral visual field (rod cell loss-of-function) or a loss of color vision and the central visual field (cone cell loss-of-function).

Both the rod and cone photoreceptor cells each consist of an outer segment, an inner segment, a cell body, and a synaptic terminal that allows for their transmission to the second-order neurons of the retina. The inner segment of the phot...

Table of contents

• Cover
• Halftitle
• Title Page
• Copyright
• Contents
• Introduction
• Chapter 1: Pathology and Mechanism of Eye Diseases
• Chapter 2: Ophthalmic Imaging
• Chapter 3: Pharmacogenomics of Response to Anti-VEGF Therapy in Exudative Age-Related Macular Degeneration
• Chapter 4: Dry Eye Therapy
• Chapter 5: Ocular Inflammation Therapy
• Chapter 6: Nanoparticles for Ocular Drug Delivery
• Index