Animal Models of Retinal Disease

doi:10.1016/B978-0-12-384878-9.00006-6

Progress in Molecular Biology and Translational Science

Volume 100, 2011, Pages 211-286

https://doi.org/10.1016/B978-0-12-384878-9.00006-6 Get rights and content

Diseases of the retina are the leading causes of blindness in the industrialized world. The recognition that animals develop retinal diseases with similar traits to humans has led to not only a dramatic improvement in our understanding of the pathogenesis of retinal disease but also provided a means for testing possible treatment regimes and successful gene therapy trials. With the advent of genetic and molecular biological tools, the association between specific gene mutations and retinal signs has been made. Animals carrying natural mutations usually in one gene now provide well-established models for a host of inherited retinal diseases, including retinitis pigmentosa, Leber congenital amaurosis, inherited macular degeneration, and optic nerve diseases. In addition, the development of transgenic technologies has provided a means by which to study the effects of these and novel induced mutations on retinal structure and function. Despite these advances, there is a paucity of suitable animal models for complex diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, largely because these diseases are not caused by single gene defects, but involve complex genetics and/or exacerbation through environmental factors, epigenetic, or other modes of genetic influence. In this review, we outline in detail the available animal models for inherited retinal diseases and how this information has furthered our understanding of retinal diseases. We also examine how transgenic technologies have helped to develop our understanding of the role of isolated genes or pathways in complex diseases like AMD, diabetes, and glaucoma.

Introduction

Over the last 100 years, major advances in understanding the pathogenesis of retinal diseases has occurred largely from initial studies on animals that show signs similar to human disease. A detailed understanding of retinal disease in animals has not only furthered our understanding of disease mechanisms, but has also provided a means with which to test novel therapeutic agents.

Like the variety of presentations of retinal diseases in humans, animals suffer from a similarly broad range of conditions. Since the initial observations over 40 years ago that prolonged or bright light exposure can induce retinal degeneration in rodents, many advances have been made in our understanding of the pathogenesis of these specific diseases. As will be documented below, studying the detailed cellular changes that occur in animals that exhibit similar diseases to humans has been critical to this understanding. Over the last few years, a range of more sophisticated genetic tools have also allowed a number of gene mutations causing retinal disease to be identified in both humans and animals. This has expanded our knowledge of the role that particular molecules or pathways play in cell dysfunction and loss.

Although the development of transgenic animals has led to a tremendous improvement in our knowledge of the cause of retinal disease, there remain many diseases, where animals do not adequately reflect the condition in humans. These typically involve common diseases in our society which present with complex etiologies manifesting through either complex genetic and environmental interactions. Moreover, it is now recognized that even in diseases caused by a single mutation, genetic variation at other sites within the same gene can lead to changed severity, penetrance, or disease type.

The aim of this review is to provide an overview of the characteristics of retinal diseases that affect animals and how this has helped us understand the underlying pathogenesis of disease. In particular, we examine the information gained from studying animals that carry naturally occurring mutations, or where there has been genetic modification so that specific molecules or pathways become dysfunctional. In addition, we consider animal models in complex diseases that involve multiple susceptibility genes and/or interactions with the environment. We evaluate how disease in these animals does not always replicate human disease, and what might be necessary to improve the development of the “ideal” animal model for some complex conditions.

Section snippets

Overview of Retinal Structure and Function

The retina is a multilayered outpouching of the central nervous system that consists of alternating layers of neurons and synapses (Fig. 1A). Light passes through all layers of the retina prior to being absorbed by photopigments located within the outer segments of photoreceptors.¹ Photoreceptors convert light into a neurochemical signal that is passed to second order neurons, called bipolar cells. Bipolar cells communicate in turn with the temporally acting amacrine cells and ganglion cells,

Mendelian Inherited Conditions

The sequestration of light energy and its conversion into a neuronal response through the photoreceptors is based on both an intricate protein structure and a high energy demand, both of which require a large number of genes for normal function. This dependency may explain why in excess of 200 retinal genes have been mapped through linkage analysis and over 150 of these identified as disease causative in humans as of January 2010 (http://www.sph.uth.tmc.edu/RetNet/). Hereditary retinal disease

RP: A Family of Inherited Photoreceptor Degenerations

RP denotes a family of hereditary disorders that primarily affects rod photoreceptors and retinal pigment epithelial function and that lead to progressive vision loss and blindness. It has a prevalence of between 1 in 3000 and 1 in 5000 and in developed countries is ranked second behind DR as a cause of visual impairment in those between 16 and 50 years of age. The characteristic cellular features include gradual loss of rod photoreceptors, followed by cones at a later stage.

It is generally

LCA: A Severe Retinal Degeneration Caused by Anomalies in RPE, Glial or Photoreceptor Dysfunction

LCA refers to a family of inherited retinal degenerations that cause visual impairment before the age of 1 year.¹¹⁴ It is characterized by severe and early vision loss, sensory nystagmus, amaurotic pupils, and absent retinal function as tested by electroretinography. It is recognized as the most severe form of retinal degeneration. To date, it is associated with mutations in 14 genes, many of which also cause various types of RP. The genes that cause LCA encode a variety of proteins important

CSNB: An Opportunity to Better Understand Outer Retinal Signaling

In contrast to the inherited retinal degenerations described above, some mutations affecting photoreceptor associated proteins can cause loss of rod function, in the absence of cell death. CSNB is a genetically and clinically heterogenous nonprogressive, inherited disorder of the retina that affects the visual function of patients. As the name suggests, inability to see at night (nyctalopia) is the most common symptom and is often picked up in children as a fear of the dark. Other symptoms that

Inherited Macular Degenerations

The macula is a highly specialized region of the retina that provides high visual acuity central vision. It is defined by the region that contains the pigment, xanthophyll, beneath the retina. The fovea which is found at the center of the macula is highly specialized for maximizing visual acuity, consisting of a foveal pit, where the inner retinal layers are shifted to the side of a small depression. This region contains the highest density of cones, in particular red and green cones, and lacks

Age-Related Macular Degeneration

AMD represents the leading cause of adult-onset blindness, affecting 1.5% of all people of Caucasian background over the age of 50, and 10% over 75 years of age.195, 196, 197 In order to understand the mechanism of AMD, the contributions that the choroid, Bruch's membrane, RPE, and photoreceptors make to the disease needs to be understood. As shown in Fig. 1, the RPE forms a single layer of cells between the choroid and the photoreceptors. The basement membrane on which the RPE sits is called

Animal Models of Retinal Vascular Diseases

Diseases of the retinal vasculature, which include conditions like retinopathy of prematurity (ROP) and DR are leading causes of blindness in both infants and those of working age. Vascular pathology, in particular pathological angiogenesis, is recognized as the main visually detectable sign of change in these two conditions. In addition to retinal vascular pathology, neuronal, and glial cell anomalies also develop, often prior to the development of overt vascular disease.²²⁶

Inheritable Optic Neuropathies

The inherited optic neuropathies are a group of diseases that are characterized by optic nerve dysfunction, primarily due to alterations in ganglion cell function and ultimately cell death. These disease pathologies exhibit hereditability based on familial expression or genetic analysis, however, their clinical phenotype is somewhat heterogeneous both within and between the various disease states. Despite this, the end point of the respective diseases is similar, exhibiting optic disc atrophy

Conclusions

A great deal has been learned from the careful evaluation of animal models of retinal disease. Three major changes have led to significant advances in our understanding of human retinal disease. First, careful analysis of the retinal changes that occur naturally or can be induced in animals helped elucidate the animal models that share features with human disease. Secondly, with the advent of molecular tools and the unraveling of the human and mouse genomes, it was possible to correlate

Acknowledgments

This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (No. 566814 and No. 566815 to ELF), NHMRC Practitioner Award (RHG), NHMRC Centre for Clinical Research Excellence No. 529923—Translational Clinical Research in Major Eye Diseases (PNB, RG), the Australia–India Strategic Research Fund (AISRF) jointly through the Department of Biotechnology, Government of India and the Department of Innovation, Industry, Science and Research, Government of Australia

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Chapter 6 - Animal Models of Retinal Disease

Introduction

Section snippets

Overview of Retinal Structure and Function

Mendelian Inherited Conditions

RP: A Family of Inherited Photoreceptor Degenerations

LCA: A Severe Retinal Degeneration Caused by Anomalies in RPE, Glial or Photoreceptor Dysfunction

CSNB: An Opportunity to Better Understand Outer Retinal Signaling

Inherited Macular Degenerations

Age-Related Macular Degeneration

Animal Models of Retinal Vascular Diseases

Inheritable Optic Neuropathies

Conclusions

Acknowledgments

Prog Retin Eye Res

Prog Retin Eye Res

Prog Retin Eye Res

Am J Hum Genet

Prog Retin Eye Res

Mol Ther

Prog Retin Eye Res

J Biol Chem

Neuron

Prog Retin Eye Res

Neuron

Vision Res

Vision Res

Neurosci Lett

Exp Eye Res

Prog Retin Eye Res

Vision Res

Exp Eye Res

Neuron

Parallel processing in the mammalian retina

Nat Rev Neurosci

The retinal pigment epithelium in visual function

Physiol Rev

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Nat Neurosci

ATP mediates rapid microglial response to local brain injury in vivo

Nat Neurosci

In vivo visualization of dendritic cells, macrophages, and microglial cells responding to laser-induced damage in the fundus of the eye

Invest Ophthalmol Vis Sci

Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

Science

Microcirculation disturbances at the onset of diabetic retinopathy. New therapeutic procedures?

Klin Monbl Augenheilkd

Retinal hypoxia in long-term diabetic cats

Invest Ophthalmol Vis Sci

Effect of gene therapy on visual function in Leber's congenital amaurosis

N Engl J Med

Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial

Hum Gene Ther

Safety and efficacy of gene transfer for Leber's congenital amaurosis

N Engl J Med

Gene transfer into the mouse retina mediated by an adeno-associated viral vector

Hum Mol Genet

Gene therapy restores vision in a canine model of childhood blindness

Nat Genet

Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis

Hum Gene Ther

A systematic meta-analysis of genetic association studies for diabetic retinopathy

Diabetes

New era for personalized medicine: the diagnosis and management of age-related macular degeneration

Clin Experiment Ophthalmol

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

Proc Natl Acad Sci USA

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)

Proc Natl Acad Sci USA

Complex genetics of complex traits: the case of primary open-angle glaucoma

Clin Experiment Ophthalmol

A point mutation of the rhodopsin gene in one form of retinitis pigmentosa

Nature

Mutant rhodopsin transgene expression on a null background

Invest Ophthalmol Vis Sci

Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments

Proc Natl Acad Sci USA

Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene

Proc Natl Acad Sci USA

A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment