Vision Research

Needs, Gaps, and Opportunities

NIH...Turning Discovery Into Health®
DIRECTOR’S MESSAGE

I am pleased to present this newest update that provides a 

comprehensive review of highlights of recent progress in vision 

research and considers opportunities that lie ahead. This document 

reflects the intellectual energy of more than 300 individuals who 

contributed to identifying and distilling a compendium of “Needs, Gaps, 

and Opportunities in Vision Research.” In majority they represented 

expertise in biomedical disciplines closely tied to vision research. With 

so many opportunities created by substantial advances in both new and 

traditional research areas, this document represents the critical first step 

in our efforts to identify the broad spectrum of vision research priorities. 

It will also increase public awareness of the importance of vision 

research and the accomplishments that the vision research community 

has delivered in recent years. 

With this thorough accounting of the current state of vision research in place, and in consultation 

with the National Advisory Eye Council (NAEC), the National Eye Institute (NEI) will now embark 

on the next phase of the planning process and will extend and expand our efforts to include 

broad and diverse input from academia, industry, private foundations, and other governmental 

agencies and individuals. The emphasis will be to look beyond the next steps and to the horizons 

where great opportunities may lie that could be captured through careful investment in the future. 

Historically, great advances have developed from unlikely sources, and with assistance from NAEC, 

we are planning a process to solicit novel framing of far-reaching goals in consultation with creative 

scientists and individuals from disciplines beyond vision science alone. Careful ascertainment and 

identification of ideas and approaches from across the full spectrum of science and engineering 

can well be expected to energize our research efforts further. The outcomes of this process will 

help frame Institute priority setting and resource allocation in support of our mission to reduce the 

burden of ocular disorders and diseases in this country and worldwide. 

I invite you to visit our website to learn about our most current strategic planning efforts to develop 

and support a national vision research agenda (http://www.nei.nih.gov/strategicplanning).

Paul A. Sieving, M.D., Ph.D.

Director, National Eye Institute

August 2012
TABLE OF CONTENTS 1

TABLE OF CONTENTS

INTRODUCTION .........................................................................................................................................2

PANEL REPORTS

Retinal Diseases ................................................................................................. 4

Corneal Diseases .............................................................................................. 19

Lens and Cataract ............................................................................................ 30

Glaucoma and Optic Neuropathies............................................................... 37

Strabismus, Amblyopia, and Visual Processing ........................................... 48

Low Vision and Blindness Rehabilitation ..................................................... 54

APPENDICES

Appendix 1: Framework for Vision Research ............................................... 63

Appendix 2: The Planning Process ................................................................ 66

Appendix 3: Contributors ............................................................................... 68
2 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

INTRODUCTION

NATIONAL EYE INSTITUTE MISSION

As part of the federal government’s National Institutes of Health (NIH), the mission of the 

National Eye Institute (NEI) is to “conduct and support research, training, health information 

dissemination, and other programs with respect to blinding eye diseases, visual disorders, 

mechanisms of visual function, preservation of sight, and the special health problems and 

requirements of the blind.”

Since its inception more than 40 years ago, 

the National Eye Institute (NEI) has engaged 

in strategic planning activities, which have 

culminated in a series of national plans and 

workshop reports that identify needs and 

opportunities in vision research. NEI strives to be 

inclusive by requesting input from the community 

of vision researchers as well as professional and 

patient advocacy organizations. NEI planning 

activities are conducted under the auspices of 

the National Advisory Eye Council (NAEC), a 

committee of clinicians, researchers, patients and 

stakeholders that advises the Institute on funding 

decisions, initiatives, and strategic planning. 

Planning allows us to assess the current 

state of vision science by highlighting recent 

achievements, and helps prepare for the future 

by identifying gaps in our knowledge, new 

opportunities that have arisen because of recent 

advances in knowledge or technology, and 

challenges and barriers to our understanding 

of ocular function in health and disease. The 

plan is useful to clinicians and scientists who 

are considering applying for NEI support to 

identify high-priority research areas. The 

plan also provides confidence to the vision 

research community, patients, patient-advocacy 

organizations, and Congress that NEI stewardship 

of vision research is well-placed. The national 

plan is not intended to be a detailed blueprint 

for research, but an overview that represents the 

state-of-the-science at the time of publication. 

NEI recognizes that new ideas and concepts are 

constantly emerging, and that the main engine 

for scientific discovery is investigator-initiated 

research. The most important priority is to 

support the highest quality research that will help 

achieve the mission of NEI.

NEI ADMINISTRATIVE PROGRAMS

1. Retinal Diseases

2. Corneal Diseases

3. Lens and Cataract

4. Glaucoma and Optic Neuropathies

5. Strabismus, Amblyopia, and Visual Processing

6. Low Vision and Blindness Rehabilitation

 7. Ocular Genetics

 8. Ocular Infection, Inflammation, and Immunology

 9. Myopia and Refractive Error

10. Oculomotor Systems and Neuro-Ophthalmology

11. Ocular Pain

12. Collaborative Clinical Research

13. Small Business Innovation Research

14. Research Training and Career Development

15. Research Resources
INTRODUCTION 3

FRAMEWORK FOR VISION 

RESEARCH

Biomedical research is a highly specialized 

endeavor, but a number of concepts are common 

to virtually every biomedical research field. NEI 

thus established a Framework for Vision Research 

that consists of the following overarching core 

principles in the context of vision research: 

I. Gather comprehensive knowledge of the 

molecular basis of ocular health and disease, 

and use that knowledge to improve diagnosis, 

treatment, and prevention of eye disease.

II. Understand the systems biology underlying 

visual function.

III. Accelerate the translation of basic research 

into clinical studies.

IV. Use clinical, epidemiological, and statistical 

tools to identify populations at risk of blinding 

eye diseases and visual disorders, evaluate 

new therapeutics, and improve functional 

consequences of visual loss.

V. Strengthen the clinical research of 

visual disorders.

VI. Strengthen the pool of vision researchers.

These core principles are developed more 

fully in Appendix 1. They were developed by NEI 

staff in consultation with a planning advisory 

panel and NAEC (see Appendix 2). 

NEEDS, GAPS, AND 

OPPORTUNITIES IN VISION 

RESEARCH – SIX PANEL REPORTS

NEI assembles experts in vision research to 

identify recent advances and to outline current 

and future scientific needs and opportunities. 

Since the early 1980s, panels of experts have been 

assembled every 5–7 years for each of the first six 

administrative program areas established by NEI 

(see #1–6 on the previous page). These program 

areas are not statements of scientific priorities 

or disease burden, but primarily reflect a need to 

partition and manage a large portfolio of grants. 

Over the past 30 years, new biomedical research 

areas have emerged, and the NEI budget has 

increased more than five-fold with a concomitant 

increase in the number of awarded grants. NEI has 

kept pace with the changing scientific landscape 

and increased workload by creating new crosscutting programs (#7–15 on the previous page). 

Although we considered holding separate 

panel meetings for each of the 15 program 

areas, a more integrated approach was used 

that maintained the six traditional program 

panels. Panel members consisted primarily of 

experienced, NEI-funded investigators and were 

selected with careful attention paid to include 

expertise from the cross-cutting scientific areas 

(see #7–15 on the previous page) as well as other 

newer disciplines such as bioengineering, stem 

cell technology, and nanotechnology. Each panel 

was charged with highlighting important vision 

research advances and generating a set of needs, 

gaps, and opportunities for basic, translational, 

and clinical research. 

Each panel report begins with a short 

Introduction, which is intended to introduce 

all audiences to the importance of the research 

area, followed by Highlights of Recent Progress, 

and then more detailed and technically oriented 

Research Needs, Gaps, and Opportunities. 

A full description of the NEI planning process 

is described in Appendix 2 and on the NEI Website 

(http://www.nei.nih.gov/strategicplanning).
4 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

RETINAL DISEASES

The retina is the marvelously thin and 

translucent layer of tissue at the back of the 

eye where photoreceptor cells (called rods and 

cones) absorb light and convert it to an electrical 

signal. This signal is then processed by a web 

of interconnected retinal neurons before being 

transmitted to the brain. The energetically 

active photoreceptors are nourished by a layer 

of support cells called the retinal pigment 

epithelium (RPE); the entire complex is fed by an 

intricate network of blood vessels both within 

and underneath the retina (the retinal and the 

choroidal vasculature). There are also lightsensing functions that are independent of rods 

and cones, such as control of pupil size, sleep–

wake cycles, and possibly seasonal moods. 

The leading cause of visual loss among the 

elderly in the United States is age-related macular 

degeneration (AMD), a disease with both genetic 

and environmental risk factors. Severe vision 

loss can result from the “wet” form of AMD, in 

which new, abnormal choroidal blood vessels 

start to grow and leak blood under the retina. In 

recent years, U.S. Food and Drug Administration 

(FDA)-approved therapies that improve vision 

in patients with wet AMD have been developed. 

In contrast, there is currently no FDA-approved 

treatment for the nearly 90 percent of patients 

of AMD who have the “dry” form, which is 

characterized by a thinning of the RPE and can 

lead to photoreceptor cell death. As the number of 

elderly individuals increases in the United States, 

AMD prevalence is expected to increase and exert 

an even greater social and economic impact. 

Another major cause of blindness, especially 

in the working-age population, is diabetic 

retinopathy (DR), which can result in newly 

formed, abnormal retinal blood vessels breaking 

through the retina and hemorrhaging into the 

normally transparent, gelatin-like vitreous in the 

middle of the eye. Scar tissue may subsequently 

form and pull the retina away from the back of the 

eye, causing a blinding retinal detachment. 

Ocular inflammation appears to play a role 

in many disorders of the posterior segment, 

including AMD and DR. Posterior uveitis is a 

collection of inflammatory conditions that may 

be acute or chronic. Uveitic conditions, including 

viral and parasitic infections, autoimmune 

inflammatory diseases, macular edema, and 

vasculitis, carry high risk for vision loss. 

Inherited retinal degenerations, typified by 

retinitis pigmentosa (RP), are significant causes 

of blindness. As a group, these diseases are 

characterized by progressive dysfunction and 

death of the photoreceptor cells and the RPE 

and affect people of all ages. Approximately one 

third of individuals with RP and related disorders 

also have associated nonocular disease such as 

deafness and polycystic kidney disease. 

Central to learning the causes and treatments 

of these diseases is an understanding of the 

normal function of the retina and its supporting 

structures. Many retinal diseases that cause 
RETINAL DISEASES 5

catastrophic vision loss are characterized by 

abnormalities in the retinal and choroidal 

blood vessels. Thus, it is critical to understand 

normal vascular development and events 

leading to abnormalities in these vessels. 

Photoreceptors have a unique biology in which 

the outer segments of the cells contain stacks of 

membranous discs loaded with the photosensitive 

pigment proteins (e.g., rhodopsin). When excited 

by light, pigment proteins initiate a biochemical 

cascade called phototransduction. The stacked 

photoreceptor discs are constantly renewed. New 

discs are added at the base of the outer segment 

as older discs are displaced, shed, and engulfed 

by the RPE, so that the visual pigment can be 

recycled. The photoreceptors and RPE are closely 

associated, and an abnormality in one leads to 

dysfunction in the other.

More than 75 different types of neurons and 

glia (cells that support and protect neurons) 

in the retina interconnect and communicate 

with one another to transform the signals from 

photoreceptors into a neural code that subserves 

our perception of color, form, and motion, and 

together produce our visual experience. This 

complex retinal circuitry develops through an 

intricate process of regulated gene expression, 

sequential signaling, cellular differentiation, cell 

migration, and input from the visual environment. 
6 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

RETINAL DISEASES 

HIGHLIGHTS OF RECENT PROGRESS

GENETICS AND GENE THERAPY

In the past decade, biomedical science has 

undergone a paradigm shift as a result of the 

progress in genetics, DNA sequencing technology, 

and the mapping of the human genome. Applying 

these new tools in genetics studies has led to 

the identification of genes responsible for many 

Mendelian (single-gene) retinal degenerative 

diseases as well as complex diseases (involving 

many genes and environmental influences). Gene 

therapy is a promising new field of medicine that 

replaces mutant genes with functioning genes. 

Pioneering studies in ocular gene therapy were 

initiated partly because the eye is easily accessible 

and somewhat immunologically isolated from 

the rest of the body, which minimizes adverse 

systemic side effects (see sidebar page 7).

One example of ocular gene therapy’s success 

has been in developing viral-based strategies 

to deliver genes to adult tissue. Advances in the 

understanding of gene expression as well as 

virology have facilitated the development of cellspecific promoters that can target replacement 

genes specifically to individual cell types within 

the retina and RPE. In a major early success, 

teams of scientists and clinicians used this 

approach to add a correct copy of the RPE65 gene 

to the RPE cells of patients with a severe, earlyonset retinal degeneration called Leber congenital 

amaurosis (LCA). After receiving a correct copy of 

the gene for RPE65, patients performed better on 

tests of visual function and had improved ability to 

perform visual tasks when using their treated eye.

Gene therapy requires that the diseasecausing mutations already be known. Fortunately, 

in the past decade, great advances have been 

made in identifying genes responsible for many 

Mendelian retinal degenerative diseases. The 

number of such genes underlying major diseases 

has been surprisingly large. For example, LCA can 

be caused by a mutation in any one of 12 different 

genes expressed in either the photoreceptors 

or the RPE. RP also exhibits several patterns 

of inheritance. At present, 51 genetic loci have 

been implicated in nonsyndromic autosomalrecessive RP, each accounting for only a few 

percent of RP cases. An additional 56 loci are 

associated with syndromic disease, and still, the 

identified disease genes account for only half of 

affected patients. Classical genetics approaches 

have led to the discovery of many RP genes, and in 

some cases, the combined approaches of human 

genomic sequencing, animal modeling, and in silico

prediction of protein function identified a genetic 

variation linking RP to a biological pathway. 

In the past decade, it has become apparent 

that some of the most common blinding diseases, 

like glaucoma and AMD, are complex and may 

involve the individual’s immune response and 

environmental factors. In the first successful 

application of Genome-Wide Association Studies 

(GWAS) for identifying genes that contribute 

to common diseases, geneticists discovered a 

major contribution to AMD from a variant of 

a gene involved in the innate immune system, 

complement factor H. Since this discovery, other 

risk factors in the complement pathway have been 

associated with AMD. In addition to identifying 

genes that either protect from or predispose 

individuals to AMD, epidemiological studies have 

identified environmental risk factors such as 

smoking, hormone therapy, and possible dietary 

factors that may either contribute to or protect 

from AMD risk. Such factors likely operate both 

independently and through their interactions 

with various genes.
RETINAL DISEASES 7

For complex degenerative diseases in 

which single-gene therapy is insufficient, 

major advances have been made in animal 

models by expressing neurotrophic genes that 

promote cell survival. In cases where either 

these cell survival strategies are ineffective 

or photoreceptor degeneration already has 

occurred, an alternative strategy is to deliver 

genes for light-sensitive proteins and channels to 

other retinal neurons that are normally unable to 

detect light. Cellular expression of these lightsensitive molecules turns neurons into functional 

substitutes for the dead photoreceptors. This 

approach, called optogenetics, is becoming 

widely used in neuroscience research to 

manipulate neuronal function. 

Restoring Sight One Gene at a Time

We are learning that the most common diseases are genetically complex. That is, 

many genes may contribute to the course of a disease, and the influence of these 

genes, termed risk factors, may vary tremendously from patient to patient, depending 

on other factors such as excess weight or smoking. However, there are thousands of 

rare diseases, many of which primarily affect the eye, that are caused by a defect, i.e., 

mutation, of a single gene. Gene therapy consists of replacing a mutated gene with a 

healthy gene to cure patients. The eye is particularly well-suited to test gene replacement therapy because the eye is 

easily accessible and somewhat isolated from the rest of the body. Therefore, injections of relatively small quantities of 

the replacement gene can be targeted specifically to the diseased tissue without much exposure to other tissues in the 

body. This helps to minimize side effects. 

The first ocular gene therapy success—one of the first successes in any tissue—was achieved in 2009 in a clinical 

trial for patients with Leber congenital amaurosis, a disease that usually begins in childhood and eventually leads 

to blindness. Vision improved after a single treatment with a normal gene. This NEI-supported landmark clinical trial 

validated gene therapy as a viable investigational therapy and paved the way for additional gene therapy trials of other 

ocular diseases such as retinitis pigmentosa, choroideremia, age-related macular degeneration, and Stargardt’s disease. 

To identify individuals with inherited blinding disorders that could potentially benefit from gene therapy, and to 

facilitate patient recruitment for gene therapy trials, NEI created eyeGENE®, a nationwide partnership of 250 clinical 

organizations that was formed to broaden accessibility of diagnostic genetic testing. Since it was established in 2006, 

eyeGENE® has tested more than 3,500 patient samples for 70 mutant genes and created a repository of DNA from 

patients and their families that is available to researchers for future studies on the genetic causes of eye diseases.
8 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

IMMUNOLOGY AND 

INFLAMMATION

The spectrum of ocular disease associated 

with immune system function and dysfunction 

has continued to expand in the past decade. The 

discovery that several of the major genetic risk 

factors for AMD are components in the immune 

system (i.e., specific alleles of complement 

factors, including H and B) strongly suggests that 

the pathogenesis of many blinding diseases is 

tied to immune system function or dysfunction. 

Proteomic characterization of drusen confirmed 

the presence of inflammatory processes in AMD. 

Substantial progress has been made 

in advancing our understanding of uveitic 

diseases of the vitreous, retina, and choroid. 

The achievement of consensus clinical scoring 

systems provides a common language to 

describe inflammatory conditions. Substantial 

progress in understanding the pathogenesis of 

experimental posterior uveitis models such as 

Experimental Autoimmune Uveitis (EAU) includes 

characterization of cytokine and chemokine 

profiles, as well as a detailed description of the 

roles of specific T-cell subsets, including the 

recently described Th17 and Treg. The first large 

randomized clinical trial of uveitis treatments for 

intermediate, posterior, and panuveitis provided 

important information on treatment outcomes 

of different regimens. Large-scale retrospective 

studies have documented the safety of several 

small molecule immunosuppressive drugs used to 

treat more severe forms of uveitis.

Substantial strides have been made in the 

diagnosis of retinal inflammatory disease. Several 

viruses, such as rubella and HHV-6, have been 

associated with specific retinal inflammatory 

conditions. Molecular characterization of 

specific pathogens such as Toxoplasma gondii, a 

parasite responsible for the most common form 

of retinochoroiditis in the world, has revealed 

unexpected diversity that may account for 

variable responses to treatment. Host-factor 

genes have proven to be important in infectious 

diseases, such as cytomegalovirus retinitis and 

HIV-related neuroretinal damage. 

ANGIOGENESIS 

The growth of new abnormal blood vessels is 

a common feature in a number of blinding retinal 

diseases, including wet AMD, DR, and retinal vein 

occlusion. Vascular endothelial growth factor 

(VEGF) promotes blood vessel proliferation, 

but the abnormal vessels that appear in AMD 

and DR leak and lead to vision loss. Drugs that 

block VEGF are successful in stabilizing and 

reducing vision impairment and, in some wet 

AMD patients, improve vision. This class of drugs, 

introduced in 2006, is now in widespread use (see 

sidebar page 18). Anti-VEGF drugs are also being 

tested in patients with other retinal vascular 

diseases such as DR and retinal vein occlusion. 

Studies of the vasculature in other tissues have 

revealed the importance of additional molecular 

pathways (e.g., Delta/Notch, Angiopoietin/

Tie2, erythropoietin, Norrin/Frizzled4) in the 

development and maintenance of normal retinal 

vessels. These represent potential additional drug 

targets that could complement VEGF therapy. 

The concept of blood vessels simply as 

conduits for blood and nutrients has evolved; 

retinal health depends on interaction between 

the endothelial cells that form the vessel walls 

and the surrounding tissue. The neurosensory 

retina and RPE are nourished by two vascular 

systems, the retinal vasculature found in the inner 

retina, and the choroidal vasculature (also called 

the choriocapillaris) which is found under the 

RPE in the outer retina. Interestingly, ischemic 

retinopathies such as diabetes are associated 

with abnormalities in the retinal vessels whereas 

neovascularization associated with AMD affects 

the choroidal vasculature. Our understanding of 

development and disease-associated changes in 

both the retinal and choroidal vasculatures has 

increased significantly and, with the advent of 

new in vivo imaging modalities such as optical 
RETINAL DISEASES 9

Impact of Clinical Trials: The Patient’s Perspective

Robert Watts was diagnosed with diabetes 46 years ago. Now age 70, he still carefully 

monitors his blood sugar levels, which he tests several times each day, and injects 

himself with insulin to regulate the amount of glucose in his blood. However, even 

with his fastidious attention to the demands of his disease, about 10 years ago, 

Robert noticed that his vision was declining. He learned he had diabetic retinopathy, 

one of the leading causes of blindness in the United States.

“Street signs became difficult to read when I was driving at night, and it became 

challenging to read the numbers at the bottom of my television screen during a 

sporting event,” he recalls. “When I went to my eye doctor a little over three years ago, 

he told me that my vision was going to continue to deteriorate. He told me about a clinical trial that was testing a new 

course of therapy for people with my condition.” 

Diabetic retinopathy can lead to diabetic macular edema (DME), where abnormal blood vessels in the back of the eye 

leak fluid into the retina. The retina swells, damaging the light-sensing photoreceptor cells that enable sharp central 

vision for tasks such as reading, driving, and recognizing faces. For more than 25 years, DME has been treated with a 

very fine, high-intensity laser light beam to destroy the abnormal blood vessels. Although laser treatment slows the 

loss of vision, repeated treatments are often necessary and sometimes visual acuity can worsen despite treatment. 

In an attempt to improve outcomes, ophthalmologists introduced an additional treatment using a corticosteroid 

(triamcinolone) that was shown to reduce retinal swelling and seemed to improve visual acuity.

More recently, another drug, Lucentis, was developed to block vascular endothelial growth factor (VEGF), a protein 

that induces blood vessel growth and plays a central role in neovascular eye diseases like DME and age-related 

macular degeneration (AMD). Previous clinical trials found that Lucentis improved vision in advanced (“wet”) AMD, so 

it was possible that patients with diabetic retinopathy also might benefit from this drug.

Robert Watts was one of the 691 participants in a clinical trial for diabetic retinopathy. The trial was designed with 

three major treatment groups of patients. The first group received the standard care of treatment—in this trial, laser 

light to destroy abnormal vessels; the second was treated with laser and injected with Lucentis; and the third received 

laser plus triamcinolone. 

The results demonstrate that, compared to patients treated only with laser, vision improved in patients who received 

the Lucentis along with the laser treatment for the two years of the trial, and they experienced few side effects. Equally 

important, the trial showed that patients treated with triamcinolone plus laser had similar visual acuity gains as those 

receiving laser alone. However, many of the patients treated with triamcinolone developed vision-threatening side 

effects such as cataracts and glaucoma, which also required treatment. 

During the trial, Robert was not told which group he was in, but later he was informed that he received Lucentis 

injections in combination with laser treatment. “I keep going back to the doctor monthly for my exams, but I haven’t 

had to have a [followup] treatment in about a year and a half. My vision has improved big time,” Robert says proudly. 

This comparative effectiveness trial is one of many protocols conducted by the Diabetic Retinopathy Clinical Research 

Network (DRCR.net) supported by NEI. DRCR.net is a collaborative network of scientists and eye doctors. It supports 

the identification, design, and implementation of clinical research on diabetic retinopathy. An important DRCR.net 

priority is to examine a broad range of promising new therapeutic approaches for patients with diabetic eye disease. 

“It was an easy decision to enter the trial,” says Robert. “I have four grandchildren. I want to see them grow up. I love 

them more than anything, and that is why I try to take good care of myself.” Robert also recognized an opportunity 

to help others with diabetes. “I knew that by participating in this trial, I would be helping the researchers gather more 

information about diabetic retinopathy that would help them develop new treatments.”
10 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

coherence tomography (OCT), will further 

expand our understanding of how these vessels 

respond to disease. The role of the vascular 

microenvironment under conditions of health and 

disease, as well as nonvascular cells associated 

with the vasculature, are critical in maintaining 

vascular homeostasis. 

Large, retina-specific cells that support the 

neurons, called Müller glia, play an important role 

in regulating the amount of water and electrical 

current in the retina through their contacts with 

both retinal neurons and vascular endothelial 

cells. Müller cells are damaged in certain diseases 

and can lead to significant changes in the retinal 

vasculature. Following hypoxic injury—where 

the tissue is deprived of oxygen—microglia and 

circulating white blood cells are “activated” in 

the retina and facilitate the repair and regrowth 

of blood vessels. Thus, the importance of cellular 

cross-talk in development and maintenance of a 

healthy retinal vasculature is critical to normal 

retinal function. 

PHOTORECEPTOR AND 

RPE BIOLOGY

The absorption of photons in rod and cone 

photoreceptors is the first step in a chain of 

biochemical events known as phototransduction, 

which initiates electrical signals that lead to 

visual perception. Photon absorption occurs 

in the visual pigments, rhodopsin and cone 

opsins, which consist of protein polypeptides 

and the vitamin A-derived chromophore, 11-

cis retinal. In the last decade, major advances 

occurred in understanding how 11-cis retinal is 

provided to rods and cones and in determining 

the consequences when the chromophore is not 

synthesized in adequate quantities. The enzymes 

responsible for chromophore production 

and regeneration, the visual cycle, have been 

identified in both photoreceptors and the RPE. 

RPE regeneration of 11-cis retinal is not its only 

source. An alternative recycling pathway, via Müller 

cells selectively feeding back to cones but not 

rods, was recently discovered. This pathway may 

contribute to faster regeneration of visual pigment 

in cones, which must maintain light sensitivity 

in much brighter light conditions. Because 11-

cis retinal is important for normal folding and 

trafficking of visual pigments, this new pathway 

may be important for treating RP and LCA since 

these diseases often stem from improper folding 

or trafficking of visual pigment proteins. 

Phototransduction is a model system for 

cellular signaling and is one of the most highly 

amplifying signaling mechanisms known 

in biology. Absorption of photons triggers a 

molecular chain reaction with signal amplification 

at each step in the chain. The amplification can 

be modified by feedback systems that alter the 

sensitivity or activation of signaling molecules. A 

recent advance is the discovery that the G-protein 

coupled receptor, rhodopsin, remains active 

for only a short time after it absorbs a photon. 

Subsequent G-protein signaling molecules 

remain active for a longer time, which may 

have functional consequences for the temporal 

resolution of vision. Indeed, mutations that slow 

down G-protein inactivation cause bradyopsia in 

humans, a disorder characterized by difficulties 

in perceiving low contrast moving objects and 

adapting to large changes in light intensity. 

Another important area of progress related to 

photoreceptor biology is the recognition that the 

outer segments of rods and cones are specialized 

sensory cilia. It is now evident that primary cilia 

are present on most vertebrate cell types. These 

structures are typically sensory organelles, 

and are involved in many critical aspects of cell 

biology. Like other cilia, the outer segments 

contain an axoneme, which begins at the basal 

bodies, passes through a transition zone (also 

called the “connecting cilium”) and into the outer 

segment. An important benefit of recognizing 
RETINAL DISEASES 11

photoreceptor outer segments as cilia is that it 

connects retinal degenerative disorders such as 

LCA and RP to other cilia disorders such as cystic 

renal disease, polydactyly, mental retardation, 

obesity, gonadal malformations, and diabetes.

The ability to adapt to large variations in light 

intensity is important for human vision. In the 

past few years, our understanding of adaptation 

has changed dramatically, owing to the discovery 

that many phototransduction proteins move in 

and out of subcellular compartments in response 

to different levels of illumination. Such large-scale 

movements reduce the light-generated signals, 

thereby contributing to the protection and health 

of photoreceptors and their function in bright light. 

Another discovery with both research and 

therapeutic implications is that the retina 

contains neurons other than the rods and 

cones that are directly light responsive. These 

intrinsically-photosensitive retinal ganglion 

cells (ipRGCs) use an 11-cis retinal-based visual 

pigment called melanopsin, and project not only 

to the midbrain and hypothalamus, but also to 

the thalamus. As such, ipRGCs are important for 

signaling overall luminance levels needed for 

circadian entrainment and the pupillary light 

reflex and also play a direct role in the general 

perception of light. 

RPE cells are polarized, compartmentalized, 

and have 22 known functions to date. They play 

critical roles in maintaining photoreceptor and 

choroidal function by producing key neural and 

blood vessel growth factors, such as VEGF and 

pigment epithelial–derived factor, recycling 

photoreceptor components, phagocytosing shed 

photoreceptor outer segments, and regulating 

subretinal fluid. Recent advances have identified 

new roles in orchestrating the immune response 

of the outer retina through complement 

regulators and secreting proteins and lipoproteins 

that contribute to drusen formation. 

RETINAL STRUCTURE, FUNCTION, 

AND CIRCUITRY

With only a handful of different neuronal 

classes (photoreceptors, horizontal cells, bipolar 

cells, amacrine, cells and ganglion cells), the 

retina functions across 10 log units of luminance 

intensity and also performs the initial processing 

of visual information. For example, within the 

retinal circuit, salient features of the visual 

world become encoded, including color, contrast, 

motion, and direction of visual stimuli. The 

unique experimental accessibility and anatomy of 

the circuitry have allowed rigorous investigations 

of synaptic and circuit function unlike anywhere 

else in the brain and serves as a model system 

for understanding the behavior of circuits in the 

central nervous system (CNS). 

In recent years, understanding of the diversity 

of retinal cell types has greatly expanded due to 

the ability to identify molecular markers unique 

to individual classes of cells. This “molecular 

fingerprinting” has led to an increase in the 

identification of specific promoters that control 

which genes get turned on in a given cell type. 

Using these promoters, researchers can identify 

specific types of retinal cells much more easily, 

which has led to a better understanding of cell 

fate and development, and the role of specific cell 

classes in circuit function. Knowledge of these 

cell-specific promoters also has been critical for 

optogenetics studies to restore light-sensitivity to 

specific types of cells in nonfunctional retinas in 

animal models of disease. 

Retinal neurons communicate with each other 

through an interlaced network of branched axons 

and dendrites. The identification of molecular 

cues (DSCAM, sidekick, semaphorins, and other 

proteins) that govern the development of laminar 

organization of the inner plexiform layer is 

important for understanding normal retinal 

development and circuitry.
12 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

REGENERATION AND 

STEM CELLS

There has been a virtual explosion of 

knowledge about stem cells and their application 

to better understanding basic development, drug 

screening, and therapeutic applications in the 

eye. By studying ocular development, scientists 

have identified a number of pathways that govern 

cell fate determination. Factors that regulate 

this developmental program can be used to 

manipulate cell fate for therapeutic applications, 

and it is now known that there are retinal stem 

cells residing in both the embryonic and adult eye 

that may serve to generate “replacement parts” 

for diseased eyes in the adult. These resident stem 

cells rescue distressed retinal cells by secreting 

survival factors (trophic support) or directly 

contacting them in animal models of retinal 

degeneration. Although adult stem cells are 

committed to developing into certain tissue types, 

researchers have touted embryonic stem cells for 

their potential to develop into any type of cell, or 

pluripotency. The recent discovery of a method 

of turning adult cells into induced pluripotent 

stem cells (iPSCs) may allow doctors to convert 

a patient’s cells into iPSCs, and then reprogram 

those cells to grow into replacement cells for a 

diseased retina (see sidebar page 46).

Advances in stem cell biology have led to 

the therapeutic application, in animal models, 

of stem cells for treating diseases in which cell 

degeneration leads to loss of vision. For example, 

healthy RPE cells have been generated from both 

embryonic stem cells and adult iPSCs to replace 

degenerated RPE. It may therefore be possible 

to generate autologous RPE grafts from adult 

human skin cells for RPE cell replacement in 

dry AMD. Using noninvasive, real-time imaging, 

ocular therapeutic application and monitoring of 

labeled stem cells serves as a paradigm of stem 

cell therapy. 

A key goal is ensuring that retinal stem 

cells, particularly those that produce rod and 

cone photoreceptors, will be able to integrate 

into diseased retinas and form the appropriate 

connections with remaining retinal neurons. 

Integration, in the context of a diseased 

photoreceptor layer, will require a better 

knowledge of the factors that control the wiring 

between a cone photoreceptor synaptic terminal 

and the multiple types of downstream neurons to 

transmit images to the optic nerve for processing 

by the visual cortex.

Retinal glial cells, which nourish and support 

neurons, are critical in maintaining normal retinal 

structure and function, and have now also been 

observed in selective targeting of certain stem 

cells to sites of glial activation, and thus to sites of 

retinal, vascular, and neuronal injury. In addition, 

the signals produced by glial cells may provide 

trophic rescue activity under conditions of 

stress; selectively targeted stem cells expressing 

these molecules may provide enhanced rescue 

activity in a variety of retinal vasculo- and 

neurodegenerative diseases. 
RETINAL DISEASES 13

IMAGING, DIAGNOSIS, AND 

THERAPEUTIC GUIDANCE

 Recent advances in noninvasive imaging of 

the retina by advanced optical techniques have 

transformed human retinal research and clinical 

practice. Using adaptive optics, technology 

originally developed by the field of astronomy 

that compensates for wavefront distortions of 

light, researchers now can image individual rods 

and cones in the human eye to examine their size, 

density, and geometry. Adaptive optics permits 

quantification of changes in cell integrity over 

time, well before functional visual deficits occur.

OCT is a powerful, noninvasive imaging 

technique now commonly used in clinical practice 

to generate high-resolution three-dimensional 

images of the retina, vessels, and RPE. Faster 

cameras and new spectral domain imaging 

software has improved the OCT signal and 

increased image acquisition speed. The higher 

speed has facilitated imaging in patients with 

poor visual fixation, which commonly occurs 

with severe visual impairment. Widespread use 

of OCT for retinal imaging in clinics facilitates 

diagnosis and is invaluable for monitoring 

disease progression and responses to therapeutic 

interventions over time.
14 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

RETINAL DISEASES 

NEEDS, GAPS, AND OPPORTUNITIES

GENETICS AND GENE THERAPY

• Develop better gene delivery methods, 

including viral-mediated or new technologies, 

such as nanoparticles, that target specific 

subclasses of neurons, glia, and RPE. 

• Expand, improve, and coordinate shared 

bioinformatics approaches and resources 

to analyze and annotate genetics data, 

including improved predications of potential 

pathogenicity of identified sequence variants.

• Develop higher throughput experimental 

methods to assess the functional significance 

of sequence variants identified by nextgeneration sequencing (NGS) and GWAS 

studies in retinal cells. 

• Explore the role of non-Mendelian genetics, 

including epigenetic modifications, microRNA 

gene regulation, mitochondrial genetics and 

genetic modifier effects during development, 

normal aging, and neurodegeneration in order 

to understand the causes of complex disease 

and the risk of disease development.

• Understand how individuals’ genetic makeup 

may predict their response to a treatment, 

since not all individuals respond the same to 

standard therapies.

ANGIOGENESIS

• Identify and characterize new angiostatic and 

antipermeability agents, especially for use 

in individuals who are unresponsive to antiVEGF therapy.

• Test the combination therapy of angiostatic, 

antipermeability, anti-inflammatory, and 

neuroprotective agents for retinal vasculoand neurodegenerative diseases.

• Explore the potential use of targeted, cellbased therapies for the treatment of retinal 

vascular diseases.

• Identify and better understand the potential 

use of microRNAs, antimicroRNAs, and other 

RNA-based therapeutics for the treatment of 

retinal vascular diseases.

• Analyze the role of nonendothelial cells (e.g., 

astrocytes, Müller glia, microglia, pericytes, 

macrophages) in the maintenance of normal 

retinal vasculature and their role during 

retinal vascular disease.

• Gain a better understanding of mechanisms of 

choroidal involution and its role in providing 

nutrition to the RPE and photoreceptors. 

PHOTORECEPTOR, RPE, 

AND GLIAL BIOLOGY

• Elucidate the molecular mechanisms that 

lead to photoreceptor degeneration, including 

signal transduction pathways, defects in 

protein folding, ciliogenesis, functional 

compartmentalization, and trafficking. 

Translate these molecular footholds into 

therapies for Mendelian and complex diseases. 

• Understand the molecular mechanisms and 

pathways in cone photoreceptors that have not 

been as extensively studied as rods. Primates 

rely on cone-based color vision (concentrated 

in the macula), unlike many animal models 

commonly used for vision research, such as 

rodents, that do not have a macula. 

• Understand the natural neuroprotective 

mechanisms in photoreceptors, including the 

regulation of energy metabolism in order to 

develop therapeutic strategies extending the 

healthy lifetime of these cells.
RETINAL DISEASES 15

• Translate research progress in rod and cone 

retinoid visual cycles into clinical trials with 

retinoid/retinoid-like compounds. Recent 

discoveries that several retinal degenerations 

result from enzyme malfunctions at different 

points in the retinoid generation cycles 

provide a therapeutic opportunity to supply 

missing retinoids. 

• Better understand highly differentiated RPE 

functions and elucidate mechanisms for 

maximizing RPE health over the lifespan of 

an individual.

• Better understand the role of various 

posterior segment extracellular matrices 

(e.g., Bruch’s membrane, vitreous) in 

maintaining normal retinal functioning.

• Characterize and better understand the roles 

for various resident and transient populations 

of glia present in the retina.

• Characterize the macula and perifoveal 

regions of the retina to better understand the 

predilection of the macula for disease.

PHOTORECEPTION AND 

RETINAL CIRCUITRY 

• Understand and model the structure, function, 

and circuitry of retinal neurons. This research 

forms the basis for interpreting tests of retinal 

function such as the electroretinogram and 

various psychophysical paradigms that are 

used to detect retinal diseases, monitor the 

progression of disease, and assess treatments. 

Also, for stem cell replacement therapies to 

become a reality, transplanted neurons must 

functionally integrate and synapse with the 

existing retina. 

• Decode the electrical patterns used by retinal 

neurons to transmit visual information to the 

brain. Opportunities include newly developed 

techniques of viral-mediated pathway 

tracing and large-scale multielectrode 

arrays, genetically directed cell-specific 

labeling, updated and automated serial EM 

reconstruction, and single-cell recordings to 

achieve high-resolution maps of functional 

retinal circuits. New technologies such as 

optogenetics and multiphoton microscopy 

confer an ability to manipulate neuronal 

activity at the cellular level and visually and 

functionally dissect circuits by activating or 

suppressing specific activity in the retina. 

• Build on the existing arsenal of tools to 

develop methods for measuring activity 

in large groups of neurons during light 

responses. Neuroscientists have been able 

to simultaneously study large populations of 

neurons through optical techniques that track 

activity with fluorescent markers introduced 

in groups of cells. However, many of these 

techniques focus light in the visible spectrum 

onto the tissue, which limits their use in the 

retina, in which cells are activated by this 

light. The light may bleach the photoreceptor 

pigments. Two-photon technology, which uses 

infrared light outside the visible spectrum 

and large microelectrode arrays, will help 

overcome these barriers.

• Characterize the molecular mechanisms that 

establish and maintain synapses and define 

circuits in the inner and outer plexiform 

layers. This would include determining the 

extent to which those contacts are structurally 

and functionally modifiable to predict 

pathological consequences as well as to 

predict the best retinal layer at which to aim 

treatments to restore visual sensitivity. 

• Improve understanding of the role of retinal 

glial cells (Müller glia, astrocytes, microglia) 
16 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

with regard to wound healing (e.g., gliosis), 

angiogenesis (e.g., neovascularization) and 

neuronal survival. These cells have been 

viewed as largely structural, but recent 

advances have demonstrated a much more 

dynamic role (paracrine and autocrine) in 

most of the diseases that lead to vision loss.

IMMUNOLOGY 

• Continue the process of standardizing 

nomenclature of uveitic diseases. The 

Standardization of Uveitis Nomenclature 

working group is continuing to validate 

descriptions of specific syndromes to allow 

standardization of criteria for clinical research.

• Recognize the heterogeneity of posterior 

uveitis in clinical trial design such that diverse 

entities such as birdshot chorioretinopathy, 

pars planitis, serpiginous choroiditis, sarcoidassociated uveitis, and Behcet’s disease–

associated uveitis are treated as unique 

diagnoses for any assessment of outcome.

• Understand the role of innate immune 

responses (including the complement, 

chemokine, and inflammasome system) in 

retinal degenerative diseases, and determine 

how the immune system influences survival 

or death of retinal cells. Develop tools and 

markers to identify subsets of microglia, 

dendritic cells, circulating myeloid cells, and 

progenitors to establish their role in ocular 

immunity. Identify commonalities across 

different retinal degenerative diseases and 

degenerative diseases of the CNS such as 

Alzheimer’s disease and other dementias.

• Understand the roles of specific adaptive 

and innate immune mediators in specific 

inflammatory syndromes. While EAU is 

relatively well characterized, few other 

animal models of uveitis have been studied 

mechanistically. Understanding the functions 

of specific cytokines and chemokines in a 

range of models (including rodent models 

of autoinflammatory diseases as well as 

spontaneous uveitis models in animals such as 

dogs and horses) will inform the application 

of emerging biologic treatments to specific 

classes of uveitis.

• Integrate advances in understanding of 

immune regulatory mechanisms to advancing 

our understanding of ocular immune 

privilege. The first human clinical trials of 

both virally mediated retinal gene therapy 

and retinal stem cell transplantation are 

underway, and understanding mechanisms 

of tolerance induction in the eye will assume 

increased importance.

• Advance diagnostic tools for ocular 

inflammatory disease by using new molecular 

information to inform clinical studies. 

Improvement in imaging techniques for 

immune cells in the retina will allow in vivo

assessment of specific inflammatory mediators.

• Pursue delivery technologies for sustained 

treatments of chronic ocular inflammatory 

diseases, including cell-mediated, virally 

mediated, and sustained-release technologies 

for anti-inflammatory biologics and small 

molecules. The ability to enhance the 

delivery of drugs locally to the eye should be 

complemented by a greater understanding of 

the role of the immune response within the eye 

as opposed to the systemic immune response.

• Characterize the immune response to 

intraocular therapies such as monoclonal 

antibodies or gene therapies so that those 

treatments can be optimized.

• Test novel therapies including monoclonal 

antibodies, kinase inhibitors, and 

resolvins for their potential to control 

intraocular inflammation.

IMAGING AND DIAGNOSIS

• Translate high-resolution retinal imaging 

technologies, like adaptive optics, into costeffective and easy-to-use platforms for routine 

clinical use. 
RETINAL DISEASES 17

• Develop novel, noninvasive imaging 

techniques for monitoring electrical or 

metabolic activity of retinal neurons in 

vivo, ideally at the spatial resolution of 

photoreceptors or better for early detection 

of disease and monitoring of therapeutic 

intervention. This would be a more cost- and 

time-effective approach to studying retinal 

function than current biophysical techniques 

(e.g., single-cell electrical recordings), with the 

additional benefit of studying cellular activity 

in its native environment. 

THERAPEUTICS 

• Develop appropriate animal models for 

pathological features of complex human 

diseases, including aging, noninjury-based 

choroidal neovascularization, proliferative 

diabetic retinopathy, cone visual transduction 

in macula, atrophic AMD, and retinal 

degenerations, including syndromic disorders 

such as Usher’s disease.

• Explore the impact of cholesterol and 

lipoproteins for AMD, inflammation, and 

angiogenesis. Multiple GWAS studies have 

identified gene variants in the cholesterol 

and lipid pathway associated with AMD risk. 

The role of lipids in AMD had been suggested 

based on their presence in both drusen and 

Bruch’s membrane in AMD patients. Recent 

results from the Women’s Health Study, a 

large prospective epidemiological study, also 

showed a substantially reduced risk of AMD in 

individuals with lower lipid intake in their diet. 

• Explore the use of stem cells and other cellbased therapy as targeted delivery vehicles 

for trophic/survival factors to the retina. 

Neuroprotection in the face of ongoing 

underlying disease may serve to maintain 

retinal function. 

• Understand how to direct stem cells (adult, 

embryonic, or iPS cells) down specific cell 

lineages for targeted cell replacement therapy 

for diverse retinal neuronal cell types as 

well as RPE. Regenerative medicine and 

cell replacement therapy require further 

understanding of retinal stem cell niches and 

key developmental regulators and pathways. 

• Propel research on retinal transplantation 

therapy by investigating requirements for 

functional integration of photoreceptors 

within a degenerate retina. The abnormal 

microenvironments in diseased eyes 

could affect transplanted cell survival, 

differentiation, and integration with the host.

IMPROVING PUBLIC HEALTH 

• Understand why certain at-risk populations 

with systemic diseases do not develop ocular 

manifestations, e.g., diabetes patients who do 

not develop retinopathy. African Americans 

appear to develop drusen at the same rate as 

Caucasians, yet have a lower risk of developing 

end-stage AMD. The opportunity to identify 

which factors (molecular, environmental) 

protect these populations from progression or 

disease will be informative in understanding 

the disease progress and designing 

therapeutic interventions. 

• Evaluate implementation of recent clinical 

discoveries in retinopathy of prematurity 

(ROP) and their impact on reducing childhood 

blindness. Clinicians have developed a webbased algorithm based on postnatal weight 

gain, IGF-1, and omega-3 fatty acids, which 

accurately predicts those infants who will 

develop ROP an average of three weeks after 

birth. These treatment decision tools, coupled 

with results of trials evaluating telemedicine 

for ROP, can be used to concentrate care on 

vulnerable patients. 

• Expand efforts in telemedicine to manage 

retinal diseases like diabetic retinopathy and 

AMD via web-based networks, increasing 

access to specialists for populations in rural 

and/or underserved areas. Determine how 

these tools can be adapted to improve vision 

in different health delivery environments, such 
18 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

as in developing countries where diabetes in 

particular is becoming epidemic.

• Understand the connections between obesity 

and metabolic syndrome and vision loss, 

especially in aging eye diseases.

• Evaluate the long-term use of therapeutics 

in patients with chronic retinal disease 

(including retinal degenerative disease, 

atrophic AMD, aging retina, chronic rejection 

of transplants) to minimize chronic sideeffects and manage adherence issues. 

• Translate progress in research into best 

clinical practices to reduce preventable 

blindness or reduce the functional 

consequences of visual impairment. 

Evaluate disparities in optimal treatment 

by determining how research findings are 

implemented by eye care providers and 

barriers which prevent optimal treatment. 

Further understanding why patients stop 

effective therapies (such as glucose control in 

diabetes, or VEGF injections in AMD) and what 

cost-effective practices could be implemented 

to identify and bring to early diagnosis and 

treatment patients who present with vision 

loss due to preventable causes. 

• Explore potential similarities between AMD 

and other diseases of aging that affect the CNS 

(e.g., amyloid and Alzheimer’s).

• Expand the use of “omics” (e.g., 

transcriptomics, proteomics, metabolomics) to 

characterize ocular and systemic fluids from 

patients with various diseases and stages of 

various diseases.

Comparing Two Effective Treatments for AMD

The NEI Comparison of Age-related macular degeneration Treatments Trials (CATT) 

research group published results from their two-year clinical trial, which demonstrated 

that the two most widely administered drugs for treating neovascular AMD, Avastin and 

Lucentis, are equally effective. Neovascular AMD is an advanced form of this blinding 

disease in which abnormal blood vessels grow into the center of the retina, the macula, 

leaking fluid and blood that damage the photoreceptor-rich macula. 

Avastin was originally developed by Genentech to treat metastatic colon cancer. 

Genentech then developed Lucentis, a drug similar to Avastin, specifically for treating 

AMD. While awaiting FDA approval for Lucentis, which occurred in 2006, eye doctors reported success in treating AMD 

with “off-label” Avastin. Off-label use of drugs, that is use for treating other diseases not specifically approved by the 

FDA, is common, and word of success with Avastin for AMD spread rapidly. By the time CATT was launched in 2008, 

more than 60 percent of patients with neovascular AMD received Avastin. Owing to the widespread use of Avastin, NEI 

felt compelled to conduct a clinical trial to compare the effectiveness of these two drugs. 

Avastin is still prescribed off-label for AMD, and continued use owes to its therapeutic value, now confirmed by CATT, 

and the large price differential between the two drugs. Avastin costs an average of $50 per dose while Lucentis is 

$2,000 per dose. Greater than 200,000 patients are treated each year in the United States for neovascular AMD, and 

the vast majority of those patients are Medicare beneficiaries. Currently, Medicare covers both drugs, but a 20 percent 

co-payment is required. For those with fixed and limited incomes, Lucentis may be prohibitively expensive, making 

Avastin their only option. 
CORNEAL DISEASES 19

CORNEAL DISEASES

The normal cornea appears to be a simple 

crystal-clear structure; however, it is an elegant, 

complex living tissue that prevents infectious 

agents and debris from entering the eye. The 

cornea and tear film together form the primary 

refractive (light bending) element in the optical 

path, and are essential to precisely focus light 

on the retina. These characteristics are possible 

due to unique functional properties of the three 

primary corneal tissue layers (outward-facing 

epithelium, central connective tissue or stroma, 

and inner corneal endothelium), the resident 

immune cells, and the sensory nerve cells. In fact, 

the corneal epithelium has one of the highest 

densities of sensory nerve endings in the body, 

rendering an extremely painful sensation when 

even a tiny particle becomes trapped under the 

eyelid. Ocular surface tissues uniquely remain 

healthy and nourished despite the fact that the 

cornea has no blood vessels. Understanding the 

normal and diseased cornea and tear-secreting 

glands remains a critical need in order to reduce 

the burden of visual disorders worldwide.

In the United States, most visits to eye 

care professionals are due to either the need 

to correct refractive errors for better vision 

or to treat ocular surface disorders such as 

dry eye or ocular injuries. The need for vision 

correction is evidenced by the huge market in 

corrective spectacles, contact lenses, and most 

recently, laser refractive surgery (LASIK). While 

highly successful, none of these are perfect, and 

development of lenses and surgical procedures 

by a number of companies continues. Research 

remains important for the small, but significant, 

numbers of individuals whose refractive error 

cannot be satisfactorily corrected, and to reduce 

postsurgical complications. Indeed, a number of 

corneal vision disorders, such as keratoconus, 

cannot be treated by these corrective techniques 

and therefore require a corneal transplant. 

Although highly successful, immunological 

complications may arise from transplants, 

underscoring the need to understand and 

modulate the inflammatory and immune reactions.

In low-income countries, more than 10 million 

people suffer from blindness primarily attributed 

to uncorrected refractive errors, corneal opacities, 

and infectious diseases. Although worldwide 

efforts have led to substantial progress in 

understanding and treating infectious diseases, 

such as trachoma and river blindness, neither 

has been eradicated and they continue to place a 

heavy burden on affected societies. 
20 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

CORNEAL DISEASES

HIGHLIGHTS OF RECENT PROGRESS

ANGIOGENESIS AND 

LYMPHANGIOGENESIS

Corneal avascularity is the result of a fine 

balance between angiogenic (vessel-forming) 

and anti-angiogenic factors. Infection, injury, 

and inflammation can tip the balance in favor of 

blood vessel formation (hemangiogenesis) and 

lymph vessel formation (lymphangiogenesis). 

Recent studies have shown that many regulators, 

including VEGF, integrins, and semaphorins, play 

a central role in regulating corneal angiogenesis. 

Epithelial-derived soluble VEGF receptor-1 (sflt1) maintains corneal avascularity by acting as a 

decoy receptor, suppressing the major angiogenic 

factor, VEGF-A. Similarly, epithelial-derived 

soluble VEGF receptor-2 and cell surface-bound 

VEGF receptor-3 serve as decoys for VEGF-C/-D, 

thereby inhibiting lymphangiogenesis. 

TRANSPLANTATION

Corneal transplantation is the most common 

solid organ transplant performed in the United 

States. Researchers have recently found that blood 

and lymphatic vessels have a role in initiating 

and promoting immune rejection of corneal 

grafts. Recent findings implicating molecular 

attractants (chemokines) and their receptors 

may lead to the development of therapeutic 

compounds to prevent corneal graft rejection. 

Specifically, the addition of interleukin 17 to the 

list of known Th1 cytokine mediators of corneal 

graft rejection broadens the armamentarium of 

potential anti-rejection drugs. Similarly, recent 

evidence suggests that immune cells (e.g., Treg 

cells) and molecules (e.g., PD-1/PD-L1) that help 

prevent our immune system from attacking our 

own tissue can be exploited to prevent rejection 

of corneal grafts. Finally, improved imaging 

technology has facilitated real-time observation 

of the innate and adaptive immune cells that 

infiltrate the corneal graft, greatly expanding our 

understanding of the interplay of these cells in 

rejecting the graft or promoting tolerance and 

graft survival. 

Methods to surgically replace abnormal corneal 

tissue have advanced considerably. Endothelial 

keratoplasty techniques for the endothelial 

dystrophies have largely supplanted the use of 

full-thickness-penetrating keratoplasty, resulting 

in faster recovery times and fewer side effects. 

The limited availability of donor tissue, 

especially worldwide, as well as the possible 

rejection of donor corneas, makes the development 

of artificial, bioengineered corneas highly 

desirable. Artificial corneas engineered from 

cross-linked collagen have undergone extensive 

in vitro testing and are currently being tested 

in both animals and humans. Based on results 

from early studies, tissue-engineered corneas 

have been shown to maintain clarity, strength, 

biocompatibility, and are well-integrated in the 

eyes of patients, but further study is necessary.

REGENERATIVE MEDICINE

The ability to isolate and expand limbalderived stem cells to generate confluent 

sheets of tissue on a support structure, such 

as decellularized amniotic membrane or 

other carriers, and successfully resurface the 

corneal epithelium represents an honorable 

accomplishment for regenerative medicine. This 

breakthrough resulted from a combination of 

basic research on the biology of epithelial stem 

cells and enhanced clinical understanding of 

anterior surface diseases, yielding one of the first 

therapeutic uses of stem cells. 
CORNEAL DISEASES 21

WOUND HEALING

Corneal epithelial injury resulting from 

mechanical or chemical trauma, as well as 

elective refractive surgeries (e.g., LASIK or 

PRK), involves a loss of nerves and keratocytes 

at the site of injury. Delayed wound healing is 

associated with diseases such as diabetes. Recent 

studies using animal models of corneal injury 

show the accompanying inflammatory response 

proceeds as a cascade of events that supports 

epithelial, nerve, and keratocyte recovery. 

Recruitment of inflammatory leukocytes to the 

injured cornea is orchestrated by specific celladhesion molecules, chemokines and cytokines. 

Several components of the inflammatory cascade 

that are critical to the beneficial healing effect 

have been identified at the limbus and include 

epithelial γδ T cells, stromal neutrophils, and 

platelets. Growth factors such as VEGF are critical 

for nerve regeneration and show increased 

expression in the wounded cornea that depends 

on recruited neutrophils and platelets.

TEARS/DRY EYE DISORDERS

Improved understanding of the composition 

and multiple functions of tears includes new 

understanding of anti-bacterial defensins; 

functional characterization of a tear-specific 

protein, lacritin; understanding the structure 

and function of lipocalin; and identification of 

meibomian gland lipids. A desiccating stress 

animal model has led to new information on the 

role of inflammation in dry eye as it relates to 

environmental stress. A model of spontaneous 

ocular surface inflammation demonstrated the 

genetic susceptibility to cholinergic impairment of 

lacrimal gland and goblet cell secretion that leads 

to a chronic disease involving proinflammatory 

Th17 T cells. Another important finding is the 

association of dry eye disease with an increase 

in corneal lymphangiogenesis driven by VEGF 

receptor 3. Important advances have also been 

made in understanding the regulation of goblet 

cell mucin secretion and the role of membranespanning mucins in protecting the ocular surface. 

A large multicountry study has recently 

developed strict diagnostic criteria for Sjögren’s 

syndrome, a disease in which immune cells attack 

and destroy the exocrine glands that produce 

tears and saliva, allowing future studies to focus 

on the particular syndrome rather than a group of 

unrelated disorders. Epidemiological studies on 

dry eyes have documented the incidence, dietary 

and associated drug-related influences, and 

impact on the quality of life. 

BIOMECHANICS, IMAGING, AND 

REFRACTIVE ERROR CORRECTION

Effective treatments for diseases of the cornea 

require early and definitive disease diagnosis, 

well-defined staging, and clinically relevant 

endpoints. The location and transparency of the 

cornea lends itself to noninvasive assays and 

monitoring. Recent developments in imaging 

technology have advanced our understanding 

of corneal structure, function, and dysfunction 

in corneal diseases. Advances in confocal 

and multiphoton microscopy have enabled 

direct imaging and real-time characterization 

of the cornea at the cellular scale. Dramatic 

improvements in OCT technology now allow 

for rapid, volumetric imaging of the cornea 

and anterior segment visual pathway, with 

the promise of enabling routine biometric and 

biomechanical measurements in normal as well 

as surgically altered corneas. 
22 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

Fundamental recent advances in theory and 

modeling of corneal optics and biomechanics are 

laying the groundwork for optimizing corneal 

surgical interventions and bioengineered 

implants. Improved schematic and personalized 

ray-traced modeling of corneal optics have been 

introduced, coupled with new methods for 

measuring high-order and dynamic aberrations. 

Optimized finite-element numerical modeling 

techniques have been developed, which promise 

to improve predictions of corneal structural 

response to refractive surgery. 

New wavefront-sensing techniques are being 

used to identify higher order aberrations of the 

eye, which can then be corrected during refractive 

surgery, making glare and haloes less common 

and improving visual acuity. Femtosecond 

lasers have moved rapidly into widespread use 

in LASIK refractive surgery and increasingly in 

corneal transplantation. Femtosecond lasers have 

improved the safety of these procedures while 

hastening the recovery time after surgery. 

Advances have been made in our 

understanding of the progressive loss of corneal 

biomechanical stability found both in keratoconus 

and sometimes after laser vision correction 

surgery. New nonsurgical techniques for 

keratoconus that use a combination of riboflavin 

and UV lights to crosslink collagen fibrils in the 

cornea hold promise to markedly strengthen the 

cornea and prevent progression of corneal ectasia.

GENETICS/GENOMICS

There has been substantial progress in 

understanding the genetic mechanisms involved 

in the pathogenesis of the hereditary corneal 

endothelial dystrophies. Causal mutations have 

been identified, associated with pathogenesis 

of Fuchs corneal dystrophy (FCD), congenital 

hereditary endothelial dystrophy (CHED) and 

posterior polymorphous dystrophy (PPD). 

Interestingly, some genes are associated with 

several hereditary dystrophies, such as SLC4A11 

with FCD and CHED, and TCF8 (ZEB1) with FCD 

and PPD. These findings suggest that although 

clinically distinct, these endothelial dystrophies 

may have a common genetic origin. Recently, a 

genome-wide association study identified a single 

nucleotide polymorphism in the intronic region 

of TCF4 as highly associated with FCD. However, 

the causality associated with this locus remains 

elusive. 

MOLECULAR AND CELL BIOLOGY

Aquaporins (AQPs) are ubiquitous water 

channels in corneal tissues. Research using 

knockout mice lacking individual aquaporins has 

implicated their involvement in maintenance of 

corneal hydration and transparency (AQPs 1 and 

5), hydration of the tear film (AQPs 3 and 5), and 

repair of corneal surface wounds (AQP3). At the 

cellular level, new research has elucidated roles 

of various aquaporins in transepithelial fluid 

transport, angiogenesis, cell migration, and cell 

proliferation.
CORNEAL DISEASES 23

INFECTIONS

Recent advances in understanding viral 

infections in the cornea have revealed the 

following: 1) the importance of vascularization 

(blood and lymphatic) in herpes stromal 

keratitis (HSK), an immunoinflammatory 

response orchestrated by T cells that leads 

to progressive scarring and blindness; 2) 

the role of CD8+ T cells and microRNA in the 

reactivation of herpes simplex virus 1 (HSV-1) 

from latency in sensory neurons that innervate 

the cornea; and 3) the crystal structure of a 

human adenovirus, facilitating the design of 

novel antiviral compounds for treatment of 

acute keratoconjunctivitis, and exploitation of 

adenoviruses as vectors for gene therapy. 

Contact lens wear and ocular trauma are major 

risk factors for bacterial and fungal keratitis, and 

Candida yeasts are associated with complications 

from ocular surgery in the United States. Recent 

studies have increased our understanding of the 

role of innate immunity in recognizing bacteria 

at the corneal surface. Toll‐like receptors (TLRs) 

expressed on the surface of epithelial cells, 

macrophages, and dendritic cells in the stroma 

recognize conserved bacterial products such 

as lipopolysaccharide (LPS), leading to rapid 

production of proinflammatory and chemotactic 

cytokines and recruitment of neutrophils to the 

corneal stroma. A number of Candida virulence 

factors have been identified, and the role of TLRs 

and C-type lectins in the elicitation of innate 

immune response in the pathogenesis of fungal 

keratitis has been established.

Major WHO programs have yielded significant 

progress in the fight to eliminate two of the 

leading causes of corneal blindness: river 

blindness and trachoma. River blindness caused 

by the filarial nematode, Onchocerca volvulus, 

was a major cause of blindness in Africa, South 

America, and the Middle East. These worms 

harbor endosymbiotic Wolbachia bacteria that are 

released into the corneal stroma when the larval 

worms die. The released bacteria stimulate an 

inflammatory response in the cornea that leads to 

loss of vision. Wolbachia are killed by antibiotics, 

which also leads to worm death. Trachoma 

is caused by immunopathologic response 

to repeated infections with the Chlamydia 

trachomatis bacteria. Large, randomized trials 

of antibiotic treatment of entire villages, using 

azithromycin, have demonstrated different 

approaches to dramatically reduce the burden 

of infection, although clinical disease is slower 

to respond. Trials have demonstrated the 

effectiveness of antibiotics used postoperatively 

to prevent recurrence of trichiasis, the late stage 

of trachoma, following corrective surgery. Large 

programs are treating communities in Africa 

to reduce infection and prevent progression 

toward blindness, although the pathway from 

conjunctival scarring to trichiasis is unclear (see 

sidebar next page).
24 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

Efforts To Eliminate a Global Scourge

Trachoma is a bacterial infection of the 

eye and is the leading infectious cause 

of blindness in the world. According 

to the World Health Organization 

(WHO), more than 1 million people 

are blind from trachoma, and more 

than 40 million more suffer from 

active infection. Over the years, 

repeated infections cause the eyelid 

and eyelashes to turn in—a condition 

known as trichiasis—painfully 

scraping and irritating the cornea and 

conjunctiva, and eventually leading 

to severe vision loss and blindness. 

Children are particularly apt to contract 

trachoma because it is spread by 

simple contact from other infected 

individuals and by flies that carry 

discharge from the eyes of one child to 

another. The disease is endemic to the 

poorest areas of developing countries 

in overcrowded communities with poor 

hygiene and lacking clean water. 

Trachoma is curable and its spread is preventable. In 1998, WHO called for global elimination of trachoma by 2020. 

WHO initiated the “SAFE” strategy to eliminate trachoma through Surgery for in-turned lashes, Antibiotics for 

active disease, Facial cleanliness, and Environmental improvement. As part of its commitment to global health, NEI 

conducted several clinical trials to compare antibiotic treatment strategies in trachoma-endemic regions of Ethiopia 

and Tanzania. Investigators in these trials asked the following questions: Is it effective to treat most individuals in a 

community, termed mass treatment, with the antibiotic, azithromycin, to eliminate trachoma in that community? If so, 

how often must it be administered and for how long? Is it safe? Do the bacteria develop drug resistance? The results 

not only demonstrate that mass antibiotic treatments are an effective strategy for dramatically reducing the burden of 

infection, but azithromycin may also improve the outcome of trichiasis surgery and help treat other serious infections 

such as diarrhea and malaria. 

NEI-supported research has provided critical information for the global efforts to eradicate trachoma. The 

pharmaceutical company, Pfizer, has agreed to continue to provide the azithromycin free of charge to needy 

communities if progress toward elimination continues to be made. To learn more about research on trachoma, read 

the NEI Story of Discovery (http://www.nei.nih.gov/news/scienceadvances/discovery/trachoma.asp).
CORNEAL DISEASES 25

CORNEAL DISEASES 

NEEDS, GAPS AND OPPORTUNITIES

ANGIOGENESIS AND 

LYMPHANGIOGENESIS

• Examine the long-term effects of VEGF 

inhibition, particularly since corneal nerve 

regeneration and wound healing are 

compromised by VEGF blockade. Elucidate 

the interplay between various angiogenic and 

anti-angiogenic factors and their resultant 

signal transduction pathways. 

• Identify regulators of lymphangiogenesis in 

addition to VEGF (e.g., integrins, members 

of a family of cell surface receptors whose 

ligands are extracellular matrix proteins and 

immunoglobulin superfamily molecules, and 

macrophages, either as progenitor cells or as a 

source of prolymphangiogenic growth factors 

and proteases) to facilitate the development of 

therapeutic strategies for minimizing corneal 

transplant rejection. The mouse corneal 

micropocket assay, as well as development of a 

specific lymphatic marker (LYVE-1), offer new 

possibilities for studying hemangiogenesis 

and lymphangiogenesis.

• Develop new anti-angiogenic drugs besides the 

monoclonal antibody bevacizumab given that 

more than 20 different angiogenic factors exist 

in addition to VEGF-A, which bevacizumab 

targets. Conventional therapy for corneal 

neovascularization involves steroid therapy, 

but there are potential negative treatment side 

effects such as glaucoma and cataract.

TRANSPLANTATION

• Determine how dendritic cells are modified by 

the ocular microenvironment, as corneal graft 

rejection occurs almost exclusively by indirect 

allo-recognition.

• Understand the interaction of recruited innate 

and adaptive immune cells at the site of 

transplantation and corneal graft destruction.

• Improve understanding of host responses 

in high-risk corneal transplantation, which 

involves an incredibly complex array of 

interactions that may act at different times 

or contemporaneously, with either additive 

or opposing effects on the cells central to 

transplant tolerance or graft rejection. Find 

a balance between stimulation and costimulation and induction of tolerance to 

alloantigens in anti-rejection therapy.

REGENERATIVE MEDICINE

• Resolve major questions of limbal epithelial 

stem cell biology, such as the following: 

o What keeps stem cells in their quiescent 

state yet enables these cells to periodically 

divide to give rise to their progeny? A 

better understanding of the “stem cell 

niche” will provide answers to this gap in 

our knowledge. 

o How are the conjunctival, limbal, and 

corneal epithelial boundaries established 

and maintained? Unraveling the 

complexities of inter-cell communication 

will help fill this void. 

o How do limbal epithelial stem cells and 

their progeny regulate their metabolism? 

• Improve the ability to culture epithelial 

cells using safe media components, develop 

an efficient system to ensure safety and 

reproducibility, and generate better carrier 

components to improve the success of 

transplantation of cultured epithelial cells.
26 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

• Define the ability of corneal endothelial cells 

to regenerate and improve techniques to 

cultivate endothelial cells, whether from the 

patient or from allogenic sources. Develop 

new carrier substrates with improved 

handling characteristics to allow diffusion and 

optical clarity for use in transplantations. 

• Identify new materials that provide a better 

transparency and possess biomechanical 

strength that are similar to the native 

cornea, and are biocompatible. Develop 

new biodegradable constructs that allow 

replacement by normal corneal or native 

corneal tissue and cells over time. Develop 

other approaches such as synthetic stromal 

equivalents that could obviate the need for 

functional endothelium. 

• Translate findings on defining and 

characterizing corneal keratocyte progenitor 

cells and their utility in restoring corneal 

transparency in the mouse model into 

the human. 

• Develop an understanding of the epigenetic 

regulation of wound healing and develop 

methods to accelerate wound closure and 

control epithelial cell proliferation to 

prevent hyperplasia.

INFLAMMATION AND IMMUNITY

• Increase our understanding of leukocyte 

and epithelial cell trafficking in the cornea, 

and develop strategies geared toward the 

enhancement of the wound-healing process. 

Elucidate the beneficial roles played by 

macrophages, dendritic cells, Langerhans 

cells, and other lymphocyte subsets in corneal 

inflammation. Investigate the role of hypoxia 

and the chemokine/cytokine network driving 

inflammatory cell recruitment. 

• Develop new prostheses and interventions that 

can effectively treat severe scarring diseases, 

including trachoma and onchocerciasis, and 

ocular surface inflammation. 

• Generate models of acute or chronic ocular 

allergy that closely mimic human disease and 

identify new targets in order to develop more 

effective therapies to treat extreme pain and 

discomfort caused by this condition. 

• Develop an understanding of the underlying 

mechanism behind why atopic patients have a 

higher incidence of, and are more susceptible 

to, dry eye disease and to DNA viruses, 

including the human papillomavirus and 

herpes simplex viruses. 

TEARS/DRY EYE DISORDERS

• Develop an understanding of the regulation of 

tear production and, in particular, the role of 

innervation and other factors (e.g., hormones, 

inflammatory mediators) in controlling 

meibomian gland secretion.

• Characterize the normal regulation of 

lacrimal gland, meibomian gland, goblet 

cell, and conjunctival stratified squamous 

cell secretion to identify the dysfunctions 

occurring in dry eye.

• Understand the causes and mechanisms of dry 

eye pathology and inflammation, including the 

role of the different types of mucins, lipids, 

toll-like receptors, the effect of sex-related 

hormones, and the role of autoimmunity.

• Understand the effect of aging on tear 

production and on corneal and conjunctival 

function, and characterize the effect of 

diabetes on ocular surface disease. 

• Develop new animal models of dry eye disease 

and meibomian gland dysfunction, and 

identify transcription factors and promoters 

that can be used to develop transgenic animals 

with tissue specific over-expression of genes. 

• Develop novel ocular therapeutics based on 

pathophysiology of different dry eye subtypes, 

for example, modulation of AQP expression 

and function. Increasing AQP expression, for 

example, may have utility for treatment of dry 

eye syndromes and corneal injury.
CORNEAL DISEASES 27

• Facilitate the development of effective 

treatments by identifying new diagnostics 

to define dry eye conditions, including 

biomarkers or paradigms that use multiple 

diagnostic tests, and correlate the impact on 

quality of life and patient symptoms with new 

diagnostics or paradigms. 

• Understand the impact of contact lens wear 

in dry eye conditions, including meibomian 

gland dysfunction.

OCULAR PAIN AND SENSITIVITY

• Develop a better classification of ocular pain 

syndromes. A common nomenclature and 

classification scheme would enhance future 

research in both the laboratory and the clinic. 

See the report of the NEI Workshop on Ocular 

Pain and Sensitivity.1

• Correlate the molecular and structural 

composition of corneal nerves with their 

function. Elucidate the peripheral and central 

mechanisms for long-term ocular pain 

syndromes, using approaches that include, 

but are not limited to, electrophysiological 

analysis and advanced esthesiometry. 

• Develop topical and/or systemic anesthetics 

or analgesics that are targeted for ocular pain, 

as well as novel agents capable of stimulating 

appropriate corneal nerve regeneration.

BIOMECHANICS AND IMAGING

• Develop noninvasive methods to “interrogate” 

the cornea for the presence of biomechanical 

instability prior to the onset of clinical disease, 

which may prevent the development of 

corneal ectasia secondary to keratoconus or 

postrefractive surgery.

• Increase understanding of biomechanical 

properties of the cornea and how they change 

during aging and in patients with glaucoma.

1 http://www.nei.nih.gov/strategicplanning/pain_workshop.asp

• Develop high-resolution imaging techniques 

to diagnose and guide treatment of common 

corneal disorders, including inflammation, dry 

eye, corneal ectasia, scarring, infection, and 

neuropathic conditions.

• Increase our understanding of the cornea as 

the portal to the entire optical system of the 

eye, using personalized systems (e.g., retinal 

photography, scanning laser ophthalmoscopy, 

and OCT). Develop new technologies for 

surface-resolved aberrometry that could 

facilitate wavefront-optimized corneal and/or 

lens transplants. 

• Advance the analysis of nerve morphology 

to allow for diagnosis of clinical syndromes 

based upon corneal nerve imaging. Develop 

new automated instruments capable of higher 

resolution images with better registration 

coupled with advanced software.

GENETICS/GENOMICS

• Identify the major genetic factors that are 

involved in FCD, which is responsible for 

the majority of corneal transplantations 

performed each year in the United States. 

Many loci have been identified for FCD with 

large intervals, but the relation of genetic 

factors to the pathophysiology of disease 

remains elusive. Better defined regions could 

be obtained using newer techniques such as 

next-generation sequencing.

• Improve the identification of the phenotypic 

variations in the severity and progression of the 

endothelial dystrophies, including longitudinal 

studies of the disease phenotype in subjects 

with known genotypes, especially when 

therapeutic interventions are contemplated. 

• Identify novel common causal variants of 

corneal endothelial dystrophies to help our 

understanding of the genetic interaction 

between “corneal dystrophies” genes and 

how they modulate the expressivity of the 
28 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

phenotype. Although clinically distinct, 

corneal endothelial dystrophies may be allelic 

variants of the same disease.

• Link recent data identifying both gene 

expression profiles and regulatory pathways 

in the tissues of the anterior eye during 

development and disease to 1) predict who 

is at high risk of developing corneal diseases 

and 2) define disease initiation, progression, 

and staging requisite for the design and 

implementation of appropriately targeted 

preventions and therapies. 

• Identify the mechanisms of regulation of 

cellular gene expression in corneal health 

and disease. Use epigenetic chromatin 

markers to connect the environment and the 

genome, possibly revealing key mechanisms 

for how experience can feed back into cellular 

genetic identity. 

INFECTIONS

• Resolve major questions of viral infection, 

such as the following:

o Generate new animal models for 

studying varicella zoster virus (VZV) 

corneal infections and latency as well as 

postherpetic neuralgia.

o Characterize mechanisms and regulation 

of the innate immune response that clears 

HSV-1, VZV, and adenovirus from the 

cornea.

o Develop therapeutic and prophylactic 

vaccines aimed at augmenting T cell 

control of HSV-1 latency in sensory ganglia 

and replication in the cornea.

o Develop novel and specific antiviral 

compounds for treating adenovirus 

corneal infections.

o Characterize the immunopathology 

mechanisms associated with HSV-1, 

VZV, and adenovirus keratitis; and 

translate this knowledge of mechanisms

of immunopathology into improved 

clinical management.

• Further characterize the pathogenesis of 

fungal, acanthamoebal, and bacterial keratitis, 

including mediators of innate and adaptive 

immunity, and microbial virulence factors that 

have potential as targets for novel therapies.

• Elucidate the epidemiology and 

pathophysiology of emerging pathogens 

in contact-lens related keratitis, including 

mechanisms of resistance.

• Develop novel and sustainable delivery 

methods for the prevention and treatment of 

ocular surface infection.

CLINICAL RESEARCH

• Apply new in vivo corneal biomechanical 

measurement and modeling techniques for 

larger clinical studies of corneal response to 

injury, ectatic disease, and the aging cornea.

• Characterize the extra-ocular anomalies 

associated with corneal dystrophies, including 

those with extra-ocular phenotypes such as 

the Harboyan syndrome.

• Investigate application of nanoparticles for 

use in drug delivery in inflammation and to 

control immunity in corneal transplantation. 

• Develop nanotechnology to improve imaging 

of the various ocular structures. 

• Conduct treatment studies, preferably 

definitive clinical trials, which are critical to 

establishing an evidence-based approach 

to treatments for dry eye and meibomian 

gland dysfunction; endothelial replacement 

surgeries; treatment of fungal, viral, bacterial, 

and acanthamoeba keratitis; laser and 

lens replacement approaches to treating 

moderate to high myopia; and use of corneal 

crosslinking for keratoconus. 
CORNEAL DISEASES 29

IMPROVING PUBLIC HEALTH

• Address cataract surgery outcomes for the 

aging population of postrefractive surgery 

patients, whose altered corneas challenge the 

assumptions underlying current diagnostic 

technology. Apply new volumetric corneal 

imaging technologies, such as OCT, coupled 

with improved optical and biomechanical 

modeling capabilities.

• Improve outcomes and surgical 

reproducibility in selective lamellar 

keratoplasty techniques and develop 

automated screening technologies to evaluate 

donor corneas, including the detection 

of post-LASIK donor corneas. Improve 

refractive outcomes through pre-operative 

measurement and modeling of the refractive 

and biomechanical properties of the donor 

and recipient corneas. 

• Use new opportunities in connection with 

trachoma and oncocerciasis control programs 

to cost-effectively test novel and optimal 

intervention strategies for control of global 

infectious causes of blindness.

• Develop methods for early detection of 

ophthalmic epidemics, such as recent 

epidemics of keratitis due to Fusarium 

spp., and the Acanthamoeba spp., using 

networks of sentinel laboratories, disease 

reporting, web-based information tracking, 

etc. Surveillance may also include infectious 

causes of viral conjunctivitis, corneal ulcers 

and endophthalmitis caused by bacteria or 

fungi, and monitoring for antibiotic and 

anti-mycotic resistance. 
30 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

LENS AND CATARACT

The healthy lens is optically clear and flexible. 

Loss of lens transparency (cataract) and/or 

reduced ability to focus on near objects with age 

(presbyopia) are visual impairments that afflict a 

large portion of the world’s population. Although 

cataract surgery is an effective procedure, it is 

not available in many less developed areas of the 

world. According to WHO, 48 percent of global 

blindness (corresponding to 18 million people) is 

attributable to age-related cataract.2

 The largest 

single risk factor for cataract is age, although it 

can result from genetic factors or environmental 

stresses. Cataract afflicts more than 50 percent 

of people over the age of 80. Even in developed 

countries, cataract remains a significant 

cause of blindness and low vision, especially 

for individuals who have limited financial 

resources, or rare but potentially blinding 

surgical complications. When the lens loses its 

flexibility, the ability to adjust the curvature of 

the lens to focus on objects at different distances 

(accommodation) is impaired. Presbyopia, the 

age-related loss of accommodative ability, usually 

manifests in midlife, causing difficulty when 

reading or doing other near work. Although 

not a blinding condition, presbyopia is a nearly 

universal visual impairment that requires 

eyeglasses or other corrective devices. 

Understanding the unique physical and 

developmental attributes of the lens has 

advanced our knowledge of fundamental 

biological processes. For example, the lens 

mainly consists of densely packed, transparent 

fiber cells that differentiate from a single layer 

of epithelial cells in the periphery. The fiber 

cells do not turn over, which means they must 

last for a lifetime. Consequently, investigators 

have used the lens in studies of cellular and 

molecular longevity, proliferation, and death. 

2 Resnikoff, S. et al. (2004). Bulletin of the World Health 

Organization, 82, 844-851. 

Insights into the molecular aging of lens 

proteins (crystallins) serve as a paradigm for 

understanding aging of structural molecules. 

Another common physiological property of living 

tissues is communication between neighboring 

cells. In the avascular lens, intercellular 

communication plays a key role in delivering 

nutrients and removing waste products. The 

connections between communicating cells are 

termed gap junctions, and the major proteins 

(connexins) in gap junctions are expressed at 

extraordinarily high levels in fiber cells, causing 

a tight coupling of fiber cell behavior. The 

abundance of gap junctions and the relative ease 

with which connexin genes can be manipulated 

in the lens have contributed greatly to a general 

understanding of cell–cell communication. 

Finally, studies of the lens may provide a 

window into understanding other diseases. 

Recently, it was discovered that amyloid-β 

protein accumulates in the lenses of patients with 

Alzheimer’s disease. The formation of amyloid- β 

plaques in the brain is a well-known characteristic 

of Alzheimer’s patients, but detecting the plaques 

early in a noninvasive manner is challenging. 

Now, there is promise that a new, simple optical 

technique that measures light scattering by 

clumped proteins in the lens may serve as a tool 

for screening and early detection of Alzheimer’s 

and other neurodegenerative diseases. In sum, 

discoveries from lens research are providing new 

insights not only into lens function (refraction 

of light and accommodation) and dysfunction 

(cataract and presbyopia), but also into the 

biology and pathobiology of other tissues and 

organ systems. 
LENS AND CATARACT 31

LENS AND CATARACT 

HIGHLIGHTS OF RECENT PROGRESS

GENETICS/GENOMICS 

To date, more than 200 genes contributing 

to many different forms of cataract have been 

identified, providing insights into molecular 

pathways essential for lens transparency. For 

example, mutations in the Tudor domaincontaining 7 (TDRD7) gene have recently been 

shown to underlie inherited cataract. TDRD7 is a 

component of RNA granules, which are believed 

to play critical roles in the post-transcriptional 

regulation of gene expression in the lens. Candidate 

gene association studies and, more recently, GWAS 

provide evidence that variations in some of the 

genes associated with Mendelian forms of cataract 

may also be associated with age-related cataract 

(e.g., CRYAA, GJA8, EPHA2, FYCO1). 

PROTEIN STRUCTURE AND 

AGGREGATION

Structures of the lens-specific water channel, 

AQP0 reveal how it conducts water while 

remaining impermeable to protons, and add to 

understanding the structural basis for its role in 

forming membrane junctions between fiber cells. 

New high-resolution electron crystallographic 

structures of AQP0 reconstituted into membranes 

provide unique insights into the interaction 

of integral membrane proteins with their 

surrounding lipids.

The abundant, normally soluble lens crystallin 

proteins are critical to maintaining optical clarity 

and the refractive index in the lens. An inevitable 

consequence of lens aging is the unfolding and 

aggregation of crystallins and changes in their 

surface properties, culminating in decreased 

solubility. Investigations of the structure, folding 

pathways, and interactions of the crystallins are 

unraveling the molecular mechanisms by which 

age-accumulated protein modifications lead to 

crystallin aggregation. The loss of chaperone 

regulation and the role of α-crystallin in apoptotic 

pathways are major contributors to inherited 

cataract. Crystallin expression has also been 

demonstrated in the retina. Two crystallin 

genes, CRYBB1 and CRYBB2, are expressed more 

frequently in drusen from patients with AMD, 

suggesting that crystallins may be implicated in 

AMD pathogenesis. 

CELL SIGNALING

Virtually all major signaling pathways are 

represented in the lens and have been shown 

to play key roles in lens development, cell 

differentiation, and homeostasis. For example, the 

FGF receptor pathway is fundamental for lens cell 

survival and for fiber cell differentiation in vivo. 

Wnt signaling is required for the differentiation 

of lens epithelial cells and for lens cell polarity. 

Members of the TGF-β superfamily are expressed 

in the lens, and there is a fundamental role for 

BMP receptors in lens induction. Recently, a 

novel procedure to generate lens cells in vitro

was developed by sequentially exposing human 

embryonic stem cells to a series of extracellular 
32 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

signals that recapitulate the signaling events 

during early embryonic development. Since 

development of the retina and other ocular 

components is tied to development of the lens, 

this advancement provides a basis for future 

engineering of ocular tissues for transplantation 

and disease repair. 

DIFFERENTIATION AND CELLULAR 

ORGANIZATION

Targeted disruptions of specific genes in 

mouse experimental models have begun to 

reveal the molecular basis for key events in 

morphogenesis and lens fiber cell differentiation. 

For example, the lens-specific intermediate 

filament proteins, CP49 and filensin, play 

indispensable roles in fiber morphogenesis and 

contribute directly to the mechanical properties 

of the tissue. Similarly, the formation of fusions 

between lens fiber cells, which permit the 

intercellular diffusion of proteins, depends on 

the expression of Lim2, an integral protein of the 

fiber cell membrane. Investigators have begun 

to integrate information from molecular studies 

with knowledge of the detailed three-dimensional 

cellular organization of the lens obtained using 

advanced imaging techniques to provide a more 

complete understanding of lens transparency, 

biomechanics, and presbyopia.

OXIDATIVE DAMAGE, PROTECTION, 

AND REPAIR

It is well accepted that oxidative stress plays a 

key role in the formation of cataract and other 

age-related degenerative diseases. Recent 

studies have identified multiple systems that 

protect against oxidative damage and novel 

repair systems that defend the lens against 

oxidative damage. These systems are shared by 

the retina and brain and the information derived 

from these lens studies could provide further 

basis for understanding these systems in more 

complex tissues. Oxidative damage in cataractous 

lenses points to the importance of identifying 

and dissecting the lens antioxidant and repair 

pathways. Precise measurements of oxygen 

tension in the human eye and that of various 

animal models have shown that the lens fiber cells 

exist in a low-oxygen environment. Mitochondrial 

respiration in the metabolically active outer layers 

of the lens contributes to an extremely hypoxic 

lens nucleus. Recent studies point to a critical 

role for mitochondrial protection and repair in 

the ability of lens cells to resist oxidative damage. 

There is now evidence that elevated oxygen levels 

in the center of the lens may contribute to nuclear 

cataract formation. Both age-related liquefaction of 

the vitreous gel and surgical vitrectomy (removal 

of the vitreous gel) result in elevated levels of 

oxygen around the lens and, significantly, both are 

well-recognized risk factors for nuclear cataract. 
LENS AND CATARACT 33

LENS AND CATARACT 

NEEDS, GAPS AND OPPORTUNITIES

PROTEIN STRUCTURE AND 

FUNCTION

• Develop advanced optical and mass 

spectroscopic imaging techniques and 

introduce novel model systems to help 

guide the development of effective anticataract strategies. Recent biochemical 

studies have provided a detailed mechanistic 

understanding of crystallin stability, 

interactions, and chaperone function, and 

in vitro studies will continue to provide 

critical data on crystallin structure/function 

relationships in the future. There needs to 

be an emphasis on testing the physiological 

validity and implications of biochemical data 

obtained from in vitro experiments. 

• Unravel the noncanonical functions of lens 

proteins. Originally believed to function 

exclusively in refraction, it is now clear that 

lens crystallins have multiple roles in the 

lens, retina, and elsewhere that represent 

an important area of future study. The 

multiplicity of roles played by crystallins 

might be the rule rather than the exception 

for lens proteins. For example, AQP0 acts 

as a water channel in the lens, but likely 

also serves an important adhesive function. 

Similarly, connexin50, a channel-forming 

protein, also interacts with multiple signaling 

pathways to help regulate epithelial cell 

proliferation and lens size. 

• Further investigate the various 

posttranslational modifications (PTMs) 

to lens proteins, particularly those that 

correlate with lens aging or lens opacity. The 

functional impact of PTMs and proteolysis is 

probably best studied in situ, or in a milieu 

that replicates the highly concentrated protein 

solution of the fiber cell cytoplasm.

SYSTEMS BIOLOGY AND LENS 

PHYSIOLOGY

• Apply systems biology approaches to lens 

physiology and pathophysiology. Consisting 

of only two differentiated cell types and 

isolated from the blood supply, the lens 

represents a unique opportunity to define 

the specific physiological events and 

factors that govern cell differentiation and 

development. For instance, understanding 

the mechanisms that orchestrate the 

specific degradation of individual organelles 

during lens fiber cell maturation is critical. 

Recent advances such as the identification 

of DNAseIIb as a component of nuclear 

degradation in lens fibers and the possible 

role of autophagy in lens cell maintenance and 

differentiation should be further explored. 

Gene transcription profiles from lens cells 

at various developmental stages need to be 

integrated with lens epigenetic and posttranscriptional regulatory mechanisms. Shotgun proteomic and lipidomic approaches 

and MALDI imaging promise to provide an 

unprecedented view of lens cell biology and 

the causes and consequences of cellular aging. 

Lens cell membranes are unique in their lipid 

composition and investigating changes with 

cataract and aging presents an opportunity for 

needed insights into protein-lipid interactions. 

Improving spatial resolution of imaging 

techniques will uncover the molecular fate 

of cells in specific regions of the lens, from 

embryonic epithelial cells to aged fiber cells. 
34 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

MODEL SYSTEMS

• Develop robust, quantitative methods to 

accurately measure lens aberrations in small 

animal models. The size and shape of the lens 

are fundamental to its refractive properties 

and the genetic determinants of lens refractive 

function are beginning to emerge. Although 

considerable insights into lens morphogenesis 

and physiology have been achieved using 

avian, rodent and, more recently, fish systems, 

modeling lens pathology has proved more 

challenging. Because no animal model fully 

recapitulates the growth kinetics of the human 

lens, the time course of presbyopia, or the 

development of age-related cataract, new 

physiologically relevant models are needed. 

CELL SIGNALING

• Continue studies of key developmental and cell 

signaling pathways. The lens is an exceptional 

system for studies of signaling pathways that 

control cell proliferation, differentiation, 

fiber cell migration, polarity, and tissue 

organization. New reagents allow lens gene 

expression to be temporally modulated 

in vivo in a cell-type specific fashion. This, 

coupled with the geometric organization 

of the tissue and the availability of optical 

probes to visualize the consequence of genetic 

manipulations, ensures that studies on the lens 

will continue to make important contributions 

to the broad field of cell signaling. 

• Study the mechanism of TGF-β-mediated lens 

fibrosis in order to develop effective means 

of preventing posterior capsule opacification 

(PCO), the most common long-term 

complication of cataract surgery. The fibrotic 

process that underlies PCO is an example of 

aberrant cell signaling. TGF-β has emerged 

as a central mediator of lens fibrosis and is 

believed to induce epithelial/mesenchymal 

transdifferentiation, an early step in the 

fibrotic response leading to PCO.

DEVELOPMENT AND 

REGENERATIVE MEDICINE

• Understand the regulation of epithelial cell 

proliferation. Specifically, identify the factors 

that promote cell division in the germinative 

zone of the epithelium and suppress mitosis 

in the central zone. The optical role of 

the lens mandates that its size and shape 

must be regulated within very narrow 

tolerances and yet little is known about the 

regulatory mechanisms that control epithelial 

proliferation and the number of cells in 

the tissue. 

• Settle the issue of whether there is a stem 

cell population in the lens epithelium. The 

lens grows throughout life and this is often 

taken as a priori evidence for the presence of 

a stem cell population in the lens epithelium. 

However, the location of lens stem cells, if such 

exist, has remained a matter of debate for 

many years. 

• Gain an in-depth understanding of the 

temporal and morphogenetic stages of fiber 

cell differentiation to determine whether 

it may be possible to produce human 

lenses in vitro for transplantation. Growing 

mechanically functional transparent tissue 

in vitro will also require the identification 

of biocompatible scaffolds. Delineating the 

influence of the lens on the differentiation 

of surrounding ocular tissues and structures 

is very important for understanding overall 

ocular development and function.

• Investigate the consequence of lacking a natural 

lens in the adult eye for long time periods. 

Early in development, the lens plays a central 

role in ocular physiology and development, but 

little is known about its contribution to these 

processes in the aging eye. 
LENS AND CATARACT 35

Restoring Sight to Children Helps Scientists 

Understand the Brain

Project Prakash is a unique merger between medical 

research and humanitarianism, partly funded by NEI 

and led by Dr. Pawan Sinha, a computer scientist at 

the Department of Brain and Cognitive Sciences at the 

Massachusetts Institute of Technology.

India has the world’s largest population of blind 

children. Many of these children live in poor, remote 

villages, and are born blind. According to Dr. Sinha, half 

of the visually impaired children could recover vision if 

they had access to professional eye care. For example, 

many children have dense congenital cataracts in 

both eyes, and cataract removal surgery, commonly 

performed on older adults in the United States, could 

eliminate this blinding condition. Project Prakash works 

with the Shroff Charity Eye Hospital in New Delhi, India, 

to find and treat these children. Since 2003, the project 

has screened thousands of children and provided 

vision to hundreds. It has also helped raise awareness 

about treatable blindness in India. 

Project Prakash also investigates how the brain turns what we see into images we recognize. We learn to recognize 

objects just after birth, but studies of how infants recognize objects can be challenging. However, the children treated as 

part of Project Prakash are old enough to describe the objects they are beginning to see and learning to recognize after 

gaining sight. Dr. Sinha uses behavioral tests and brain imaging techniques to study these newly sighted children. So far, 

the results have provided remarkable insights into how the brain processes visual information. For example, contrary to 

previous theories, Project Prakash is showing that even after years of being blind since birth, children can still acquire 

complex visual abilities, providing hope for restoring functional vision to many children. 

“Prakash” is Sanskrit for “light” and is an appropriate name for a project that provides light to the blind in India and 

enlightenment to scientists around the world.
36 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

BIOMECHANICS AND IMAGING

• Develop high-resolution optical imaging 

technologies and new fluorescent reporter 

molecules to allow the visualization of 

individual cells and molecular species in 

vivo and in organ-cultured lenses. In model 

organisms, imaging will provide answers 

to fundamental cell biological questions 

and insights into the cellular basis of 

accommodation and presbyopia. 

• Study the microscopic changes that accompany 

accommodative changes in lens shape. 

A more complete understanding of the 

biomechanics of accommodation is needed to 

form an integrated model describing cellular 

and molecular parameters. Determine how 

cytoskeletal elements within the lens fiber 

cells influence the mechanical parameters of 

the tissue, and how structural forces generated 

during accommodation impact lens physiology. 

The effects of aging on the underlying 

structural elements need to be determined. 

MECHANISMS OF CATARACT 

FORMATION, CATARACT 

PREVENTION, AND PUBLIC HEALTH

• Conduct comprehensive, long-term, 

epidemiological studies to identify genetic 

determinants and environmental factors 

that contribute to cataract formation. 

Furthermore, well-designed studies to 

identify genes and mutations associated with 

syndromic, nonsyndromic and particularly 

age-related cataract, and the interaction with 

known environmental cataractogenic agents, 

are warranted.

• Evaluate the effects of elevated oxygen levels 

and altered redox states on lens function and 

cataract formation. Identify the proteins, lens 

organelles, and signaling pathways that are 

altered in response to altered oxygen levels 

and redox conditions. Chronic exposure of 

fiber cells in the center of the lens to elevated 

levels of oxygen may contribute to age-related 

nuclear cataract, and acute oxygen exposure 

could be the cause of postvitrectomy cataract. 

Implementing new strategies to prevent 

oxygen exposure or mitigate the effects of 

exposure may therefore prevent certain types 

of cataract. 

• Determine the efficacy of noninvasive optical 

techniques used in lens research, such as 

dynamic light scattering, and take advantage 

of cross-disciplinary opportunities for use 

in measuring amyloid-β accumulation/

aggregation, and evaluate its use as a 

prognostic indicator for neurological diseases. 

• Investigate the etiology of diabetic cataract, 

which is likely to increase in frequency as 

obesity rates continue to rise in the United 

States. Understanding the etiology of diabetic 

cataract is important toward developing 

preventative strategies for this condition that 

will aid in the management of other diabetic 

conditions, including diabetic retinopathy. 

• Determine reasons for disparities in access 

and outcomes of cataract surgery across 

populations, and evaluate cost-efficiencies in 

approaches to cataract surgery. Such research 

has applicability to populations worldwide and 

would address this leading cause of blindness.
GLAUCOMA AND OPTIC NEUROPATHIES 37

GLAUCOMA AND 

OPTIC NEUROPATHIES

The optic nerve conducts visual information 

from the retina to the brain. Damage to the 

optic nerve from glaucoma or other optic 

neuropathies can lead to vision loss. Glaucoma 

is a group of diseases that includes primary 

open-angle glaucoma (POAG), the most common 

form, as well as closed-angle glaucoma, 

congenital glaucoma, and glaucoma secondary 

to other ocular conditions such as eye injury, 

infection or inflammation of the eye (uveitis), 

neovascularization, and steroid use. 

Glaucoma is a disease of both the front 

(anterior chamber) and back of the eye (retina 

and optic nerve). The disease often begins with 

a defect in the anterior chamber where a clear 

fluid, the aqueous humor, circulates to provide 

nutrients to the lens and cornea. Aqueous humor 

normally drains through two filtration systems: 

the uveoscleral outflow pathway and the spongy 

trabecular meshwork at the angle where the 

cornea and iris meet. In closed-angle glaucoma, 

the iris is displaced, blocking fluid outflow. In 

POAG, the drainage angle is open, but outflow 

rate is reduced, leading to elevated intraocular 

pressure (IOP), the major identified risk factor 

for glaucoma. Elevated IOP induces damage 

and death of the retinal ganglion cells (RGCs), 

the neurons whose axons comprise the optic 

nerve. The level of IOP required to produce optic 

nerve damage varies widely among individuals, 

and damage can also occur in the absence of 

apparently elevated IOP, likely due to individual 

variations in optic nerve structure, blood supply, 

difficulties in accurate IOP measurement, and 

other factors that are not yet well understood. 

Other significant glaucoma risk factors include 

age, family history, and ethnicity. As with 

Alzheimer’s and other neurodegenerative 

diseases, which have interesting parallels with 

glaucoma, the loss of the affected neurons in 

glaucoma is slow, chronic, and progressive. 
38 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

As one of the leading causes of visual disability 

in the United States (more than 2.7 million cases) 

and throughout the world (more than 60 million 

cases),3

 glaucoma represents a major public health 

challenge. Significantly, glaucoma is a leading cause 

of irreversible blindness among African Americans 

and Hispanics.4

 With the aging of the U.S. 

population, increased life expectancy, and higher 

incidence of glaucoma in older persons, the number 

of patients with glaucoma is expected to increase 

considerably. Furthermore, individuals with ocular 

hypertension (elevated IOP but no apparent 

optic nerve damage) are at risk of developing 

glaucoma. Although glaucoma is the most common 

optic neuropathy, optic neuritis, ischemic optic 

neuropathy (optic nerve stroke), Leber’s 

hereditary optic neuropathy (LHON), and traumatic 

optic nerve injury also lead to significant vision 

loss, morbidity, and mortality.

3 Vajaranant, T.S., et al. (2012). Investigative Ophthalmology 

and Visual Science, 53, 2462-2466; Quigley, H.A., et al. 

(2006). British Journal of Ophthalmology, 90, 262-267. 4 Higginbotham, E.J. (1997). Maryland Medical Journal, 90(5), 

262-267; Varma, R., et al. (2004). Ophthalmology, 111(8), 

1439-1448.

Screening, early detection, regular followup and 

timely treatment are key to preventing or reducing 

vision loss. In patients with ocular hypertension or 

glaucoma, long-term reduction in IOP is currently 

the only proven strategy for preventing or reducing 

progressive peripheral vision loss. 

Uveitis refers to a group of approximately 

30 diseases characterized by intraocular 

inflammation and encompassing autoimmune, 

infectious, neoplastic, toxic/drug induced, 

and traumatic etiologies. Uveitis can lead to 

glaucoma, but can also cause severe vision loss 

without inducing glaucoma. Treatment depends 

on the location of the inflammation in the eye 

and whether the disease is infectious or not. 

Autoimmune or autoinflammatory uveitis is treated 

with corticosteroids and sometimes systemic 

immunosuppression, whereas infectious forms of 

uveitis are treated with antimicrobial therapy.
GLAUCOMA AND OPTIC NEUROPATHIES 39

GLAUCOMA AND OPTIC NEUROPATHIES 

HIGHLIGHTS OF RECENT PROGRESS

PHYSIOLOGY AND MOLECULAR 

AND CELL BIOLOGY 

Family history and ethnic background are 

strong predictors of glaucoma risk, and yet, 

genes involved in POAG have remained elusive 

for years. Large-scale GWAS, such as the NEI 

Glaucoma Human Genetics Collaboration, have 

identified new genes that contribute to increased 

glaucoma risk in both rare and common complex 

forms. Among the genetic regions that have 

been identified are the CAV1/CAV2 locus, the 

CDKN2B/2A locus, and LOXL1 (exfoliation 

syndrome and glaucoma). These findings will help 

doctors predict disease risk in patients, and will 

point to new molecular pathways—and potential 

therapeutic targets—in glaucoma. These studies 

have validated the importance of using POAGrelated quantitative endophenotypes such as 

central corneal thickness and cup-to-disc ratio for 

disease gene discovery.

Improved animal models for glaucoma have 

facilitated their use in studies to understand 

cellular mechanisms of optic nerve damage from 

elevated IOP. An anterior chamber hypertonic 

saline perfusion model has become widely 

accepted. New murine genetic models for glaucoma 

have been developed that complement existing 

models, such as the DBA/2 mouse. In a particularly 

useful model developed in recent years, aqueous 

outflow is inhibited by injecting microbeads into 

the anterior chamber of mice. Models of anterior 

ischemic optic neuropathy (AION) and posterior 

ION, optic neuritis, and mitochondrial optic 

neuropathies have also been characterized, and are 

providing new testing grounds for diagnostic and 

therapeutic investigations.

As increased IOP remains the major identified 

glaucoma risk factor, considerable effort has been 

devoted to studying various pathways through 

which aqueous humor drains. Studies focused on 

contributions of the juxtacanalicular extracellular 

matrix, juxtacanalicular trabecular meshwork 

cells, Schlemm’s canal inner wall endothelium, 

and uveoscleral outflow have slowly shifted the 

paradigm for understanding outflow resistance 

to provide a more comprehensive view of 

aqueous outflow. 

The initial site of RGC damage in glaucoma 

remains unclear, but increasing evidence suggests 

the principal site of insult may be the optic nerve 

head (ONH), the location where RGC axons exit 

the eye to form the optic nerve. At this location, 

these unmyelinated axons are subjected to 

mechanical stress and are particularly sensitive 

to changes in IOP. The biomechanics of the ONH 

in turn contribute to the health of the RGCs with 

respect to their structural, nutritional, and cellular 

homeostasis. Structural biomechanics determined 

by both the 3D anatomy and the material 

stiffness of the load-bearing tissues are likely to 

be different among patient populations, which 

may underlie the differential susceptibilities 

to glaucoma. RGCs die through the process of 

apoptosis, but the molecular details are just now 

being understood. A key recent finding is that 

mechanisms of damage to RGCs at the optic nerve 

head, within axons, may be separate from those 

affecting retinal ganglion cell bodies. Purified 

cell populations, obtained by laser capture 

microdissection and other methods paired with 

microarray studies, which can provide a profile 

of gene transcripts expressed in a single cell type 

(transcriptome), have identified some of the gene 

expression changes and pathways associated with 

RGC development, injury, and death. Microarray 
40 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

studies of the ONH have also identified gene 

changes that may reflect initial responses to 

elevated IOP and initiating events in RGC axonal 

injury. Additionally, there have been advances in 

high-resolution imaging of RGC in animal models, 

making possible the definition of dendritic trees 

and capillary beds in situ and their response to 

elevated IOP.

Other risk factors for glaucoma are being 

identified, such as properties of the cornea 

(central corneal thickness, corneal hysteresis). 

Additionally, the role of glial cells in RGC health 

and disease and in regulating degenerative 

and regenerative processes has recently been 

recognized. Inflammatory mediators and signals 

derived from these cells influence the life and 

death of RGCs in glaucoma and other retinal and 

optic nerve pathologies. This includes research 

identifying TNF-α as a causative agent in a mouse 

model of glaucoma, and complement factors that 

may play a role in the mechanisms of RGC injury.

BIOMARKERS AND IMAGING 

FOR GLAUCOMA DIAGNOSIS 

AND PROGRESSION

Advances in imaging of the optic nerve and 

retina have aided in understanding disease 

processes and in the developing novel diagnostic 

technologies. Recent advances include confocal 

laser scanning ophthalmoscopy, scanning laser 

polarimetry, Fourier-domain OCT, and adaptive 

optics imaging of the retina. Longitudinal 

studies have shown that these tools accurately 

detect early abnormalities and small changes 

in the retina and the optic nerve in patients 

who ultimately experienced glaucomatous 

degeneration in their visual field. Studies 

applying new tools like laser Doppler flowmetry, 

color Doppler ultrasound, and Doppler OCT 

have documented a relationship between 

glaucomatous damage and decreased blood flow 

in the optic nerve head and retina.

Animal studies using continuous IOP sensors 

suggest that previously undetected variations in 

IOP may be significant for progressive visual field 

deterioration, even when average IOP is within 

a normal range. In addition, cerebral spinal fluid 

pressure and perfusion pressure (defined as 

the pressure difference between arterial blood 

pressure in the eye and IOP) interact with IOP 

and may have a role in glaucomatous optic 

nerve damage.

Newer phenotypic definitions for patients 

with narrow angles, patients at risk of developing 

angle closure, and those with closed-angle 

glaucoma have provided insights into the 

mechanisms of acute and chronic angle closure. In 

addition to the role of anatomical abnormalities, 

dynamic changes in the iris and choroid have 

been implicated in the development of angle 

closure. Newer, OCT-based methods of imaging 

the anterior chamber and the angle have provided 

a better understanding of the mechanisms 

underlying angle closure. They have also helped 

identify novel anatomical risk factors for the 

development of angle closure.

GLAUCOMA AND OPTIC 

NEUROPATHY TREATMENT

Important advances have been made in the 

development of a variety of neuroprotective 

molecules that may promote the survival of RGCs, 

even in the presence of increased IOP and other 

potentially harmful stressors. Neuroprotection 

therapy has the potential to complement 

current glaucoma therapies that target ocular 

hypertension. Some molecules/approaches are in 

clinical trials for ION (optic nerve stroke). Gene 

therapy approaches for LHON, which results from 

a mitochondrial gene dysfunction, have also been 

developed and are moving toward clinical trials.

Injured RGC axons can degenerate from 

the site of the insult to the cell body, leading 

to cell death. Recently, researchers found 
GLAUCOMA AND OPTIC NEUROPATHIES 41

that axon regeneration can be enhanced 

using pharmacological agents, growth factors 

secreted from cells of the innate immune 

system; genetically blocking genes encoding 

suppressors of intracellular signaling; altering the 

expression of transcription factors that regulate 

RGC developmental states; or counteracting 

extracellular signals that normally suppress 

axon growth. 

Research on trabecular contractility in the 

regulation of aqueous outflow has led to two new 

drug classes, which are currently in human clinical 

trials to test their ability to safely reduce IOP: 

Rho kinase inhibitors and actin depolymerizing 

agents. New surgical procedures such as the EXPRESS shunt, Trabectome, and canaloplasty have 

been developed to lower IOP with the potential 

for fewer complications than trabeculectomy. 

However, more research is needed to assess the 

safety and efficacy of these therapies.

PUBLIC HEALTH

Population-based epidemiological studies have 

contributed significantly to our understanding 

of the burden of glaucoma in various racial and 

ethnic communities and highlighted difficulties 

with standardizing definitions of disease and 

progression. Recent studies have shown that the 

prevalence rate of POAG in Hispanics/Latinos is 

estimated to be as high as that noted previously in 

African Americans.

Long-term followup in the large, multicenter 

Ocular Hypertension Treatment Study provided 

insight into the factors that modulate glaucoma 

risk, helping clinicians personalize medicine 

for their patients. Based on certain risk 

factors, clinicians can decide which patients 

should be treated, and which only need careful 

observation and followup. Longitudinal studies 

in patients with glaucoma have also helped refine 

progression analysis algorithms for both visual 

field and retinal and optic nerve imaging data.

INFLAMMATION, IMMUNOLOGY, 

AND UVEITIS

In the past decade, an increased number of 

diseases such as glaucoma, AMD, DR, and dry 

eye have shown involvement of the immune 

system in the disease mechanism. Similarly, 

immune-pathogenic studies provided important 

insights into autoimmune ocular inflammation. 

The discovery of new pathogenic (Th17) 

autoreactive T cells led to research on the roles 
42 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

of pathogenic and regulatory T cell subsets in 

ocular inflammation. In experimental models of 

autoimmune uveitis, understanding the role of 

Th17 cells and the involvement of interleukins 

has resolved paradoxes of autoimmune uveitis, 

while expanding the understanding of the role of 

Th1 and Th2 cells. Microbial proteins, including 

toll-like receptor ligands and alterations of 

microbiota, play a crucial role in causing immune 

dysfunction, leading to immune-related diseases 

such as uveitis and keratitis.

Genetics advances have illuminated 

mechanistic pathways in ocular immunology 

and uveitis. Correlation of polymorphisms of 

genes involved in immune modulation, such as 

TNF-α and interferon gamma, with the severity 

of ocular inflammation in uveitis has provided 

possible disease severity predictors. Mutations 

in NOD2/CARD15 proteins have been detected 

in an expanded spectrum of uveitic syndromes, 

providing insight in their etiology. 

Consensus on clinical grading of ocular 

inflammation and standardization of research 

reporting (Standardization of Uveitis 

Nomenclature Working Group) has facilitated 

meta-analyses across standardized clinical 

studies and provides a common language to 

describe inflammatory conditions. In anterior 

uveitis, increased levels of proteins and cells 

cause turbidity in the aqueous humor, called flare, 

which can be objectively measured with laser 

flare photometry and used as an outcome metric 

in clinical trials. Development and validation of 

a scale for photographic grading of vitreous haze 

allows it to be used as an outcome measure of 

intermediate and posterior uveitis. Diagnosis 

of infectious uveitis with molecular techniques 

optimized for ocular specimens has facilitated 

characterization of uveitis as infectious versus 

autoimmune or autoinflammatory. Additionally, 

several forms of chronic uveitis, including 

glaucomatocyclitic crisis (Posner-Schlossman 

syndrome) and Fuchs heterochromic iridocyclitis 

were definitively linked to infection with specific 

viral infections.
GLAUCOMA AND OPTIC NEUROPATHIES 43

GLAUCOMA AND OPTIC NEUROPATHIES 

NEEDS, GAPS AND OPPORTUNITIES

BASIC BIOLOGY

• Define the complete genetic architecture of 

glaucoma. Glaucoma is a family of complex 

diseases with potentially many genetic and 

nongenetic factors; identifying specific genetic 

variants has been a difficult challenge. Genetics 

not only provides direct potential targets for 

therapy, it might point to novel glaucomarelated pathways. Risk alleles could be used 

to screen individuals before irreversible 

blindness develops and to help establish 

individual prognostic expectations and 

treatment responses, making a personalized 

approach to glaucoma therapy possible. 

Increasingly powerful genetic techniques, 

such as next-generation sequencing, offer the 

opportunity to identify the presumed genetic 

factors that modulate glaucoma, but have thus 

far eluded researchers. 

• Develop new cell and animal models that 

better approximate human glaucoma and 

other optic neuropathies. In particular, models 

should be developed that can be used in a 

laboratory setting, with events occurring 

over days to months, to provide a better 

understanding of the chronic injury processes 

that occur in glaucoma patients over years 

and decades. Another research gap is to find 

a model suitable for testing RGC vulnerability 

to different genetic and environmental factors. 

Another need is to develop approaches to 

predict whether therapies developed in 

animal models will translate into safe and 

efficacious treatments for humans.

• Determine the mechanisms by which risk 

factors, such as age and prior glaucomatous 

injury, influence susceptibility of remaining 

RGC axons to elevated IOP.

• Characterize pathological changes of 

RGCs caused by elevation of IOP. A better 

understanding of the condition of injured 

RGCs and axons in chronic glaucoma could 

lead to neuroprotective interventions that 

preserve these cells while their connections 

through the ONH to brain targets still exist. 

Protecting injured RGCs has fewer technical 

challenges than regenerating new RGCs and 

getting them to grow appropriate connections.

• Resolve the relative contributions to 

aqueous outflow resistance by various 

components. This entails understanding 

the molecular nature and regulation of the 

cellular cytoskeleton, extracellular matrix 

components, the endothelium in the inner wall 

of Schlemm’s canal, and uveoscleral outflow 

pathway. Combining novel molecular, genetic, 

proteomic, ultra-high resolution (sub-cellular) 

real-time optical imaging and bioengineering 

methods provide an untapped opportunity in 

this field.

• Apply molecular biology techniques to RGC 

neuroscience to dissect factors important for 

survival, axon regeneration, and physiology. 

Determine the overlap and differences 

between molecular pathways that promote 

RGC survival versus those that control 

neuronal function and axon regeneration. This 

will help answer the question of whether the 

functionality and survival of injured cells can 

be improved. While progress has been made 

in therapies that promote axon regeneration 

in the optic nerve, more research is needed 

to understand if regenerated axons lead to 

the formation of appropriate, functional 

connections in the brain. Appropriate 

connections in regenerated axons would 

need to recapitulate the topographic maps 
44 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

formed in normal development and ultimately 

lead to recovery of vision. Establish whether 

particular classes of retinal ganglion cells 

are especially capable of restoring their 

connections, and if so, identify molecular 

features, such as transcription factors or 

microRNA, that may underlie this capability. 

• Explore biomechanical responses of cell 

populations in the ONH to better understand 

the remodeling response of the ONH to 

chronic IOP elevations. Cell populations such 

as glia, lamina cribrosa cells, and scleral 

fibroblasts in the ONH control damage 

responses and remodeling in glaucoma, so it is 

important to understand their biomechanical 

responses to strain (stretch, compression, and 

shear), as well as the effect these remodeling 

responses have on axonal injury and altered 

perfusion. Biomarkers reflecting initial 

response to RGC injury may be present as 

early molecular and signaling events.

• Understand “collateral” injury to retinal 

cells (horizontal and bipolar cells) that may 

result from loss or dysfunction of RGC from 

glaucoma. Understand how these events can 

contribute to other, less well understood but 

clinically significant aspects of altered visual 

function in glaucoma, such as reduced contrast 

sensitivity and glare. 

DIAGNOSIS, IMAGING, AND 

BIOMARKERS

• Establish a consensus definition of POAG 

and standardize tools to assess its various 

phenotypes. Absence of a highly sensitive 

and specific definition of POAG remains 

a major impediment to sharing data and 

gaining further insights into genes, risk 

factors, diagnosis, and treatment. Common 

instruments and collection methods need to be 

developed to standardize disease definitions 

across various studies; improved statistical 

methods are required for determining 

progression; novel bioengineering methods 

are needed for diagnostic tools that do not rely 

solely on visual function to better characterize 

the phenotypes.

• Develop and deploy continuous monitors 

for IOP, blood pressure, and cerebrospinal 

fluid pressure (CSFp) that are reliable in 

various human body postures and positions. 

Elevated IOP is an important risk factor for 

glaucoma, but new evidence suggests ONH 

biomechanics are also influenced by CSFp and 

ocular perfusion pressure (a function of blood 

pressure and IOP). The role of variations in 

IOP needs to be better characterized over 

time; body posture can have a big impact on 

various internal fluid pressures.

• Engineer and apply new imaging methods 

and image processing techniques to study 

the aqueous outflow system and blood flow 

in the retina and the optic nerve. These 

methods will provide a better understanding 

of pathophysiology, development of 

glaucomatous damage, and response to 

treatment. Imaging the dynamic behavior 

of the iris and choroid should be assessed 

as potential biomarkers that denote risk of 

closed-angle glaucoma.

• Model the ONH and scleral biomechanics 

using experimental and computational inputs 

from genetic, molecular, proteomic, histologic, 

and imaging modalities to determine the 

cellular and extracellular architectures in 

the normal and diseased sclera and lamina 

cribrosa. Studies coupling in vivo imaging and 

biomechanics have the potential to identify 

markers for increased individual susceptibility 

to disease onset and progression.

TREATMENT STRATEGIES

• Explore neuroprotection as an approach for 

prolonging RGC function and survival. This 

involves improving our understanding of 

endogenous retinal protection mechanisms, 

identifying additional potent neuroprotective 

molecules, demonstrating their application 
GLAUCOMA AND OPTIC NEUROPATHIES 45

in animal models, and translating this 

research into clinical trials. Leveraging 

progress in other areas of neuroscience, such 

as mechanisms in other neurodegenerative 

diseases, will inform glaucoma research. 

Develop long-term drug delivery systems 

and devices to enhance diagnostics and 

therapeutics. Recent identification of 

molecular targets in the aqueous outflow 

system and RGC survival provides an 

opportunity to specifically target drugs for 

glaucoma and other optic neuropathies.

• Expand research on differentiating pluripotent 

stem cells into retinal cells (see sidebar 

page 46). Although more progress has been 

made in differentiating pluripotent cells into 

photoreceptor and RPE-like cells, creation of 

RGCs could help restore vision in glaucoma 

and other optic neuropathies.

INFLAMMATION, IMMUNOLOGY, 

AND UVEITIS

• Characterize the role of inflammation and 

immune responses in the development and 

progression of glaucomatous damage, with 

attention to the role of the complement 

system in response to RGC injury, and to the 

dual role of glial cells in supporting retinal 

cells and mediating their injury.

• Understand the interaction between 

innate and adaptive immunity in ocular 

inflammation, including molecular, 

cellular, and physiological mechanisms of 

inflammation; uveitis; and immunological 

regulation. Evaluate the role of innate 

immunity in uveitis, including the role of 

complement, toll-like receptors, macrophages, 

natural killer cells, gamma delta T cells, 

natural antibodies, and T cell subsets (e.g., 

Th17 cells, Treg cells), the role of cell adhesion 

molecules, and immune cell entry into the eye. 

Evaluate the mechanism by which immune 

privilege is lost (and restored) in the eye, 

resulting in spontaneous autoimmune uveitis. 

Identifying key immune factors will advance 

research not only on uveitis, but also glaucoma, 

AMD, DR, and dry eye.

• Identify the specific antigenic targets of the 

aberrant immune response in uveitis and 

scleritis and determine the role of antigens 

derived from apoptotic cells in disease. 

Emerging evidence supports the role of both 

genetic and environmental triggers in many 

autoimmune diseases. Compared to the 

progression in other autoimmune diseases, 

such as rheumatic diseases, understanding of 

the pathogenesis of the uveitides has lagged.

• Characterize the molecular effectors of specific 

uveitic diseases and their sequelae by gene 

expression, multiplex cytokine, and proteomic 

approaches. For example, these tools can 

help identify risk factors and pathogenic 

mechanisms leading to noninfectious 

uveitis and to its remission. Once specific 

mechanisms of uveitis are identified, the next 

step is to develop additional animal models, 

including autoinflammatory models and animal 

models of spondyloarthropathies, as well as 

animal models permitting noninvasive grading 

of inflammation and response to therapy.

• Improve diagnosis, prognosis, and treatment 

of uveitic syndromes by better identifying 

clinical phenotypes. Identify factors predictive 

of clinical response to or intolerance of 

conventional immunosuppressive drugs. 

Clarify why there is natural resolution of 

acute, but not chronic, autoimmune uveitis, 

and determine why inflammation recurs in 

some, but not all, patients. Evaluate the safety 

and comparative effectiveness of various 

treatment algorithms for autoimmune uveitis 

and its complications. Evaluate treatments 

for uveitic complications, such as macular 

edema, which is one of the most common 

causes of visual impairment in patients with 

uveitis. Identify the long-term consequences 

of chronic uveitis, which may be a life-long 

disease, and of its treatments.
46 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

Stem Cells: Divide and Conquer Blindness 

Sixteenth-century explorer Ponce de León searched far and wide but never found the legendary Fountain of Youth. 

Modern day explorers, such as developmental biologists, are beginning to harness the potential of living cells as a 

self-renewing source of life that may one day be used to regrow organs, cure disease, and counteract aging. Stem cells 

have the remarkable ability to divide and multiply over and over again, and then can be coaxed to differentiate into 

different types of cells, such as muscle, skin, and nerves. Clinical trials are underway using stem cells converted into 

RPE to treat blinding diseases such as AMD. Scientists are excited about the possibility of using human embryonic 

stem cells—known as pluripotent, meaning they have the potential to turn into every kind of cell in the body—as a 

source for replacing cells lost in degenerative diseases like AMD. A major focus of recent stem cell research has been to 

figure out protocols to convert stem cells into different cell types. Creating RPE from stem cells is a major advance, but 

creating and isolating various types of retinal neurons is an even greater challenge. An ambitious, long-term goal of 

stem cell research is to create whole organs for use in transplantation. 

One of the seminal breakthroughs in the past decade is the discovery of a new method for generating pluripotent 

cells. Fully differentiated adult cells, such as skin cells, can be induced to revert to stem cells by introducing four 

specific genes into the cells’ genome. Using these iPSCs for tissue transplantation may be particularly advantageous 

because patients will receive tissue derived from their own cells and are therefore less likely to encounter 

immunological rejection of the transplant. Also, iPSCs offer a powerful tool for studying disease. Creating stem cells 

from a patient with a disease, such as glaucoma, allows researchers to recreate and study the disease in a dish of cells 

or tissues rather than using animals or patients. Scientists can directly test the effects of potential drug therapies on 

the diseased cells, and design unique experiments to better understand the disease mechanisms. Because patients 

often react differently to various therapies, iPSC technology may eventually allow clinicians to develop personalized 

therapies that work best for individual patients, or possibly even treat the disease in the cells isolated from the 

patient, and then transplant them back to replace the diseased tissue.
GLAUCOMA AND OPTIC NEUROPATHIES 47

IMPROVING PUBLIC HEALTH

• Validate new biomarkers for early diagnosis 

and prediction of progression. Clinicians 

need tools to differentiate between small 

physiologic age-related change and small 

pathologic glaucomatous change. Biomarkers 

currently used in glaucoma trials focus on IOP 

reduction, but there is a research need for 

biomarkers of neuroprotection. Biomarkers, 

especially those related to optic nerve injury, 

would aid greatly in the design and execution 

of future cost-efficient and meaningful clinical 

trials. Investigation is needed to address 

whether such endpoints could be served by 

current technologies, including structural 

measures like retinal nerve fiber layer 

thickness, functional measures from improved 

electrophysiological testing or visual field 

interpretation, or the interplay between 

these two. 

• Find surrogates or alternatives for visual 

field testing, and to determine over time 

the correspondence to performance of daily 

activities and quality of life.

• Track glaucoma burden across the 

increasingly diversifying U.S. population. 

Glaucoma represents a significant health 

disparity for some minority groups (Hispanic/

Latino and African American populations 

have high prevalence of POAG; East Asian 

populations have a high prevalence of angle 

closure). POAG has been underdiagnosed, 

historically, and current tools used to assess 

risk in patients need to be kept in perspective 

with their recognized limitations. Up-todate epidemiology data, including diagnosis, 

monitoring, and treatment are essential in 

detecting trends that may highlight health 

disparities and inform public health officials 

on how to address these disparities.

• Establish registries and bioinformatics 

networks that integrate genetic, ocular, 

systemic, and environmental factors to 

enhance personalized medicine in ocular 

disease. Harnessing the potential of 

bioinformatics would leverage existing and 

future medical record data so that clinicians 

could select appropriate followup intervals, 

and optimize medications and dosages with 

minimal side effects with improved outcomes 

at reduced costs. 

• Assess the comparative effectiveness of 

treatments for different forms of glaucoma 

in diverse populations and communities. 

Such studies include cost-effectiveness and 

risk–benefit ratios of various diagnostic tests 

such as imaging and visual field testing, as 

well as interval assessment, particularly 

in populations at high risk of developing 

or having glaucoma (African Americans 

and Hispanics/Latinos). It is particularly 

important to determine the cost-effectiveness 

of monitoring persons with different rates 

of progression at different intervals. Closedangle glaucoma is associated with a higher 

rate of irreversible blindness than openangle glaucoma, but little is known about the 

effectiveness of various interventions for acute 

angle-closure crisis, primary angle closure, 

and closed-angle glaucoma. 

• Determine how to improve patient 

compliance with glaucoma therapy. There are 

many reasons for noncompliance, including 

cultural and economic factors. Some glaucoma 

drugs cause ocular surface discomfort, 

affecting compliance; drugs that increase 

experience of dry eye limit patient quality 

of life, despite preserving visual function. 

Studies from bioengineering approaches 

to drug delivery to social determinants of 

medication compliance are needed. Reduction 

in glaucomatous blindness depends on 

addressing causes of noncompliance.
48 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

STRABISMUS, AMBLYOPIA, 

AND VISUAL PROCESSING

Vision begins when light reaches the retina 

at the back of the eye. The light-sensitive 

photoreceptors quickly send signals to a complex 

neuronal network within the retina that processes 

photoreceptor output before sending the 

information to the brain for further processing 

that ultimately results in perception of images.

Although several areas of the brain receive, 

modify, and relay the retinal signals, the visual 

cortex ultimately processes and interprets the 

information. The visual cortex is a complex 

network of many specialized regions that process 

different aspects of an image. The largest and 

best understood area is called the primary visual 

cortex, or V1, for short. It recognizes forms and 

shapes and is connected with regions of the brain 

that control eye movements, hold long-term 

memory, and plan movements. Other areas within 

the visual cortex detect motion, color, depth, and 

place objects within the visual field. Still other 

areas analyze images to interpret meaning. And 

so, the images we see in real-time are actually 

broken down by their constituent parts and later 

reconstituted. As each second ticks by, the visual 

cortex is making millions, possibly billions, of 

calculations to produce images. Understanding 

the basic mechanisms of central visual processing 

is important for informing clinical research 

programs aimed at therapeutic interventions for 

vision disorders and other neurologic diseases 

and has a significant impact on the broader field 

of neuroscience.

The location of two eyes in the frontal position 

is advantageous because each eye offers an 

independent view of the world from a slightly 

different angle. Binocular viewing provides 

redundancy so that sight is maintained, even 

when vision is lost in one eye. The arrangement 

also allows for stereoscopic depth perception. 

Precise alignment of the two eyes is required 

for normal binocular vision of stationary and 

moving objects. Strabismus is a developmental 

or acquired condition in which the eyes are not 

aligned properly, and can result from refractive 

error, disorders of ocular muscles and their 

innervation, or central neural mechanisms 

that provide oculomotor control signals. Shortterm ocular misalignment results in blurred or 

double vision. Chronic misalignment can induce 

amblyopia, a condition in which the brain ignores 

signals from one eye as an adaptive mechanism. 

Amblyopia can also occur bilaterally and may 

be the result of cataracts, corneal scars, or from 

refractive error in either or both eyes. Anomalies 

of ocular growth and development influence 

the optical properties of the eye and contribute 

to refractive errors. Although refractive errors 

are often correctable with spectacles, contact 

lenses, or corneal refractive surgery (see Corneal 

Diseases report), understanding the development 

of refractive error may lead to prevention or new 

treatment strategies. 
STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING 49

STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING

HIGHLIGHTS OF RECENT PROGRESS

VISUAL SYSTEM CIRCUITRY

Significant advances in technology and 

analytical approaches have greatly improved 

our understanding of how visual information 

is processed by individual neurons, local 

circuits, and larger networks within the CNS. 

The high spatial and temporal resolution of 

two-photon calcium imaging allows real-time 

monitoring of activity in many cells, which has 

significantly advanced our knowledge of the 

interactions among neurons within local circuits. 

Improvements in multiple microelectrode and 

multiple-site recording technology, and the 

development of advanced decoding algorithms 

provide a new understanding of how visual 

information is contained in the activity of large 

and distributed populations of neurons. 

Studying populations and networks of 

neurons provides a better understanding of 

how multiple areas of the brain interact to 

produce visual perceptions and visually guided 

motor and oculomotor responses. Multivariate 

pattern analysis, computational modeling, 

and methods for combining electrophysiology, 

functional imaging, and psychophysical measures 

of behavior have yielded a more mechanistic 

understanding of vision. Brain–computer 

interfaces have been developed for electrical 

stimulation of neural tissue in those deprived 

of vision, and are used to produce higher-order 

signals in the visual system for the control of 

assistive devices for individuals lacking control of 

their limbs.

MULTISENSORY INTEGRATION AND 

HIGHER-ORDER FUNCTIONS

There is a high degree of homology between 

the human and nonhuman primate visual 

systems, and studies in both have led to a 

better mechanistic understanding of visual 

function. Studies using functional brain imaging 

in humans and the combination of functional 

imaging and single-unit recording in nonhuman primates have identified specific cortical 

areas that are specialized for a variety of visual 

functions, including the recognition of faces. 

These discoveries are complemented by the 

development of Bayesian models and decoding 

algorithms that have aided our understanding 

of the representation of visual information 

at the neural and behavioral levels. A better 

understanding of the perception of faces and 

recognition of objects is the result of studies in 

multiple areas of the brain, from the occipital 

to frontal cortex. Advances in this field provide 

important insights into neurodegenerative 

diseases and developmental disorders such as 

prosopagnosia, the inability to recognize faces, in 

which these perceptual functions are impaired. 

Human and animal studies have also 

demonstrated a number of multimodal cortical 

areas where visuospatial, vestibular, and eye 

position information are integrated along with 

information from other senses to produce a 

representation of where one is in relation to one’s 

surroundings and signals for navigating within 

that environment. This information provides a 

framework for understanding spatial perception 

and deficits like those observed in spatial neglect 

syndromes. Neural correlates have also been 

identified for abstract visual concepts such as 

object category and numerosity.
50 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

A better understanding of selective attention, 

decision making, and the sensory-motor interface 

for the control of reaching and eye movements 

is another result of the coupling of human and 

animal experiments. Electrophysiological and 

imaging methods used in conjunction with 

behavioral approaches relying on eye movements 

and psychophysical measures provide detailed 

knowledge of the neural circuits involved with 

these processes. Knowledge of how attention 

influences visual perception can now be 

described in terms of altered discharge rates of 

single cortical neurons. Theoretical formulations 

have evolved into testable models for the neural 

mechanisms of selective attention and how it is 

modulated by sensory and cognitive influences.

DEVELOPMENT AND PLASTICITY

New discoveries have significantly advanced 

our understanding of the development of visual 

system pathways. Genes that regulate the growth 

and development of neurons throughout the 

visual system have been identified, as well as 

important molecules that guide developing 

axons toward their synaptic targets. Our 

understanding of the role of neural activity and 

its synchronization in pathway formation has also 

progressed, along with new knowledge about 

the cellular events that accompany the formation 

and maintenance of synaptic connections during 

development. Advances have been made in 

understanding cellular mechanisms of plasticity, 

Children’s Time Outdoors May Reduce Myopia

We do not know what causes some people to need glasses or contact 

lenses. Certainly genetics plays a role, but we are now learning that 

environmental factors may come into play, as well. For example, 

spending time in bright outdoor light appears to be important for 

normal eye development. Focusing on objects close at hand, such 

as reading books, was thought to be a factor in developing myopia 

(nearsightedness), but recent studies show that spending long hours 

reading does not necessarily cause myopia. Children who play indoor 

sports do not receive the visual benefits seen in children who play 

sports outdoors, so exercise by itself does not seem to be the key. 

The most important environmental factor appears to be time spent 

outdoors. Researchers are now trying to learn how this works, as well 

as other possible risk factors for myopia.

Myopia is a common type of refractive error where close objects are in focus, but distant objects appear blurry. The 

prevalence of myopia is increasing in the U.S. population, as researchers from NEI found by analyzing data from the 

National Health and Nutrition Examination Survey. In 1972, approximately 25 percent of the U.S. population, 12–54 years 

of age, were nearsighted, compared to 42 percent 30 years later1

. Vision researchers are studying both environmental 

and genetic factors that might explain the increase.

Nearsighted parents are more likely to have nearsighted children, and several genes have been associated with myopia. 

However, children with a family history of nearsightedness might not necessarily be destined to a myopic future. 

Research shows that when children spend more time outside, the likelihood of becoming nearsighted decreases 

significantly, even if both parents are nearsighted. 

1 Vitale et al. (2009). Arch Ophthalmol.127(12), 1632-1639.
STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING 51

including knowledge of events leading to the critical 

period. The understanding of plasticity in adults 

is the result of new experimental paradigms and 

models of perceptual learning. These studies have 

important implications for clinical rehabilitation for 

a variety of visual system disorders.

EYE MOVEMENTS

New discoveries have shed light on how eye 

muscles are structured and controlled in health and 

disease. Each eye muscle has its own pulley-like 

structure that plays a role in precisely aligning and 

moving the eyes toward visual targets. Eye muscles 

have anatomical compartments with specialized 

patterns of innervation that may be targeted 

differentially by disease processes. A newly 

described signal from eye muscles provides the 

brain with information about current eye position 

that is important for directing the gaze to the 

objects of interest. Eye muscles have a complement 

of genes and proteins that differ from normal 

skeletal muscle, which may explain why some 

diseases target eye muscles preferentially, whereas 

other muscle disorders spare the oculomotor 

system. These new discoveries regarding the 

control of eye muscles and their unique properties 

provide avenues for the creation of novel 

treatments for infantile and acquired disorders that 

can affect the accuracy of eye movements and the 

ability to maintain stable gaze.

CLINICAL ADVANCES

Studies in large numbers of patients have 

revealed the genetic basis of some forms of 

strabismus and regions of chromosomes that are 

important in the development and progression of 

myopia. New discoveries demonstrate how genes 

and the visual environment interact to influence 

the development and progression of refractive 

error. These studies show that spending more 

time outdoors significantly lowers the chances 

of children becoming myopic (see sidebar page 

50). Animal experiments also indicate that higher 

ambient light levels such as those that occur 

outdoors alter eye growth signals and have a strong 

protective influence, slowing myopia development. 

Recent work in both animals and humans indicates 

that these growth signals can come from the entire 

retina and not just the central portion. These 

discoveries are stimulating new approaches in 

myopia treatment, from changing children’s visual 

environment to sophisticated optical design in 

glasses or contact lenses that optimizes focus for 

the entire eye.

New treatments show promise for the 

treatment of amblyopia, the loss of vision in one 

eye that often results from strabismus or severe 

defocus during early childhood. Clinical trials 

demonstrate that atropine eye drop therapy has 

advantages over patching the dominant eye in 

some situations. Advanced behavioral methods 

using perceptual learning have also been shown to 

improve vision in these patients, even at ages that 

are beyond the critical period in development. 

EMERGING TECHNOLOGY

Optogenetics is a newly developed technology 

that allows for targeted neuronal populations to be 

activated or inhibited by the presentation of light. 

Genetic methods are used to insert light-sensitive 

ion channels into specifically targeted cells. This 

provides a method of cellular control not possible 

with existing microelectrode technology. The 

method has been applied to tissue slices and whole 

animal models and offers a significant new advance 

for the field of visual prostheses as well as an 

important research tool for dissecting the functions 

of retinal and central neural circuits.
52 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING

NEEDS, GAPS AND OPPORTUNITIES

VISUAL SYSTEM CIRCUITRY

• Improve understanding of the roles of 

neuronal activity and molecular events in the 

formation of central visual circuits during 

development. Investigate mechanisms of 

degeneration and regeneration within the 

central visual pathways and the neural basis 

for changes in plasticity with age.

• Further develop genetic and optogenetic 

techniques, computational approaches, and 

advanced decoding algorithms for discovering 

the anatomical and functional properties of 

neural circuitry and the functions of individual 

cell types within complex circuits. Many 

genetic diseases have been shown to affect 

the function of subsets of neurons or glia and 

thereby affect circuit function.

VISUAL PROCESSING AND 

HIGHER-ORDER FUNCTIONS

• Improve multielectrode and multisite 

stimulation and recording methods to 

study the encoding of visual information in 

populations of cells and how these signals are 

transformed into those that underlie visual 

perception and guide behavior. 

• Develop and improve neural imaging 

technology and methods for combining 

imaging and electrophysiological data in order 

to improve spatial and temporal resolution 

in human studies and provide direct links 

to data from animal models. Capitalize on 

human and monkey homologies to understand 

mechanisms of spatial perception, object 

recognition, and visual memory, and to address 

disorders of visual attention and cognition.

• Continue development of psychophysical 

approaches and computational methods in 

order to gain a better understanding of visual 

perception and visually guided behaviors.

MECHANISMS OF EYE GROWTH, 

MOVEMENT, AND ALIGNMENT

• Expand knowledge about refractive error 

by identifying associated genes and how 

they interact with each other and with 

environmental factors to influence the 

cascade of events involved in the regulation 

of eye growth. 

• Discover the mechanisms responsible for 

perceptual and motor stability during eye 

movements and develop strategies for using 

visual and oculomotor methods for diagnosing 

and treating visual symptoms associated with 

neurological disorders, mental diseases, and 

traumatic brain injuries. 

• Determine the mechanisms responsible 

for the occurrence of strabismus. Identify 

the genes associated with strabismus and 

elucidate their function. Understand the 
STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING 53

role of visual suppression, accommodation, 

extraocular muscle function, and sensory 

feedback about eye position in strabismus. 

Identify brain regions and circuits that are 

critical for ocular fusion and explain why they 

function abnormally in strabismus.

CLINICAL RESEARCH

• Develop and test pharmacological and 

behavioral methods for induction and 

improvement of plasticity in adults. 

Translate the basic science of plasticity 

into effective treatments for strabismus, 

amblyopia, and other disorders involving 

central visual processes.

• Develop and implement biological solutions 

and prosthetic devices for stabilizing and 

restoring visual function. Develop brain–

machine interfaces using central neural 

signals to control assistive devices. 

• Analyze vision manifestations of 

neurocognitive disorders. Many neurological 

disorders are known to have visual correlates. 

In autism, for instance, doctors report a 

weak central coherence in vision manifesting 

as a reduced influence of spatial context—

when tested with visuospatial tasks, autistic 

individuals tend to perceive constituent 

parts instead of a coherent object. These 

manifestations provide clues about the 

general nature of information processing 

disorders that characterize a neurological 

condition. However, sensory dysfunction is 

often considered a peripheral aspect of these 

conditions. Visual assessment of such patients 

serves as a gateway to understanding how the 

disorder affects brain function more generally.

IMPROVING PUBLIC HEALTH

• Evaluate the efficacy of potential treatments 

for delaying the onset or for slowing the 

progression of myopia, such as lenses that 

alter peripheral defocus, pharmaceutical 

approaches, or behavioral methods that 

harness the beneficial effects of more 

time outdoors.

• Improve screening tests to identify children 

affected by amblyopia or strabismus at 

an early age and develop more effective 

treatments to improve ocular alignment and 

to restore normal vision.

• Study the impact of vision disorders on 

attention, reading performance, and learning, 

particularly in school-age children.
54 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

LOW VISION AND 

BLINDNESS REHABILITATION

Low vision is an impairment to vision that 

hampers one’s ability to function in daily life. Low 

vision is not correctable with medical or surgical 

therapies, spectacles, or contact lenses. Although 

low vision most often includes loss of sharpness 

or acuity, there may also be reduced field of 

vision, abnormal light sensitivity, distorted vision, 

or loss of contrast.

Visual impairment can range from mild to 

severe, including total blindness or functional 

blindness where no useful vision remains. 

Although important advances have been made 

in treating and preventing eye diseases and 

disorders that cause visual impairment, many 

remain incurable. According to WHO, about 314 

million people are visually impaired worldwide, 

of which 45 million are blind.5

 Conservative 

estimates suggest that there are at least 3.6 

million Americans who are visually impaired of 

which more than 1 million are legally blind.6

Low vision may occur as a result of birth 

defects, injury, aging, or as a complication of 

disease. More than two-thirds of people with 

visual impairment are older than 65 years of 

age, where the leading causes are age-related 

macular degeneration, glaucoma, diabetic 

retinopathy, cataract, and optic nerve atrophy. 

Visual impairment in the elderly decreases 

independence, increases the risk of falls and 

fractures, and often leads to isolation and 

depression. Visual impairments also affect 

infants and children, due to conditions such as 

retinopathy of prematurity, deficits in the visual 

centers of the brain, juvenile cataract, and retinal 

abnormalities. These conditions can severely 

5 WHO. (2010). Action plan for the prevention of avoidable 

blindness and visual impairment 2009–2013. Geneva. 6 Prevent Blindness America and NEI. (2008). Vision 

problems in the U.S.: Prevalence of adult vision impairment 

and age-related eye disease in America. Bethesda, MD.

impair a child’s quality of life and can have major 

consequences on educational advancement and 

future opportunities for employment.

Visual impairment treatment and 

rehabilitation is an important component of visual 

health care in the United States. Ophthalmologists 

and optometrists who specialize in low vision 

may choose from an assortment of specialized 

eyewear, filters, magnifiers, adaptive equipment, 

closed-circuit television systems, independent 

living aids, and may offer training and counseling 

to patients. Although assistive devices and 

services do not cure visual disorders, research 

in this field leads to improved devices and new 

approaches designed to enhance the quality of life 

for millions of visually impaired individuals.
LOW VISION AND BLINDNESS REHABILITATION 55

LOW VISION AND BLINDNESS REHABILITATION

HIGHLIGHTS OF RECENT PROGRESS

ASSISTIVE TECHNOLOGY

Because most content on the Internet is 

displayed visually, several new applications 

are geared to interpret this content for visually 

impaired users such as dynamic pin displays for 

online Braille and tactile graphics. Recent advances 

in computing power and image-processing 

have revolutionized applications for the visually 

impaired. Screen-magnifying and screen-reading 

software are widely deployed so that computers 

and smartphones are now accessible to low-vision 

and blind users, without the need for costly 

third-party software accessories.

The latest generation of smartphones has 

stimulated development of innovative products to 

aid the visually impaired. These include flexible 

image magnifiers, mobile optical character 

recognition, bar code readers, and indoor 

wayfinding aids. In the past five years, research 

and development of global positioning systembased navigation aids for visually impaired people 

has refined commercially available products.

BEHAVIORAL AND NEUROSCIENCE 

BASIC RESEARCH

When we move around our environment, 

in our mind’s eye, we construct a picture of 

the world around us. This picture, or cognitive 

map, is attributed to a neural network thought 

to be located in the medial temporal brain area. 

The parietal area of the brain is closely tied to 

accrual of perceptual information. The interaction 

between the parietal and temporal regions may 

explain how ongoing perceptual input leads to the 

formation of cognitive maps and has implications 

for understanding how visually impaired 

individuals learn different strategies for orienting 

and navigating. 

Following pathological insult to retina or 

brain, perceptual training techniques have been 

examined using videogames. Behavioral studies 

have demonstrated that extensive practice can 

improve visual sensitivity. Infants with congenital 

cataracts or other treatable eye conditions 

experience visual deprivation during a period 

of robust visual development. Studies of these 

children are finding that once vision is restored, 

substantial functional and organizational changes 

in the visual cortex occur; whether the same holds 

true later in life is an actively debated topic. This 

neuroplasticity can now be studied noninvasively 

with functional magnetic resonance imaging. 

These findings regarding plasticity hold promise 

for informing vision rehabilitation efforts (see 

sidebar page 35).

Different areas of the brain respond to 

different types of perceptual stimuli (vision, 

touch, sound). Perception depends on integrating 

this multisensory information. Research shows 

that normally sighted, as well as visually impaired 

individuals recruit the visual cortex when 

interpreting tactile or auditory information. The 

functional roles of such cross-modal activations 

are not well understood, but are hot topics of 

current research and may provide the neural 

basis for sensory substitution, where perceptual 

processing for one sensory modality is largely 

replaced for another. 

IMPLICATIONS OF VISION LOSS 

With an increased understanding of the 

interdependence of physical and mental health, 

vision loss has been shown to be an independent 

predictor of depression. Depression (both 

major depressive disorders and subthreshold 

depression) affects roughly one-third of older 

adults with vision loss, which is similar to rates 
56 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

found among medically ill populations and those 

with other chronic conditions. In the visually 

impaired, depression further exacerbates 

functional disability in everyday activities. 

Thus, visual impairment has been found to have 

widespread negative effects on quality 

of life, and psychological and social well-being.

QUALITY OF LIFE

Quality-of-life issues are gaining 

increased attention in vision impairment and 

rehabilitation research. With the development 

of standardized metrics (e.g., NEI Visual 

Functioning Questionnaire), quality-of-life 

measurements complement objective measures 

of visual function. Furthermore, there is a 

growing recognition that quality of life is a 

multidimensional concept that includes financial 

status, employment, physical and mental health, 

social relationships, and recreation and leisure 

time activities.

ACTIVITIES OF DAILY LIVING

Research on activities of daily living includes 

reading, mobility, and orientation in lab 

settings and real-world environments. Recent 

research has focused on the complicated visual 

environment encountered in the real world to 

appreciate how normally sighted and visually 

impaired individuals process a visually rich 

New Mobile Assistive Technologies

For visually impaired individuals, smart phone applications, commonly known as “apps,” are emerging as important 

tools for everyday functioning and independence. NEI-funded researchers are developing apps to assist individuals to 

maneuver around obstacles, read, and recognize faces and objects. For example, researchers are developing products 

that will allow the visually impaired to use smart phone cameras for identifying packaged food content and prices 

at the grocery store by scanning the barcodes on the package labels. Another app scans money to determine bill 

denominations, which provides confidence to the user for transactions at the cash register. Several assistive devices 

also are under development for the home or the workplace. For example, researchers are developing an app that 

immediately converts an image of the clock on a microwave oven or the temperature setting on a thermostat into an 

audio report on the phone’s speaker. Indoor wayfinding systems use scannable signs or other locators so that the visually 

impaired can navigate unfamiliar locations. 

For outdoor navigation, researchers are developing apps to capture images of 

intersections and analyze them to identify crosswalks, curbs, and the status of 

“Walk/Don’t Walk” signs in real-time. Others are creating services that provide 

subscribers with on-demand assistance, where a caller describes a situation or 

snaps a picture of an item, and an offsite assistant immediately calls back and 

describes the scene or item to the subscriber. The latest mobile technologies have 

opened up seemingly unlimited possibilities for assisting the visually impaired, and 

NEI remains committed to supporting the development of these and other cuttingedge technologies.
LOW VISION AND BLINDNESS REHABILITATION 57

environment. Extensive work relating reading 

to basic processes in visual perception (e.g., 

eye movement behavior during visual search) 

in sighted and visually impaired subjects has 

provided a solid theoretical foundation for 

developing improved rehabilitation regimens.

There has been significant progress in 

understanding visually guided behavior in natural 

settings. Using wavelet-based sensors to capture 

basic sensory information akin to a crude visual 

system, researchers are able to model which 

visual cues are needed to help individuals orient 

themselves in a complicated environment. In 

addition, real-world studies that elucidate the 

challenges that the visually impaired experience 

in complex public transportation environments, 

and evaluate technologies that enhance safe and 

efficient street crossings in demanding urban 

environments, have provided important data.

The development of objective measures of 

abilities to function in daily life have added to 

our understanding of the capacity for function, 

and adds dimensions to research beyond selfreporting of difficulties with function. 

SIGHT-RECOVERY PROCEDURES

An impressive array of sight-recovery 

procedures are being studied in clinical trials, 

including retinal prostheses, gene therapy, and 

stem cell transplants. There are also global 

health initiatives increasing access of established 

therapies, such as cataract surgery or corrective 

lenses, to communities in developing countries 

that would otherwise remain visually impaired. 

There is an opportunity to study the behavioral 

and psychosocial impact of site recovery as 

well as implications for rehabilitation and 

neurodevelopment. 
58 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

LOW VISION AND BLINDNESS REHABILITATION

NEEDS, GAPS AND OPPORTUNITIES

UNDERSTANDING VISUAL 

IMPAIRMENT

• Investigate multisensory processes and 

cross-modal plasticity. Determine whether 

cross-modal plasticity associated with visual 

deprivation differs from normal multisensory 

interactions. Determine the organizing 

principles and limits that exist for crossmodal plasticity. Determine the informational 

requirements of a task that affect whether a 

remaining sensory modality (e.g., touch) can 

substitute for the absence of sight. Further 

research using neural network approaches, 

behavioral, and neuropsychological methods 

are necessary to inform effective sensory 

substitution and improve rehabilitation efforts.

• Characterize variation in spatial cognition, 

important for many tasks such as navigation. 

Spatial cognitive abilities vary widely. 

Normally sighted individuals with poor spatial 

cognition may be able to compensate through 

parallel processing using visual areas of the 

brain as well as perspective-free cognitive 

maps. In severe visual impairment, such 

compensation is limited or impossible, so 

the consequences of poor spatial cognition 

(whether innate or through lack of spatial 

cognitive experience) could be much more 

profound for the visually impaired than for the 

normally sighted. 

• Determine spatial cognitive abilities of visually 

impaired individuals to determine the extent 

to which nonvisual cues contribute to spatial 

cognition and how the contribution of 

nonvisual cues can be enhanced to improve 

spatial cognition under conditions of 

visual impairment.

• Understand the use of multisensory spatial 

representations, or cognitive maps, in learning 

strategies and whether learning strategies 

change with cross-modal plasticity. Does 

visual impairment result in fundamentally 

different learning strategies and does this 

differ by age?

SCREENING AND TESTING 

• Design and validate tests of visual perception. 

Early detection of visual deficits will improve 

outcomes, but such tests can be used to 

benchmark outcomes of rehabilitative 

treatments. Sensitive, efficient testing is 

important to refine rehabilitation therapies 

and reduce burden on patients and clinicians.

• Create and validate vision tests relevant for 

the tasks of daily living. Eye charts that test 

letter acuity are not sufficient to characterize 

functional vision for people with visual 

impairment. Eye charts of high-contrast 

patterns are not useful or predictive for a 

majority of the visual tasks of daily living, 

which involve dynamic inputs of objects and 

scenes with varying color and contrast. 

• Develop and standardize tests for evaluating 

more complex visually intensive behavior, 

such as reading, face recognition, mobility, 

and driving. Such tests will be useful in 

determining disability and progress toward 

rehabilitative goals. 

• Develop testing specific to various patient 

populations. Nonverbal methods for testing 

vision (e.g., visual fields, retinal function) in 

special populations (children, neurological 

patients) are an important, yet unaddressed, 

area. In addition, developmental testing of 

visually impaired children, particularly pre- or

nonverbal children, is limited, as current tests 

require vision to accomplish some or many 

of the tasks (e.g., stack blocks; match figures). 
LOW VISION AND BLINDNESS REHABILITATION 59

Even motor milestones are affected by vision 

impairment, but details of how this occurs 

are unknown, and standards for normal 

development for visually impaired children 

are unknown.

ASSISTIVE DEVICE TECHNOLOGY

• Develop new technology to improve access to 

Internet, print, graphic display, and navigation 

resources. Some areas require specialized 

technology innovation (such as online Braille 

and tactile graphics, specialized embossers, 

and Braille software), but there are also 

opportunities for developing new assistive 

devices and products by modifying devices 

such as mobile phones, global-positioning 

system, accelerometers, and speech engines. 

Success in the visually impaired community 

depends on optimizing format and delivery 

methods, particularly for elderly, cognitively 

impaired, or technologically naïve individuals.

• Use models of eccentric vision (using 

peripheral retina when central field is 

dysfunctional) to translate technology 

developed for sighted users to visually 

impaired users. Additionally, basic science on 

navigation, limited vision use, and multimodal 

perception can inform new assistive device 

development. For instance, a fundamental 

question concerns the limits of sensory 

substitution: Conveying visual information 

via auditory and tactile means has proven 

difficult. Normally, visual recognition of an 

embossed line drawing is trivial, but using 

either auditory or tactile means is challenging. 

Even when sensory substitution succeeds, 

only fairly simple visual information can 

be conveyed via these other modalities. A 

better understanding of the key aspects of 

visual information that are difficult to convey 

via other modalities could clearly inform 

the development of assistive technologies. 

Furthermore, studies of the effectiveness of 

these technologies are needed.

VISUAL PROSTHESES 

• Determine critical parameters for continued 

improvement of prostheses. The visual 

prostheses are now being tested in patients. 

Different approaches include obtaining 

visual information (detected by a camera) to 

electrically stimulate the visual system (retina, 

or the visual cortex) (see sidebar page 60). 

Another relies on sensory substitution (e.g., 

encoding visual information into sensations 

on the tongue). In using a prosthesis, certain 

questions need to be resolved, for example, 

given a person’s state of vision and what tasks 

can be done. If synchrony between modalities 

is required, how is one modality affected when 

the other input is degraded?

• Understand the level of acceptable visual 

enhancement using prosthetics. This can be 

determined using models of low vision, such 

as low-quality images, to determine how 

much information is necessary for particular 

visual tasks. ‘Low-quality’ indicates lowresolution, reduced fields, poor color contrast 

and, more generally, any other image quality 

decrement that can be associated with low 

vision. Although normally sighted humans 

use high visual acuity to perform tasks such 

as face recognition, experiments with highly 

degraded images suggest that many of these 

skills are exceptionally robust in spite of 

acuity reductions. Such results could inform 

prosthesis design engineering and serve 

as feasibility criteria—if a planned neural 
60 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

prosthesis can only offer a low-resolution 

image, is it worth implantation? What kinds of 

visual abilities will it be able to support?

REHABILITATION 

AND IMPROVING PUBLIC HEALTH

• Define heterogeneity of visually impaired 

populations. Within the legally blind/low 

vision population, there is heterogeneity 

with respect to visual function, even within 

a particular disease group. Advanced age is 

an important variable, ultimately affecting 

vision in almost all adults. Visual disorders 

are also associated with concussion and 

neurocognitive disorders that are not well 

understood. Studying how behavior and 

neural processing are altered and differ 

across the spectrum of visual impairment will 

improve our understanding of the sources 

of the heterogeneity and in personalizing 

rehabilitative efforts. 

• Understand the causes and consequences of 

cortical reorganization in the blind. Several 

studies have demonstrated that blindness 

causes visual areas to respond to auditory 

Retinal Implants for Vision Restoration

While working to prevent blindness and to restore natural vision, NEI also 

supports development of retinal prostheses, also known as retinal implants. 

Second Sight Medical Products, Inc., supported in part by NEI and by the U.S. 

Department of Energy, has engineered the Argus II Retinal Prosthesis System, 

which provides limited sight to people blinded by retinitis pigmentosa (RP), 

a genetic eye disease that causes gradual loss of the retina’s light-sensing 

photoreceptor cells. Argus II consists of a video camera mounted on a pair 

of glasses, which captures and wirelessly transmits electrical signals through 

a 60-electrode grid surgically attached to the retina. The array bypasses the 

diseased photoreceptor machinery and directly activates the retinal ganglion cells that bring visual information 

to the brain. 

A clinical trial that included 30 RP patients equipped with the Argus II system showed that not only did the device 

not hinder performance of participants with residual vision, it improved participants’ ability to identify shapes, detect 

motion, locate objects, walk along a white line, and in the best cases, read large letters. Although tested in RP patients, 

Argus II may be suitable for other conditions that damage the photoreceptors but leave the eye’s neural networks 

intact, including AMD. Second Sight is currently developing a newer version of the device that uses a 256-electrode 

array that promises greater visual resolution. In 2011, Argus II became the 8 millionth patent issued by the U.S. Patent 

Office and it is now on the market in Europe.

Other NEI-funded projects use complementary technologies. The Boston Retinal Implant Project is developing a 

device with external parts small enough to fit on the sclera—the outer wall of the eye. Another prosthetic device 

captures images with a video camera and then converts them into pulsed near-infrared light. Special glasses worn 

by the user project the near-infrared light through the eye and onto photodiodes implanted beneath the retina, 

which then convert the light into electrical signals that stimulate optic neurons. NEI-funded researchers are working 

to overcome technical barriers to retinal prostheses. They are adapting new nanotechnology to visual prostheses, 

expanding knowledge of how devices interact with neurons, and developing neurotransmitter-based prostheses. 
LOW VISION AND BLINDNESS REHABILITATION 61

and tactile stimuli. However, the behavioral 

consequences of the plasticity are not yet 

clear. Determine if rehabilitative processes 

can improve functional plasticity. Determine 

whether such reorganization affects 

visual learning if sight is restored. Recent 

studies on establishing sight in previously 

blind individuals provide opportunities to 

investigate neuroplasticity and how the brain 

adapts to new visual input (anatomically 

and functionally). Determining which visual 

skills can be acquired, as well as how these 

changes correlate with age and extent of 

visual deprivation, will inform the prospects 

for recovery.

• Develop and test rehabilitation models 

and training paradigms. Low vision and 

blindness rehabilitation models continue to 

evolve. Interventions that are multimodal, 

multidisciplinary, and address functional and 

emotional aspects uniquely related to low 

vision, blindness, loss of vision, and vision 

restoration hold particular promise. These 

include findings from basic psychophysical 

research (e.g., training visual skills to develop 

a preferred retinal locus in central vision loss 

or for the use of a visual prosthetic), research 

on psychosocial implications of vision 

impairment (e.g., the mechanisms by which 

visual impairment leads to reduced quality 

of life), and developing training for 

prevention and adaptation strategies 

(e.g., lifestyle changes).

• Create and standardize performance-based 

outcome assessments as well as quality-of-life 

or other self-reported measures for low-vision 

interventions, whether they are prosthetic 

devices, assistive devices, or multidisciplinary 

rehabilitative strategies. 

• Compare the effectiveness of rehabilitation 

approaches using randomized, controlled 

clinical trials. Rehabilitation currently 

lacks standardized methods and outcome 

assessments. Agreement on protocol and 

instrumentation will enable large-scale, 

multisite clinical trials.

• Identify comorbidities that interact with 

vision impairment and their influence on 

rehabilitation outcomes, and integrate 

visual rehabilitation models into subacute 

rehabilitation inpatient units. Poor vision 

hampers rehabilitation in a variety of agerelated conditions (e.g., stroke, falls, hip 

fracture). Specialized rehabilitation needs 

for the visually impaired as they age (e.g., 

arthritis for life-long cane users), as well as for 

individuals with age-related vision loss, are 

not understood. Needs can vary depending on 

environment (e.g., nursing home residents) 

and comorbidities (e.g., wheelchair user; 

hearing-impaired individuals).
62 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

APPENDICES
APPENDIX 1 63

APPENDIX 1:

FRAMEWORK FOR VISION RESEARCH

Biomedical research is a highly specialized endeavor. Fundamental, overarching core principles 

drive the pursuit to understand, treat, and prevent ocular disease. A deep knowledge of the underlying 

biology of vision is critical to understand and treat the pathological mechanisms of visual disorders and 

diseases. In addition, an appreciation for the interaction of host factors with environmental factors from 

the cellular to the population level is needed to fully treat and prevent vision loss. The following provides 

a framework for considering these fundamental properties and core principles in the context of eye and 

vision research. 

The framework was provided to each of the program panels as a reference to help the panel members 

focus on the needs and opportunities of their specific programs rather than the global concepts described 

here. New general concepts that arise from planning activities may yield important information that 

could help further shape the framework in the future.

I. GATHER COMPREHENSIVE KNOWLEDGE OF THE MOLECULAR BASIS OF OCULAR HEALTH AND 

DISEASE, AND USE THAT KNOWLEDGE TO IMPROVE DIAGNOSIS, TREATMENT, AND PREVENTION OF 

EYE DISEASE

a. Develop a detailed, comprehensive understanding of the molecular, cellular, and physiological 

mechanisms that promote and maintain ocular health. 

b. Identify key signaling and transcriptional pathways in normal and pathological states.

c. Determine key genetic and epigenetic variants that prevent or cause Mendelian as well as complex 

ocular diseases.

d. Characterize the changes in molecular processes affected by nutritional, behavioral, and other 

environmental factors that impact ocular health and disease.

e. Understand the regulation of cellular oxidation, energetics, and mitochondrial function in 

maintaining healthy ocular tissues.

f. Develop a better understanding of protein–protein interactions, regulation of protein folding, and 

diseases that result from mis-folded proteins.

g. Develop the ability to specifically modulate molecular pathways, systems, and intracellular 

complexes to treat and cure ocular injury and disease.

h. Develop tools (e.g., genomic markers, gene and/or protein expression profiles, and other new 

measurable indicators) to assess an individual’s risk for particular ocular disorders. 

II. UNDERSTAND THE SYSTEMS BIOLOGY UNDERLYING VISUAL FUNCTION

a. Determine the role of inflammation, immunity, infection, blood pressure, circadian rhythms, and 

other systemic processes in complex eye diseases.

b. Understand the integration of structural, vascular, and neural processes that constitute the unique 

physiology of the ocular system. 

c. Understand visual processing in normal and pathological states.

d. Characterize the developmental stages of the visual system from its precursor cells.
64 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

e. Gain a deep understanding of the physiology of aging. Understand the contribution of the aging 

process to adult onset disease. 

f. Develop models to understand cellular pathways, systems, and interactions of systems in healthy 

and pathological ocular tissues.

III. ACCELERATE THE TRANSLATION OF BASIC RESEARCH INTO CLINICAL STUDIES 

a. Develop, refine, and set standards for new technologies (e.g., molecular imaging, telemedicine, 

small molecules) for clinical research and clinical trial application. 

b. Develop and validate biomarkers that are useful in diagnosing and stratifying patients, measuring 

disease progression, and gauging therapeutic outcomes. 

c. Foster multidisciplinary teams to develop new ocular diagnostic and therapeutic approaches (e.g., 

nanotechnology, prosthetics, cell-based therapies, molecular engineering, and synthetic biology). 

d. Develop appropriate animal models and cell cultures to study disease mechanisms and evaluate 

investigational therapies.

e. Develop and evaluate assays and high-throughput screens to further vision research and 

clinical application.

f. Improve gene delivery techniques that yield precise targeting and regulation of gene expression.

g. Integrate advances in regenerative medicine and tailor them to develop clinical applications in 

specific ocular tissues.

h. Develop new targeted therapies and combine them as appropriate to maximize treatment response. 

i. Make research tools widely available, including easy access to novel compounds, reagents, animal 

models, cell lines, etc.

j. Develop an infrastructure and distribute strategies for the collection and rapid dissemination of 

genomic, proteomic, and other molecular library data to the vision research community. 

IV. USE CLINICAL, EPIDEMIOLOGICAL, AND STATISTICAL TOOLS TO IDENTIFY POPULATIONS AT RISK 

OF BLINDING EYE DISEASES AND VISUAL DISORDERS, TO EVALUATE NEW THERAPEUTICS, AND TO 

IMPROVE FUNCTIONAL CONSEQUENCES OF VISUAL LOSS 

a. Develop strategies and/or infrastructure to foster early, well-designed pilot clinical trials to rapidly 

assess the potential of translational therapies or candidate predictive markers.

b. Conduct clinical trials for improved prevention and treatment strategies for ocular diseases 

and disorders. 

c. Improve the understanding of the burden of eye diseases and their visual outcomes at the societal 

and individual level through epidemiological and social sciences research. Identify population 

disparities and use these data to inform and enhance translational and clinical trials. 

d. Develop and apply new methodologies for epidemiological research and strategies for the 

screening and detection of visual disorders.

e. Apply epidemiological methods and clinical trial interventions to blinding global eye diseases. 
APPENDIX 1 65

V: STRENGTHEN CLINICAL RESEARCH OF VISUAL DISORDERS

a. Utilize developments in biotechnology and genomics to prioritize the testing of important 

molecular targets.

b. Develop new disease classification schemes and predictive models that incorporate genetic and 

molecular profiling.

c. Develop strategies and infrastructure to enable and encourage patients with ocular conditions to 

participate in clinical trials with special emphasis on recruiting minority populations. 

d. Develop improved methods of clinical trial design that provide the capacity to evaluate therapeutic 

agents among patient subpopulations. 

e. Develop strategies to improve efficiency in the clinical research enterprise such as common data 

elements, harmonized electronic data-capture systems, standardized training, and coordinated 

specimen management.

f. Complement bench discoveries and clinical trial results with focused behavioral and social science 

research, particularly in low-vision populations.

g. Integrate molecular and cellular knowledge with epidemiological and clinical information to 

inform clinical research priorities.

h. Promote the development and implementation of evidence-based guidelines for prevention, 

diagnosis, and treatment of visual disorders by conducting comparative effectiveness research. 

VI: STRENGTHEN THE POOL OF VISION RESEARCHERS

a. Increase recruitment of clinician-scientists to vision research. 

b. Encourage early-stage vision researchers to participate in team science. Develop multidisciplinary 

teams with expertise in fields such as bioinformatics, nanotechnology, engineering, and physics. 

c. Increase the participation of minorities in vision research. 

d. Recruit early-stage investigators from other disciplines to apply their knowledge and techniques to 

study disorders of the visual system.
66 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

APPENDIX 2:

THE NEI PLANNING PROCESS

In 2011, NEI funded more than 1,400 

research and training awards to extramural7

organizations such as universities and small 

businesses. The awards, primarily grants and 

cooperative agreements, are administered by 

scientists in the NEI Division of Extramural 

Research and are grouped into administrative 

portfolios (also referred to as programs; see 

box on page 67). NEI continues its tradition of 

identifying scientific priorities with a transparent 

and participatory process to assess progress, 

identify gaps and opportunities, and set realistic 

goals and objectives for the future. The program 

directors and the staff of the NEI Office of 

Program Planning and Analysis (OPPA) developed 

and implemented the planning process under 

the auspices of National Advisory Eye Council 

(NAEC), which represents the community of 

vision researchers and other stakeholders in eye 

research and ocular health. 

INITIAL STEPS

We began with a retrospective examination of 

the NEI strategic planning process by convening 

a planning oversight group of current and former 

NAEC members and other leaders of major vision 

research organizations. The goal was to create a 

meaningful process to help NEI identify scientific 

opportunities, fund the best science, properly 

direct resources, and attract and train the best 

and the brightest investigators to vision research. 

The oversight group endorsed the NEI 

philosophy that the bulk of extramural research 

should be driven by investigator-initiated 

projects, and NEI should continue to have a 

balance of basic, translational, and clinical 

research aims. Support was expressed for 

developing a series of important scientific goals 

7 Extramural refers to work done outside NIH, mostly at 

universities and other research organizations.

and priorities for all areas of vision research. As 

a first step, the group encouraged NEI to create 

an overarching document of general concepts 

that are common to most biomedical disciplines 

to help focus the efforts of planning panels on 

the problems and challenges specific to vision 

research. The NEI Framework for Vision Research 

(see Appendix 1) was created by NEI staff, was 

vetted by the oversight group, and then reviewed 

and approved by NAEC.

There also was recognition that an iterative, 

ongoing NEI planning process was necessary to 

keep pace with rapid advances in knowledge. 

The oversight group suggested proceeding with a 

series of workshops to identify new opportunities 

as they arose rather than in intervals of five or 

more years. Finally, it was agreed that the plan 

should identify a wide range of opportunities in 

all areas of vision research, but the NEI effort to 

implement the plan would depend on continual 

attention to program and resource management, 

new technologies, and a vibrant intramural8

 

program in basic science, translational, and 

clinical research.

INPUT TO THE NEI

In December 2010, NEI solicited input from 

the public and scientific community by issuing 

a Request for Information (RFI). NEI widely 

publicized the RFI through grantee and interest 

group e-mail lists and professional organizations. 

The RFI invited the scientific vision research 

community, health professionals, patient 

advocates, professional societies, and the general 

public to provide input on two broad questions: 

1. What are the most significant scientific 

discoveries in vision research that have 

occurred since 2004? 

8 Intramural refers to research by NEI scientists and clinicians at the NEI facilities in Bethesda, MD. 
APPENDIX 2 67

NEI ADMINISTRATIVE PROGRAMS

1. Retinal Diseases

2. Corneal Diseases

3. Lens and Cataract

4. Glaucoma and Optic Neuropathies

5. Strabismus, Amblyopia, and Visual Processing

6. Low Vision and Blindness Rehabilitation

 7. Ocular Genetics

 8. Ocular Infection, Inflammation, and Immunology

 9. Myopia and Refractive Error

10. Oculomotor Systems and Neuro-Ophthalmology

11. Ocular Pain

12. Collaborative Clinical Research

13. Small Business Innovation Research

14. Research Training and Career Development

15. Research Resources

2. What are the most significant scientific 

research needs, gaps, and opportunities 

that should be addressed by NEI? 

Responses were collected through March 

2011 from individual research scientists, small 

businesses, patient-advocacy groups, clinical 

trial networks, and professional societies. In 

particular, NEI is indebted to the Association for 

Research in Vision and Ophthalmology (ARVO)—

an international organization of more than 12,500 

individuals—for engaging its board of trustees, 

leaders of its scientific sections, and more than 

300 members who generated a detailed response 

to the RFI.

PANEL MEETINGS (SPRING 2011)

Central to the current planning effort was 

the creation of planning panels with appropriate 

vision research expertise. Panels for all 15 

administrative programs would have been too 

fragmented, and similar to previous planning 

efforts, we convened six panels. NEI program 

directors selected two internationally recognized 

co-chairs with broad expertise for each panel. 

In December 2010, all the co-chairs met with 

the NEI program directors and planning staff to 

discuss the scope and format of the plan and to 

finalize panel member selection. Expertise for 

each panel was selected to ensure that all areas of 

vision research were well represented. 

To prepare for the spring panel meetings, 

each panel member submitted answers to the RFI 

questions. Panelists received a copy of the most 

recent National Plan (2004), recent workshop 

reports, and RFI responses submitted by the other 

panelists, the public, and ARVO. NEI encouraged 

panelists to think broadly, beyond the scope 

of their own work and specific field of vision 

research and carefully consider all input received. 

Premeeting teleconferences were held so that 

cochairs, panelists, and NEI staff understood the 

expectations and goals of the planning process. 

The panels were instructed to focus on the science 

and resources (clinical needs, animal models) 

rather than NEI-specific infrastructure such as 

funding mechanisms, training, and peer review. 

Following the panel meetings, panel cochairs, 

in consultation with full panel membership and 

NEI staff drafted the panel reports found in this 

document, which were submitted to NAEC for 

comment in December 2011, prior to posting on 

the web for public comment.

The program panel reports in this document 

are the essential first step in developing a 

thoughtful strategic plan for NEI. With a thorough 

accounting of the state of vision research in place, 

NEI must begin to prioritize critical research to 

ensure that progress continues at a rapid pace. In 

the next phase of the planning process, NEI will 

re-engage the community to help prioritize the 

most pressing opportunities to develop ever more 

effective treatments for eye disease. 
68 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

APPENDIX 3:

LIST OF CONTRIBUTORS

Ted Acott, Ph.D.

Oregon Health and Science University

Portland, OR

Rando L. Allikmets, Ph.D.

Columbia University

New York, NY

Richard Andersen, Ph.D. 

(co-chair, Strabismus, Amblyopia, and Visual 

Processing)

California Institute of Technology

Pasadena, CA

Vadim Y. Arshavsky, Ph.D.

Duke University

Durham, NC

Steven Bassnett, Ph.D. 

(co-chair, Lens and Cataract)

Washington University School of Medicine 

St. Louis, MO

Michele Basso, Ph.D.

University of Wisconsin, Madison

Madison, WI

Larry Benowitz, Ph.D.

Harvard School of Medicine

Children’s Hospital

Boston, MA

Peter Bex, Ph.D.

Schepens Eye Research Institute 

Boston, MA

Alan R. Burns, Ph.D.

University of Houston

Houston, TX

Marie E. Burns, Ph.D. 

(co-chair, Retinal Diseases)

University of California, Davis

Davis, CA

Edward Callaway, Ph.D.

Salk Institute for Biological Studies

La Jolla, CA

Barbara Chapman, Ph.D.

University of California, Davis

Davis, CA

John I. Clark, Ph.D.

University of Washington 

Seattle, WA

Anne Coleman, M.D., Ph.D.

University of California, Los Angeles

Los Angeles, CA

C. Edward Connor, Ph.D.

Johns Hopkins University

Krieger Mind/Brain Institute

Baltimore, MD

Rosalie K. Crouch, Ph.D.

Medical University of South Carolina 

Charleston, SC

Darlene A. Dartt, Ph.D.

Harvard Medical School 

Boston, MA

Steven H. DeVries, M.D., Ph.D.

Northwestern University 

Feinberg School of Medicine

Chicago, IL
APPENDIX 3 69

Elizabeth Engle, M.D.

Harvard School of Medicine

Children’s Hospital

Boston, MA

Velia M. Fowler, Ph.D.

The Scripps Research Institute

La Jolla, CA 

Martin Friedlander, M.D., Ph.D. 

(co-chair, Retinal Diseases)

Scripps Research Institute

La Jolla, CA

John A. Gardner, Ph.D. 

ViewPlus Technologies, Inc.

Corvallis, OR 

Charles Gilbert, M.D., Ph.D. 

(co-chair, Planning Oversight Committee)

Rockefeller University

New York, NY

Michael Gilmore, Ph.D.

Massachusetts Eye and Ear Infirmary

Boston, MA

Adrian Glasser, Ph.D.

University of Houston 

Houston, TX

Jeff Goldberg, M.D., Ph.D.

University of Miami School of Medicine 

Miami, FL

William V. Good, M.D. 

(co-chair, Low Vision and Blindness 

Rehabilitation)

Smith-Kettlewell Eye Research Institute

San Francisco, CA

Dale S. Gregerson, Ph.D.

University of Minnesota

Minneapolis, MN

Jonathan Haines, Ph.D.

Vanderbilt University School of Medicine

Nashville, TN

Robert L. Hendricks, Ph.D.

University of Pittsburgh

Pittsburgh, PA

Amy Horowitz, D.S.W. 

Fordham University

New York, NY

 

Jonathan Horton, M.D., Ph.D.

University of California, San Francisco

San Francisco, CA

David Huang, M.D., Ph.D.

Oregon Health and Science University

Portland, OR

Joseph A. Izatt, Ph.D.

Duke University

Durham, NC

David Kaufman, D.O.

Michigan State University

East Lansing, MI

Daniel Kersten, Ph.D.

University of Minnesota

Minneapolis, MN

Robert M. Lavker, Ph.D.

Northwestern University

Chicago, IL

Gordon Legge, Ph.D.

University of Minnesota

Minneapolis, MN

Dennis Levi, O.D., Ph.D.

University of California, Berkeley

Berkeley, CA
70 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

Tom Lietman, M.D.

University of California, San Francisco

San Francisco, CA

Richard G. Long, Ph.D., COMS

Western Michigan University

Kalamazoo, MI

Jack M. Loomis, Ph.D.

University of California 

Santa Barbara, CA 

Todd Margolis, M.D., Ph.D.

University of California, San Francisco

F.I. Proctor Foundation

San Francisco, CA

M. Christine McGahan, Ph.D. 

(co-chair, Lens and Cataract)

North Carolina State University 

Raleigh, NC

Hassane S. Mchaourab, Ph.D.

Vanderbilt University Medical Center 

Nashville, TN

David C. Musch, Ph.D., M.P.H.

The University of Michigan

Ann Arbor, MI

Michael Mustari, Ph.D.

University Of Washington

Seattle, WA

Donald Mutti, O.D., Ph.D.

Ohio State University

Columbus, OH

Jeremy Nathans, M.D., Ph.D.

Johns Hopkins University

Baltimore, MD

Eric Pearlman, Ph.D. 

(co-chair, Corneal Diseases)

Case Western Reserve University

Cleveland, OH

Victor L. Perez, M.D. 

(co-chair, Corneal Diseases)

Bascom Palmer Eye Institute

Miami, FL

Margaret A. Pericak-Vance, Ph.D.

University of Miami

Coral Gables, FL

Joram Piatigorsky, Ph.D.

National Eye Institute

Bethesda, MD

Michael L. Robinson, Ph.D.

Miami University 

Oxford, OH

James Rosenbaum, M.D.

Oregon Health and Science University

Portland, OR

Mark Rosenblatt, M.D., Ph.D.

Weill Cornell Medical College

New York, NY

Krishnankutty Sathian, M.D., Ph.D. 

(co-chair, Low Vision and Blindness 

Rehabilitation)

Emory University

Atlanta, GA

Val Sheffield, M.D., Ph.D.

University of Iowa

Iowa City, IA

D.J. Sidjanin, Ph.D. 

Medical College of Wisconsin 

Milwaukee, WI

Pawan Sinha, Ph.D.

Massachusetts Institute of Technology

Cambridge, MA 
APPENDIX 3 71

Earl Smith, O.D., Ph.D. 

(co-chair, Strabismus, Amblyopia, 

and Visual Processing)

University of Houston

Houston, TX

Lois E. H. Smith, M.D., Ph.D.

Harvard School of Medicine

Children’s Hospital

Boston, MA

Alfred Sommer, M.D.

Johns Hopkins University

Baltimore, MD

Dwight Stambolian, M.D., Ph.D.

University of Houston

Houston, TX

Paul Sternberg Jr., M.D.

Vanderbilt University

Nashville, TN

Richard A. Stone, M.D. 

(co-chair, Planning Oversight Committee)

University of Pennsylvania

Philadelphia, PA

Stephen P. Sugrue, Ph.D.

University of Florida College of Medicine

Gainesville, FL

Deming Sun, M.D.

Doheny Eye Institute

Los Angeles, CA

Mriganka Sur, Ph.D.

Massachusetts Institute of Technology

Cambridge, MA

Bosco Tjan, Ph.D.

University of Southern California

Los Angeles, CA 

Frank Tong, Ph.D.

Vanderbilt University

Nashville, TN

Russell Van Gelder, M.D., Ph.D.

University of Washington

Seattle, WA

Rohit Varma, M.D., M.P.H. 

(co-chair, Glaucoma and Optic Neuropathies)

Keck School of Medicine

Los Angeles, CA

Alan S. Verkman, M.D., Ph.D.

University of California, San Francisco

San Francisco, CA

Monica L. Vetter, Ph.D.

University of Utah

Salt Lake City, UT

Thomas Walz, Ph.D. 

Harvard Medical School 

Boston, MA

Robert Weinreb, M.D.

University of California, San Diego

La Jolla, CA

Sheila West, Ph.D.

Johns Hopkins University

Baltimore, MD

Scott Whitcup, M.D.

Allergan, Inc.

Irvine, CA

Janey Wiggs, M.D., Ph.D.

Massachusetts Eye and Ear Infirmary

Boston, MA

Donald Zack, M.D., Ph.D. 

(co-chair, Glaucoma and Optic Neuropathies)

Johns Hopkins University School of Medicine

Baltimore, MD
72 VISION RESEARCH NEEDS, GAPS, AND OPPORTUNITIES

CONTRIBUTORS

NATIONAL EYE INSTITUTE STAFF

OFFICE OF THE DIRECTOR

Director, NEI

Paul A. Sieving, M.D., Ph.D.

Deputy Director, NEI

Deborah Carper, Ph.D. 

EXTRAMURAL 

PROGRAM STAFF

Director, Division of Extramural Research

Loré Anne McNicol, Ph.D.

Extramural Policy Officer

Ellen S. Liberman, Ph.D., M.B.A.

Fundamental Retinal Processes

Andrew P. Mariani, Ph.D.

Retinal Diseases

Lisa A. Neuhold, Ph.D.

Retinal Neuroscience

Thomas N. Greenwell, Ph.D. 

Corneal Diseases

Ocular Infection, Inflammation, 

and Immunology

Grace L. Shen, Ph.D.

Lens and Cataract;

Oculomotor Systems and 

Neuro-Ophthalmology; Ocular Pain

Houmam Araj, Ph.D.

Glaucoma and Optic Neuropathies

Neeraj Agarwal, Ph.D.

Strabismus, Amblyopia, & Visual Processing

Michael A. Steinmetz, Ph.D.

Ocular Genetics

Hemin R. Chin, Ph.D.

Myopia and Refractive Error

Jerome R. Wujek, Ph.D.

Perception & Psychophysics and

Low Vision and Blindness Rehabilitation

Cheri Wiggs, Ph.D.

Collaborative Clinical Research

Donald F. Everett, M.A.

Natalie Kurinij, Ph.D.

Steven Oversby, Ph.D., R.N.

Maryann Redford, D.D.S., M.P.H.

Eleanor B. Schron, Ph.D., R.N. F.A.A.N.

OFFICE OF PROGRAM PLANNING 

AND ANALYSIS

Richard S. Fisher, Ph.D., Director

Shefa Gordon, Ph.D.

Thomas G. Hoglund, B.A.

Jennifer E. Mehren, Ph.D. 
Photo Credits

Front Cover: Left image courtesy of Drs. Robert Fariss and Mercedes 

Campos. Bottom background image courtesy of Drs. Kent Sheridan 

and Michael Redmond.

Page 4: Left circle image courtesy of Dr. Wei Li; Right circle image 

courtesy of Drs. Jen-Yue Tsai and Robert Fariss.

Page 9: Image courtesy of Robert Watts.

Page 24: Image courtesy of Dr. Sheila West.

Page 35: Image courtesy of Dr. Pawan Sinha.

Page 41: Image courtesy of Drs. Thomas Johnson, Naoki Nakaya 

and Stanislav Tomarev.

Page 46: Image copywright by Terese Winslow.

Page 53: Image courtesy of Dr. Wei Li.

Page 56: Image courtesy of Dr. James Coughlan.

Page 60: Image courtesy of Second Sight.

Unless noted above, all other images are from the NEI image library.
U.S. Department of Health and Human Services

National Institutes of Health

National Eye Institute

http://www.nei.nih.gov

August 2012