Glaucoma is a major public health problem in this country. The disease
is manifest as a progressive optic neuropathy that, if left untreated,
leads to blindness. It is estimated that as many as 3 million Americans
have the disease and, of these, as many as 120,000 are blind as a result.
Furthermore, it is the number one cause of blindness in African-Americans.
Treatments to slow the progression of the disease are available; however,
at least half of those who have glaucoma are not receiving treatment
because they are unaware of their condition. Blindness from glaucoma is
believed to impose significant costs annually on the U.S. Government in
Social Security benefits, lost tax revenues, and healthcare expenditures.
Glaucoma is not a single disease but rather a heterogeneous group of
disorders that share a distinct type of optic nerve damage that can lead
to blindness caused by the death of retinal ganglion cells. These diseases
involve several tissues in the front and back of the eye. Commonly, but
not always, glaucoma begins with a defect in the front of the eye. Fluid
in the anterior portion of the eye, the aqueous humor, forms a circulatory
system that brings nutrients and supplies to various tissues. Aqueous
humor enters the anterior chamber via the ciliary body epithelium
(inflow), flows through the anterior segment bathing the lens, iris, and
cornea, and then leaves the eye via specialized tissues known as the
trabecular meshwork and Schlemm's canal to flow into the venous system.
Intraocular pressure is maintained vis-á-vis a balance
between fluid secretion and fluid outflow. Almost all glaucomas are
associated with defects that interfere with aqueous humor outflow and,
hence, lead to a rise in intraocular pressure. The consequence of this
impairment in outflow and elevation in intraocular pressure is that optic
nerve function is compromised. The result is a distinctive optic nerve
atrophy, which clinically is characterized by excavation and cupping of
the optic nerve, indicative of loss of optic nerve axons.
Primary open-angle glaucoma is, by convention, characterized by
relatively high intraocular pressures believed to arise from a blockage of
the outflow drainage channel or trabecular meshwork in the front of the
eye. However, another form of primary open-angle glaucoma, normal-tension
glaucoma, is characterized by a severe optic neuropathy in the absence of
abnormally high intraocular pressure. Patients with normal-tension
glaucoma have pressures within the normal range, albeit often in the high
normal range. Both these forms of primary open-angle glaucoma are
considered to be late-onset diseases in that, clinically, the disease
first presents itself around midlife or later. However, among
African-Americans, the disease may begin earlier than middle age. In
contrast, juvenile open-angle glaucoma is a primary glaucoma that affects
children and young adults. Clinically, this rare form of glaucoma is
distinguished from primary open-angle glaucoma not only by its earlier
onset but also by the very high intraocular pressure associated with this
disease. Angle-closure glaucoma is a mechanical form of the disease caused
by contact of the iris with the trabecular meshwork, resulting in blockage
of the drainage channels that allow fluid to escape from the eye. This
form of glaucoma can be treated effectively in the very early stages with
laser surgery. Congenital and other developmental glaucomas in children
tend to be severe and can be very challenging to treat successfully.
Secondary glaucomas result from other ocular diseases that impair the
outflow of aqueous humor from the eye and include pigmentary glaucoma,
pseudoexfoliative glaucoma, and glaucomas resulting from trauma and
inflammatory diseases. Blockage of the outflow channels by new blood
vessels (neovascular glaucoma) can occur in people with retinal vascular
disease, particularly diabetic retinopathy. The Glaucoma Program
encompasses the study of all glaucomas; however, its major focus remains
on primary open-angle glaucoma because of the large number of people
affected and its public health impact.
Primary open-angle glaucoma can be insidious. It usually begins in
midlife and progresses slowly but relentlessly. If detected, disease
progression can frequently be arrested or slowed with medical and surgical
treatment. However, without treatment, the disease can result in absolute
irreversible blindness. Even though the initial site is believed to occur
in the outflow drainage channels at the front of the eye, vision loss from
primary open-angle glaucoma is the result of damage to the retinal
ganglion cells, whose axons form the optic nerve at the back of the eye.
For many patients, the link between the block in fluid drainage in the
front of the eye and retinal ganglion cell death is thought to be an
elevation of intraocular pressure. However, as is evident from
normal-tension glaucoma, glaucomatous optic nerve damage can occur in the
absence of abnormally high intraocular pressures. Conversely, ocular
hypertension does not always lead directly to optic nerve damage.
Approximately 5 million Americans have elevated intraocular pressures
without optic nerve damage or visual field loss. Only some of these ocular
hypertensive individuals will actually develop the optic nerve damage that
defines glaucoma. Because the relationship between pressure and optic
nerve damage is not necessarily direct, high intraocular pressure is now
considered to be a risk factor rather than an essential disease
An important goal of current research is to develop methods of early
diagnosis to detect the disease in the early stages, when treatment is
most effective in minimizing irreversible vision loss. This is made more
critical by the apparent absence of symptoms in the early stages of
glaucoma. Because elevated intraocular pressure is not always accompanied
by pathology, nor does elevated intraocular pressure always lead to optic
neuropathy, the diagnosis of glaucoma now emphasizes the presence of
visual field loss and observable characteristic optic nerve damage.
Individuals with ocular hypertension present a unique dilemma for
clinicians. In the absence of any overt pathology, clinicians must decide
whether or not to treat these individuals with intraocular
pressure-lowering medications that can pose a considerable expense and
often have side effects. This dilemma can be avoided with more knowledge
concerning the natural history of the disease and whether early treatment
can prevent the onset of glaucoma.
Because characteristic visual field changes in glaucoma patients are due
to degeneration of retinal ganglion cells, clinical progress goes
hand-in-hand with progress in understanding how retinal ganglion cell loss
occurs and the role played by elevated intraocular pressure in this
process. Continued clinical and laboratory research has provided a greater
understanding of the normal functions of the ocular tissues involved in
the disease. Such studies have led to the introduction of a variety of new
drugs to reduce intraocular pressure, the development of new diagnostic
tools, better estimates of disease prevalence and incidence, and the
identification of glaucoma genes.
In Fiscal Year 1997, the National Eye Institute (NEI) funded 146
extramural research projects in the Glaucoma Program at a total cost of
The overall goal of the Glaucoma Program is to identify the biological
mechanisms responsible for glaucoma so that improved treatment can be
developed. As a means of achieving this overall goal, the Panel recommends
the following general goals:
- Develop improved measures to aid in the clinical diagnosis of
glaucoma; monitor progression of disease and treatment effectiveness;
and elucidate the pathophysiology and natural history of the disease.
- Understand the molecular and biochemical basis of aqueous humor
dynamics, with special emphasis on outflow.
- Identify genetic loci and genes contributing to glaucoma, especially
those responsible for the common forms of the disease.
- Determine the mechanisms of optic nerve damage and retinal ganglion
cell loss and survival in glaucoma.
ASSESSMENT OF PROGRESS
The development of new diagnostic and imaging methods.
Developing new visual field test procedures provide more
reliable and objective methods for the early diagnosis of glaucoma and for
determining the progression of glaucomatous damage. Unlike traditional
methods that are based on detecting a small increment of white light on a
white background, the new procedures are designed to isolate and measure
those visual functions mediated by specific subsets of ganglion cell
populations. The most promising of these new visual field procedures is
short-wavelength automated perimetry (SWAP), a procedure that isolates
short-wavelength-sensitive vision mechanisms by using a bright yellow
background and large blue stimuli.
Longitudinal investigations have established that SWAP can detect
glaucomatous visual damage 3 to 5 years earlier than conventional
perimetry. Because visual field defects appear earlier with SWAP, earlier
detection of glaucoma is a possibility. Standardization of the instrument
and its analytical software has made SWAP a viable diagnostic test
procedure for future clinical use. Recent quantitative studies have shown
a clear correlation between visual function in glaucoma and structural
measures of the optic nerve and nerve fiber layer. For instance,
information from structure and function analysis has been greatly improved
with the introduction of the confocal scanning laser ophthalmoscope.
Several new diagnostic instruments using this technology are now
commercially available. These instruments are highly reproducible and
provide more objective data in much less time than conventional methods,
such as stereoscopic fundus photography. Optical coherence tomography is
another promising imaging technique currently under evaluation.
Better estimates of the prevalence of glaucoma. Epidemiological
studies conducted in the United States and the West Indies have improved
the prevalence and incidence estimates of primary open-angle glaucoma
among white and black populations. One strength of these studies is the
adoption of more inclusive definitions of primary open-angle glaucoma that
require the presence of visual field loss or optic disc damage, but do not
necessarily require the presence of elevated intraocular pressure. The
Beaver Dam (Wisconsin) Eye Study, which studied nearly 5,000 individuals
between the ages of 43 and 84, reported a prevalence rate of 2.1 percent
in a predominantly Caucasian sample. The Baltimore Eye Study, with over
5,000 participants age 40 and older, reported a prevalence rate of 1.7
percent among Caucasian Americans and 5.6 percent among African-Americans.
These prevalence estimates for white Americans are consistent with
findings reported in epidemiological studies conducted in Rotterdam and
Australia. The Barbados Eye Study, which studied over 4,000 black
Barbadians ages 40 to 84, reported a prevalence rate of 7 percent. The
Barbados Eye Study and the Baltimore Eye Study confirm a substantially
higher prevalence of primary open-angle glaucoma in Caribbean blacks and
African-Americans than in whites.
Introduction of two new drugs to lower intraocular
pressure. Over the past 5 years, two new medical therapies
for glaucoma have been introduced: latanoprost (Xalatan) and dorzolamide
(Trusopt). These are the products of research sponsored by the NEI.
- LatanoprostInitial efforts to use the ocular
hypotensive action of naturally occurring prostaglandins (PGs) as a
glaucoma therapy were hampered by an inflammatory response they
elicited. Recently, a prodrug, an isopropylester of PGF-2 alpha
(latanoprost), was developed as an effective ocular hypotensive agent
with clinically acceptable side effects. This esterified analog of PGF-2
alpha enhances corneal penetration and reduces external side effects
without compromising the efficacy of the active moiety.
- DorzolamideAlthough orally administered carbonic
anhydrase inhibitors (CAIs) have been used clinically for many decades
to lower intraocular pressure, their use has been compromised by
systemic side effects. By improving lipid solubility and, hence,
membrane penetration, without losing water solubility, the topically
active CAI dorzolamide (Trusopt) was developed. Topical administration
of dorzolamide has far fewer systemic side effects and better patient
compliance compared to orally administered CAIs
The use of antimetabolites to improve filtration surgery
outcomes. Over the past decade, the use of antifibrotic
agents to enhance the success of glaucoma filtration surgery in patients
has become accepted practice. Filtration surgery is often undertaken for
the 40 percent to 50 percent of patients whose glaucoma is not amenable to
medical therapy. The surgical procedure, which involves opening a channel
through the sclera to allow aqueous humor drainage, frequently fails
because of an excessive healing response that involves fibroblast
proliferation and excessive collagen deposition around the wound site. Two
agents that block DNA synthesismitomycin-C and 5-fluorouracilare
effective in reducing the failure rate in trabeculectomy, the most common
form of filtration surgery, precisely by inhibiting fibroblast
proliferation. Especially in patients with a high clinical risk for
surgical failure, these agents have been valuable in increasing the
likelihood of a favorable outcome. However, adverse long-term effects of
these agents limit their use. Perhaps with a better understanding of the
biology of wound healing, new agents that prevent scar formation at the
wound site without adverse effects will be discovered.
Progress in characterizing the signaling mechanisms in the
diverse tissues of the anterior segment. The past 5 years
have seen substantial advances in characterizing the signal transduction
pathways in the iris-ciliary body and trabecular meshwork, which mediate
the responses of the eye to endogenous ligands and drugs. Besides the
classic neurotransmitters norepinephrine and acetylcholine, many
neuropeptides have been identified in the ocular autonomic and sensory
nerves that supply all tissues of the anterior segment, including the
ciliary processes and trabecular meshwork. The novel neurotransmitter
nitric oxide has been implicated in signaling by the ocular
parasympathetic nerves. At an intracellular level, isozymes involved in
the ocular synthesis (adenyl and guanyl cyclase) and degradation
(phosphodiesterases) of cyclic adenosine monophosphate and cyclic
guanosine monophosphate, two of the principal second messengers in the
ciliary processes and trabecular meshwork, have been identified. In
addition, the functions of phospholipids such as phosphatidylinositol and
calcium turnover in these ocular tissues are becoming better understood.
Advances have been made in understanding the mechanisms by which various
agents like peptides, purines, and biogenic amines regulate aqueous humor
secretion. In the ciliary body, roles for receptors of adenosine and for
peptides such as endothelin, calcitonin gene-related peptide, opioids,
natriuretic peptides, and somatostatin are being identified. Several
subtypes of alpha2 adrenoceptors and serotonin receptors are also found in
this tissue. In ciliary muscle, endothelin receptors influence calcium
mobilization and eicosanoid formation, suggesting receptor linkage to more
than one signal transduction pathway.
Quite apart from the descriptive information, several new concepts have
become widely accepted. The multiplicity of receptors, second-messenger
cascades, and target transport proteins make the second-messenger
regulation of transport unique for nearly each cell type. Synergism
between parallel hormones or stimuli is likely in regulating ciliary
epithelial secretion, a point particularly well documented for the
cooperative hormonal actions on intracellular calcium levels. There is
increased awareness of possible effects not only on unidirectional
secretion but also on reabsorption, leading to the concept that the two
processes must be coordinated.
Mapping of multiple genetic loci associated with glaucoma.
Progress in understanding the molecular genetics of glaucoma
has been achieved in the past few years. A major advance came with the
genetic linkage mapping of a locus on chromosome 1q (GLC1A) to juvenile
open-angle glaucoma. Subsequent studies confirmed the chromosome 1q
linkage and resulted in the fine mapping of the genetic interval. To date,
the following glaucoma loci have been mapped for glaucomas or ocular
diseases associated with secondary glaucomas:
- 1q23 - Juvenile-onset primary open-angle glaucoma
- 1p36 - Congenital glaucoma
- 2p21 - Congenital glaucoma
- 2qcen-q13 - Adult-onset, low-tension, primary open-angle glaucoma
- 3q21-24 - Adult-onset primary open-angle glaucoma
- 4q25 - Rieger's syndrome (RIEG1)
- 6p25 - Iridodysgenesis
- 7q35-q36 - Pigment dispersion syndrome and pigmentary glaucoma
- 11q13 - Aniridia
- 13q14 - Rieger's syndrome (RIEG2)
This work and the mapping of other glaucoma-related loci have
substantiated the concept of a genetic component to glaucoma.
Identification and characterization of glaucoma-associated
genes. In addition to mapping of glaucoma loci by genetic
linkage, significant advances in the discovery of glaucoma-causing genes
have occurred. A gene for juvenile primary open-angle glaucoma (GLC1A) was
identified. The gene codes for a protein called trabecular meshwork
glucocorticoid response protein (TIGR) that was first identified as a
protein made by trabecular meshwork cells exposed to glucocorticoid
hormones. Subsequently, this gene was found to be the same as genes
identified from cDNA libraries made from ciliary body and retina. This
gene cloned from the retina was named "myocilin" because of the
myosin-like domain within the gene. Mutations in this gene have been
associated with juvenile-onset primary open-angle glaucoma and, in a small
percentage of cases, of adult-onset primary open-angle glaucoma. The
normal function of this gene and the role that dysfunctional forms of the
gene play in the pathogenesis of glaucoma are unknown.
A gene involved in cases of autosomal recessive congenital glaucoma that
maps to 2p21 (GLC3A) has recently been identified. This gene codes for
cytochrome P4501B1. The initial mutations identified in this gene appear
to be null mutations, implying that loss of function of this gene results
in the phenotype. A gene involved in one form of Rieger's syndrome has
also been identified. This gene was identified by cloning a chromosomal
translocation breakpoint involving chromosome 4 in a patient with Rieger's
syndrome. The gene called RIEG1 codes for a bicoid homeobox transcription
factor, which has been named Solurshin. This same gene has been shown to
be involved in some cases of iris hypoplasia with associated glaucoma.
Conceptualization of retinal ganglion cell loss in
glaucoma as an active cellular process amenable to mechanistic study and
the development of novel therapeutics. Characteristic visual
field changes and eventual loss of visual acuity in glaucomatous optic
neuropathy are due to degeneration of retinal ganglion cells. The loss of
axons of the retinal ganglion cells can be seen clinically as a thinning
of the nerve fiber layer and an excavation of the optic disk, clinically
called "cupping." In many but not all patients this is
associated with elevated intraocular pressure. Explanations for how these
changes in the glaucomatous optic nerve occur and progress have primarily
been based on how elevated intraocular pressure might alter the optic
nerve tissue. Two hypotheses have been put forth to explain the effect of
high intraocular pressure: one postulates pressure-induced mechanical
damage, and a second postulates pressure-induced ischemia.
In the last few years, researchers have determined that, to understand
glaucoma, they need to understand how retinal ganglion cells die,
irrespective of whether ischemia, mechanical damage, or another mechanism
initiates the degeneration. Recent observations have brought new insights
into understanding retinal ganglion cell death after axonal damage and
have underscored the need to investigate cellular and molecular mechanisms
of neuronal degeneration. Evidence that retinal ganglion cells die by
apoptosis (programmed cell death) following inner retinal ischemia, optic
nerve transection, or elevated intraocular pressure suggests that the
molecular components of the cascade of programmed cell death should be
investigated in glaucoma. Retinal ganglion cells are sensitive to the
excitotoxic action of the neurotransmitter glutamate, and glutamate is
present in increased amounts in the vitreous of glaucoma patients and
monkeys with experimentally elevated intraocular pressure. Finally, recent
data show that retinal ganglion cells are sensitive to peptides that are
known to enhance their survival, providing a possible therapeutic
Following are the objectives of the Glaucoma Program over the next 5
- Identify genes and genetic loci contributing to glaucoma, especially
those responsible for the common forms of the disease, and characterize
the function and interaction of their gene products.
- Define the molecular and biochemical mechanisms that lead to retinal
ganglion cell death in human glaucoma and in relevant animal models of
related optic nerve injury.
- Enhance understanding of the structure and function of the aqueous
humor outflow pathways at the cellular and molecular level.
- Develop a better understanding of anterior segment immunology.
- Improve our understanding of the nature and course of glaucoma,
incorporating studies of comorbidity, natural history, and genetics,
with special emphasis on Hispanic, Native American, and African-American
- Develop improved diagnostic techniques encompassing measures of
visual function, optic nerve, and nerve fiber layer structure, in
situ and for clinical applications of genetics.
- Identify neuroprotective strategies that could prevent retinal
ganglion cell death, promote survival, or stimulate regeneration.
The needs and opportunities related to each of these objectives and the
strategies for accomplishing them will now be considered.
Objective 1: Identify genes and genetic loci contributing
to glaucoma, especially those responsible for the common forms of the
disease, and characterize the function and interaction of their gene
Research Needs and Opportunities
The application of the theory and technology of molecular genetics to
the problems of clinical medicine has produced a wealth of information
about the molecular pathogenesis of many human disorders. As with many
disorders, identifying specific genes opens up many opportunities to
understand glaucoma. Currently, many forms of glaucoma have been shown to
be inherited as Mendelian-dominant or -recessive traits, including
juvenile open-angle glaucoma, congenital glaucoma, developmental glaucomas
(Rieger's syndrome and aniridia), and pigmentary glaucoma. To date, 10
chromosomal loci associated with these glaucomas have been genetically
mapped in the human genome, and the genes for juvenile open-angle
glaucoma, congenital glaucoma, and Rieger's syndrome have been cloned.
The data on adult-onset primary open-angle glaucoma suggest that
susceptibility to the disease may be inherited. For example, twin studies
performed 20 to 30 years ago suggested a significant heritability. Other
data showed that the incidence of primary open-angle glaucoma in
first-degree relatives of affected individuals is 7 to 10 times higher
than that of the general population. These studies indicate that there is
an association between susceptibility and family history; however,
Mendelian patterns in which defined family patterns of inheritance can be
discerned were not apparent. Thus, susceptibility to glaucoma is likely a
complex trait in which genetic predisposition to the disease is modified
by other factors. The etiology of this form of the disease is likely
multifactorial, involving the interaction of multiple genes as well as
gene-environment interactions, making the genetic analysis of primary
open-angle glaucoma extremely challenging. Furthermore, genetic studies
are confounded by the late onset of the disease and its clinical
variability. The late onset of the disease limits the availability of
extended pedigrees. The clinical variability makes it difficult to define
the homogenous subgroup of patients required for genetic analysis. All
these factors necessitate the use of new statistical methodologies for
analysis, well-defined inclusion criteria to increase the likelihood of
homogeneity, and aggressive patient recruitment to ensure enough power in
Recent advances in methodology now allow the application of genetic
analysis to the study of complex late-onset diseases, increasing the
likelihood that genetic loci associated with primary open-angle glaucoma
can be identified. Over the next 5 years, these studies can contribute
valuable new information about the cause of this blinding condition and
present new opportunities for laboratory and clinical research. Genetics
may provide insight into the molecular basis underlying the higher
prevalence and higher degree of severity of glaucoma in blacks. The
identification of glaucoma genes has the potential to define subgroups of
glaucoma patients and predict progression rates based on mutations or
genetic loci involved. Likewise, it could identify molecular subclasses of
disease that respond similarly to specific treatments. The availability of
genetics as a diagnostic tool may allow clinicians to customize an
intervention strategy based on the risk of blindness for an individual
patient and balance treatment with quality-of-life considerations.
At the biochemical and cellular level, collecting sufficient quantities
of trabecular meshwork has been a difficult obstacle to understanding the
pathology of the disease. Moreover, tissue specimens taken from affected
patients undergoing glaucoma surgery have been exposed to prior medical
and laser treatments that could obscure the initial abnormalities
responsible for the disease. Because genetic analysis investigates the
disease process at the DNA level, samples of the actual diseased tissue,
or even knowledge about how the disease affects a particular tissue, is
not necessary for gene and gene product identification. Thus, the study of
the molecular genetics of glaucoma can implicate specific protein products
in the development of the disease without requiring direct access to the
diseased eye tissue.
Identifying glaucoma-causing genes and their products will give
researchers the opportunity to determine whether these genes and gene
products function normally and determine how mutations in them cause or
increase the susceptibility to glaucoma. With the identification of
glaucoma genes, issues such as how an abnormal gene product results in a
glaucoma phenotype, whether different mutations in the same gene can
explain phenotypic variability, and the possibility of gene-environment
interactions can be addressed.
Strategic Research Questions
What is the genetic component(s) of adult-onset primary open-angle
glaucoma? Recent advances in methodology now make it possible to perform
genetic analysis on complex late-onset diseases like adult-onset primary
open-angle glaucoma. Newly developed strategies increase the likelihood
that genetic loci associated with primary open-angle glaucoma can be
identified. Strategies to characterize the disease at the molecular level
are feasible once disease genes are cloned and characterized.
How do gene products responsible for glaucoma cause the disease? As
glaucoma causing/susceptibility genes are isolated, strategies to
determine whether their gene products are expressed in normal tissue, and
how mutations in them cause or increase the susceptibility to glaucoma,
must be devised.
How do specific mutations give rise to a specific phenotype? With the
identification of glaucoma genes, questions such as how an abnormal gene
product results in a glaucoma phenotype, whether different mutations in
the same gene can explain phenotypic variability, and if specific
mutations are predictive of progression or response to treatment can be
Do environmental factors or other gene products modify glaucoma gene
products? As genes are identified, prospective studies on how
gene-environment interactions affect the natural history and progression
of the disease should be implemented.
Can genetic subtypes of primary open-angle glaucoma be recognized
clinically? To date, there is no satisfactory explanation as to why there
are observed differences in progression rates and response to treatments
among glaucoma patients. Likewise, the basis of racial differences has not
been elucidated. Genetics may provide insight into the physiological
correlates that have been defined in clinical observations and
epidemiological studies. With the identification of glaucoma genes, cohort
studies should be undertaken to determine if progression rates and
response to treatment can be correlated with specific genotypes.
Can transgenic animal models be used to study the function of these
genes? Building an animal model with alterations in specific "glaucoma"
genes would greatly facilitate progress in understanding the
pathophysiology of the disease.
What are the roles of specific glaucoma-causing genes in ocular
development and function? Understanding the developmental biology of the
anterior segment will be advanced by the identification of genes and gene
products for congenital and developmental glaucomas. To study these genes
and gene products, models to test the effect of altering gene expression
during development must be developed.
Objective 2: Define the molecular and biochemical
mechanisms that lead to retinal ganglion cell death in human glaucoma and
in relevant animal models of related optic nerve injury.
Research Needs and Opportunities
Over the past century, the primary objective of glaucoma therapy and
research has been to lower intraocular pressure. Most research on glaucoma
has addressed either the mechanisms by which intraocular pressure becomes
elevated or ways to reduce intraocular pressure. More recently, there has
been a greater emphasis on the changes in the optic nerve head and retinal
nerve fiber layer as essential features of glaucoma. Furthermore, the
existence of normal-tension glaucoma and ocular hypertensives without
glaucoma has led to reassessment of the primacy of elevated intraocular
pressure in the etiology of the disease. These observations have shown
that a more comprehensive understanding of glaucoma etiology necessitates
studies of the fundamental processes controlling retinal ganglion cell
death. This recognition has stimulated research directed to those cellular
components of the posterior segment of the eye that are compromised by the
Advances in basic neuroscience have suggested ways that retinal ganglion
cells degenerate in glaucoma. During normal neuronal development,
including retinal development, cells are programmed to die and do so in a
precise manner. Research has shown that this form of cell death (called
apoptosis) may be involved in many neurodegenerative conditions, including
those involving retinal ganglion cell degeneration. For example,
transection of the optic nerve in animal models results in retinal
ganglion cell apoptosis, but the molecular program leading to cell death
remains to be established. Advances in the molecular genetics of neuronal
apoptosis have identified a number of genes that regulate neuronal cell
death and survival under normal and pathological conditions. Antiapoptotic
genes, proapoptotic genes, transcription factors, neurotrophic factors,
and cell cycle regulators have been described in these systems. Further
advances may provide a basis for experiments that will lead to an
understanding of the signaling cascades that initiate cell death vis-á-vis
transection and, more importantly, that may be involved in the axonal loss
and retinal ganglion cell degeneration that are the hallmarks of glaucoma.
Elevated intraocular pressure remains the most prominent risk factor in
the development and progression of glaucoma, yet the mechanisms by which
elevated intraocular pressure directly alters homeostasis of retinal
ganglion cells and the structure of the optic nerve head are unknown.
Mechanical forces created by pressure, flow, and stretch regulate gene
expression, cellular activity, and cell proliferation in a variety of cell
types. The signaling mechanisms or the mechanotransducers are the subjects
of intense research. Calcium, cyclic AMP, PGs, and growth factors act as
signaling molecules in several dynamic models in vitro.
Moreover, cell matrix interactions may be involved in the response to
pressure. Cell adhesion molecules like intercellular adhesion molecule-1
in the vascular endothelium are directly activated by shear stress and
appear to be responsible for inducing gene expression after mechanical
stress. The techniques used to study the effect of mechanical stress on
cells need to be adapted for studying the effect of pressure on the
retinal ganglion cells.
Hypoxia due to ischemia and decreased vascular perfusion has been
proposed as a factor leading to axonal damage, retinal ganglion cell
death, and remodeling of the optic nerve head in glaucoma. Selective
neuronal damage due to ischemia in the central nervous system (CNS) is
currently the focus of intense research. Neuronal vulnerability to damage
may be related to neuronal connectivity, vascularization, blood-brain
barrier, and trophic support by astrocytes or neurons. Recent studies have
demonstrated that cells respond to hypoxia via cellular oxygen sensors,
which regulate gene expression of glycolytic genes and a variety of growth
factors that affect vascular perfusion. Reactive oxygen species that can
be generated after ischemia may serve as triggers of neuronal apoptosis.
By extending this work to the eye, laboratory research aimed at testing
the role of vascular perfusion and hypoxia in retinal ganglion cell death
may provide mechanistic information and potential pharmacological targets
Cellular signaling pathways mediate cell-cell interactions, including
neuronal-neuronal cell interactions and neuronal and glial cell
interactions. These pathways may provide initial or secondary signals for
axonal degeneration, glial responses, and vascular perfusion in the
glaucomatous optic nerve, and for ganglion cell apoptosis in the retina.
Cellular signaling pathways, such as those mediated by nitric oxide,
neutrophins, transforming growth factor-ß (TGF-ß), and other
cytokines, may have a role in primary or secondary damage to the axons of
the retinal ganglion cells. Secondary responses may involve altering the
microenvironment surrounding the axons or modulating the extensive
remodeling of the tissue as the chronic disease process proceeds. It is
important to explore these and other regulatory pathways that may be
present in the optic nerve to establish their effect on local degenerative
and protective neuronal responses. Identification of mediator pathways in
the optic nerve is needed because these pathways may represent targets for
new therapeutic neuroprotective agents that can be developed for glaucoma.
Primate work has been critical in understanding glaucoma to date.
Although the monkey model of laser-induced elevated intraocular pressure
is probably the model most closely reflecting the human disease, it is
difficult to produce, gives highly variable results, and is expensive.
Developing a reliable model in a smaller and more readily accessible
laboratory animal in which genetic manipulations are possible would allow
experiments on specific aspects of the disease and therefore would greatly
facilitate understanding this disease process. Recently, significant
strides have been made in developing rodent models of glaucoma. One group
has reported a technique for measuring intraocular pressure in the mouse.
This methodology has the potential for genetic manipulation, giving
researchers techniques for exploring either genes that affect intraocular
pressure or genes that retard or accelerate glaucomatous loss. Using mice
and other small animals as models must be investigated, but careful
attention should be paid to demonstrating the relevance of observations in
animals to processes that occur in human tissue. Because glaucoma is a
uniquely human disease that ultimately must be studied in humans, access
to human tissue must be improved.
Strategic Research Questions
Can an animal model that is more reliable and more accessible than the
monkey model be found for the study of retinal ganglion cell death and
axonal loss in glaucoma? The use of more accessible and smaller laboratory
animals to study the mechanisms of retinal ganglion cell death and axonal
degeneration needs to be explored. Criteria for using these animals must
include susceptibility to a pressure-induced, chronic, progressive optic
neuropathy and an optic nerve structure with enough similarities to that
of humans so as to be relevant.
Can an animal model for normal-tension glaucoma be established? The
etiology of normal-tension glaucoma is poorly defined. An animal model of
normal-tension glaucoma would be highly useful in understanding neuronal
cell death in this form of glaucoma.
Can any of the rat or mouse models be used to study optic nerve damage
and retinal ganglion cell death caused by elevated intraocular pressure?
Existing models must be verified before proceeding with further studies.
Issues that must be addressed include whether intraocular pressure in
these animals can be measured accurately, whether the disease progression
mimics the chronic condition observed in humans, and whether retinal
ganglion cell death is caused by elevated intraocular pressure.
Can scientists determine whether the changes in the optic nerve head are
the result or the cause of death of retinal ganglion cells? Clinical
evidence points to the optic nerve head as the initial site of damage in
glaucoma. However, the possibility that structural changes in the optic
nerve head are the result rather than the cause of retinal ganglion cell
death needs to be considered, and experimental strategies to test this
possibility need to be devised.
Are there molecular mechanisms of mechanotransduction that may be
important in the regulation of responses to elevated intraocular pressure?
Are retinal ganglion cells or the astroglial cells supporting the axons of
the optic nerve sensitive to different levels of intraocular pressure?
Elevated intraocular pressure remains the most prominent risk factor in
the development and progression of glaucoma, yet the mechanisms by which
intraocular pressure directly alter the homeostasis of retinal ganglion
cells and the structure of the optic nerve head are unknown. Techniques
currently used to study the effect of mechanical stress on other cell
types need to be adapted for studying the effect of pressure on the
retinal ganglion cell.
How can collaborations between neuroscientists with expertise in other
neurodegenerative diseases and scientists interested in the neurobiology
of glaucoma be encouraged? Strategies to test the relevance of hypotheses
of neurodegenerative mechanisms to glaucomatous retinal ganglion cell
death need to be pursued. Collaborations with investigators studying other
neurodegenerative diseases would facilitate the transfer of generalizable
findings related to the neurodegenerative process to models of glaucoma.
Objective 3: Enhance understanding of the structure and
function of the aqueous humor outflow pathways at the cellular and
Research Needs and Opportunities
The factors that contribute to, influence, and regulate the outflow of
aqueous humor are central to understanding glaucoma, yet most of these
remain undefined. The continued lack of a suitable experimental model to
study the anterior segment components of glaucoma continues to present a
formidable challenge to progress in this area. As a direct consequence,
the armamentarium of medications available to enhance conventional outflow
facility, and thereby reduce intraocular pressure, remains limited.
Identifying and evaluating promising candidates for clinically useful
outflow drugs remain a high priority.
The long-held view that the increased resistance to trabecular outflow
results simply from a progressive accumulation of glycosaminoglycans
(GAGs) in the open spaces of the trabecular meshwork has not been borne
out. Indeed, most recent studies indicate that a progressive loss of most
GAGs in the human trabecular meshwork occurs with age alone, as well as in
glaucoma. A consensus still favors a role for GAGs in outflow, but that
role must be reevaluated.
As the view of increased outflow resistance caused by a progressive
accumulation of GAGs has waned, alternative candidates have been
identified. Many of these new candidates are structural or regulatory
proteins produced by the trabecular meshwork or are regulatory proteins
carried to the meshwork with aqueous flow. Promising avenues for study
remain in the area of meshwork constituents that regulate GAGs and related
extracellular matrix components, particularly matrix metalloproteinases
and their inhibitors. A recently identified shunt pathway that delivers
additional plasma-derived proteins from the ciliary body stroma to the
aqueous humor via the root of the iris is another potential source of
Most investigators remain convinced that the solution to the "source
of resistance" question resides within the extracellular matrix of
the juxtacanalicular region of the trabecular meshwork, either entirely or
in conjunction with factors in aqueous humor or in combination with
structural features of the inner wall of Schlemm's canal. If the
extracellular matrix is the key to understanding the mechanisms of outflow
resistance, then the cells that produce and maintain this matrix must be
the force that turns that key. Understanding the biology of the cells that
constitute the trabecular meshwork is essential to understanding the
extracellular matrix and its turnover and regulation. Modifications of
cell shape, along with an array of receptors and channels, have been
recently identified. All of these should be aggressively explored,
provided that biologically relevant assays can be demonstrated to have
clear meaning for outflow dynamics in vivo.
Among the most interesting intrinsic proteins produced by the meshwork
is the recently identified TIGR/myocilin protein, a protein whose
expression in trabecular meshwork cells in vitro is influenced
by steroids, a class of compounds known to elevate intraocular pressure in
sensitive individuals. Recent linkage of TIGR to the juvenile glaucoma
gene, and the subsequent finding that the TIGR protein is identical to
myocilin (a protein found in the retina), provide an opportunity to probe
for fundamental mechanisms of outflow. In the retina, myocilin is a
cytoskeletal protein, suggesting possible mechanisms by which this protein
may affect outflow facility. The role of TIGR/myocilin in particular and
the cytoskeleton proteins in general requires further investigation.
The biology of the trabecular meshwork presents investigators with a
number of experimental challenges. While capable of identifying the
constituents and amounts of various tissue components, biochemical studies
rarely provide information on the location of the materials being
measured. By contrast, histochemical studies can provide information on
the location of certain constituents, but the amounts present are
difficult to discern. It could easily be the case that both concentration
and location of various constituents could be critical in modulating
Developing newer methods that bridge the critical gap between
biochemistry and histochemistry appear to offer promise in addressing
basic questions of trabecular cell biology and meshwork matrix biology.
In situ hybridization and ultrastructural techniques like
quick-freeze and deep-etch, which preserve the structure of extracellular
matrices, may offer insights previously unattainable. The recent
development of several novel organ culture systems has proven a valuable
adjunct to the study of the trabecular meshwork, particularly in the
absence of a useful animal model for the anterior segment components of
human glaucoma. These systems, when used in conjunction with cell culture
and related methods, offer the potential for unraveling the basic
questions of trabecular cell function and the respective roles that each
function might play in the physiology of outflow. Recent attempts to
couple anterior segment perfusion methods with methods of molecular
genetics, while in their infancy, might offer the possibility for
ultimately providing a means to alter expression of various gene products
intrinsic to meshwork cells and then to directly determine the influence
of the alterations on outflow facility. Results of such studies could
dramatically change mechanistic hypotheses and simultaneously provide a
much-needed focus for molecular and population geneticists as they
continue their search for the gene or genes that are linked to primary
An assessment of research needs in the area of aqueous outflow also
requires consideration of the uveoscleral outflow pathway. Exploiting this
pathway to augment aqueous outflow has proven to be of tremendous clinical
value, as evidenced by the clinical efficacy of prostanoid derivatives
such as latanoprost in augmenting uveoscleral outflow. With clinical use
of this new medication, however, have come questions regarding its mode of
action. Clearly, the basic mechanisms underlying uveoscleral outflow need
to be understood more fully. To accomplish these goals, more reliable
clinical methods for measuring uveoscleral outflow will be needed, and
those presently available will need to be refined.
Strategic Research Questions
Can a suitable animal model be found that recreates the anterior segment
aspects of primary open-angle glaucoma? Investigations should be
undertaken to determine the feasibility of using animal models to study
anterior segment aspects of primary open-angle glaucoma. Such models would
greatly facilitate understanding outflow physiology and provide a means
for evaluating the efficacy of drugs that enhance outflow.
What is the molecular and cellular basis of aqueous outflow resistance?
Understanding the molecular factors that contribute to and regulate
outflow resistance in the normal pathway is critical to identifying
candidate molecules that contribute to glaucomatous pathology and
characterizing pathways amenable to drug intervention.
What are the critical changes in structure and function of cells in the
outflow tract that produce a decline in outflow facility? Because almost
all forms of glaucoma are associated with an increase in resistance to
outflow, determining the site of resistance is central to understanding
this disease. Understanding the biology and physiology of the cells and
tissue that constitute the site of resistance are essential to
understanding the alterations that cause a decrease in outflow facility in
How can novel findings from cell culture studies be related to outflow?
Because no animal model exists, much current knowledge is derived from
studies of trabecular meshwork cell culture. The relevancy of findings in
cell culture must be pursued in organ culture and other systems, where
cellular and tissue interactions can be studied.
Can researchers identify candidate cell products relevant to outflow by
coupling organ perfusion with molecular biology? Strategies that couple
anterior segment perfusion methods with methods of molecular genetics
provide a means to genetically alter expression of proteins in meshwork
cells and determine the influence of these alterations on outflow
facility. If feasible, this methodology affords the most direct way to
test the physiological role of various molecules in outflow.
Can researchers develop clinically useful trabecular outflow drugs for
reduction of intraocular pressure? Identifying and evaluating promising
candidates for clinically useful outflow drugs are high priorities. As
advances in understanding the physiology of outflow are made, strategies
based on these advances should be implemented so that they can expand
researchers' armamentarium of glaucoma medications to include drugs that
enhance conventional outflow facility.
Objective 4: Develop a better understanding of anterior
Research Needs and Opportunities
The immune system protects the eye from destructive infections. (Also
Diseases Report section on corneal inflammation and wound healing.)
As in other organ systems, the immune system within the eye must maintain
a delicate balance between protection and overreaction, since the latter
response can result in ocular diseases such as uveitis. From a clinical
perspective, progress has been made in classifying anterior segment
inflammation. However, a consensus still does not exist for the
nomenclature to describe clinical uveitis. The natural history of uveitis
remains poorly characterized.
Vision scientists are beginning to define the complex interactions of
cytokines, lipids, and free radicals in anterior segment inflammation and
immunoregulation. Improved animal models are emerging, but models of
anterior segment inflammation are still limited. These models would be
helpful in identifying new and safer ways of enhancing successful
filtration surgery. In addition to immune response genes, genetic factors
are being recognized in entities like the iritis associated with juvenile
rheumatoid arthritis and Blau syndrome. Genes responsible for a
predisposition to anterior uveitis need to be sought and characterized.
The role of apoptosis as a contributor to immunoregulation within the eye
has been recognized and should be further defined.
Marked progress has been made in identifying infectious causes of
inflammation, and further effort in this area should provide important new
information. Strides have also been made in defining the mechanism by
which leukocytes come to the eye. The potential exists to define this
system to further understand ocular inflammatory disease and develop
improved therapies. Enhanced drug development and delivery are still
necessary to control anterior segment inflammation.
Strategic Research Questions
Can a consensus on developing nomenclature and defining outcome measures
be found? Consistent classification criteria must be established and
incorporated in prospective studies aimed at determining the natural
history and progression of anterior uveitis. A consensus for
classification and outcome measurements for uveitis is needed so that the
testing of new drugs in clinical trials can proceed.
Can genetic factors that may affect the development and progression of
certain inflammatory disorders be identified? Genetic studies need to be
expanded beyond secondary inflammations like iritis associated with
juvenile rheumatoid arthritis and Blau syndrome. Strategies to carry out
studies aimed at identifying genes responsible for a predisposition to
anterior uveitis need to be designed.
What do animal models tell us? Improved animal models are emerging, but
models of anterior segment inflammation are still limited. Using animal
models may provide important insights into treating or preventing
inflammation of the anterior segment. Current animal models need to be
fully characterized and new models must be developed.
Which cytokines mediate anterior segment inflammation? Candidate
cytokines have been identified. Strategies to determine the role that each
plays in the inflammatory response are now needed.
Can additional infectious causes be identified? Marked progress has been
made in identifying infectious causes of inflammation. Further effort in
this area should provide important new information.
Can strategies be developed for improved drug development? Strategies to
develop new drug and delivery systems to control anterior segment
inflammation need to be devised and implemented.
Objective 5: Improve our understanding of the nature and
course of glaucoma, incorporating studies of comorbidity, natural history,
and genetics, with special emphasis on Hispanic, Native American, and
Research Needs and Opportunities
Results from the Baltimore Eye Study, the Beaver Dam Eye Study, and the
Barbados Eye Study have firmly established race as a significant risk
factor for primary open-angle glaucoma. Though there is variation in
estimates that reflects the different populations studied, all of these
studies confirm a substantially higher prevalence of primary open-angle
glaucoma in blacks. Furthermore, the rates for blindness due to primary
open-angle glaucoma in African-Americans are six times higher than the
rates for the Caucasian population, reflecting not only an increased rate
of the disease but also more severe disease. Other ethnic and racial
groups have been studied less rigorously. There is a dearth of information
about the prevalence and incidence of glaucoma in Hispanic and Native
American populations; therefore, studies need to be initiated in these
populations to obtain this critical information.
Questions of comorbidity have not been adequately resolved. Studies that
sought to investigate the relationship between glaucoma and myopia have
yielded ambiguous results. There is also incomplete and equivocal
epidemiologic information available on the relationship between glaucoma
and vascular disease. The need to resolve the question of comorbidity is
highlighted by the fact that the rate of hypertension is high in minority
Risk factors for glaucoma need to be identified and verified. The
question of whether there are susceptibility genes that can affect the
course of the disease, especially in regard to ethnic and racial
differences, is being actively pursued. With advances in genetics,
environmental effects also need to be understood so that researchers can
better determine the interaction of genetics and environment in the
natural history of this disease. Currently, important known risk factors
for glaucoma include elevated intraocular pressure, advanced age, optic
disc abnormalities, and family history of primary open-angle glaucoma.
However, the contribution each of these known risk factors to the
progression of glaucoma is unknown. Questions remain concerning whether or
not a compromised vascular system contributes to glaucomatous pathology.
The difficulty of adequately measuring ocular blood flow hampers progress
in understanding its impact on the survival of retinal neurons and visual
The large number of gaps in knowledge about the nature and course of
glaucoma point to the need for rigorous epidemiologic studies.
Well-designed studies that use systematically selected sample sizes (from
census tract data, for example) have high rates of participation by the
study sample, and use standard procedures for assessing disease and
measuring risk factors needed to address these issues. There is also a
critical need for better population-based screening procedures that are
simple, inexpensive, portable, and effective. Developing such methods will
be useful for testing populations that historically have limited access to
formal healthcare systems, for determining more accurately the incidence
and prevalence of glaucoma in epidemiologic studies, and for screening
large populations in remote regions of the world.
Strategic Research Questions
What are the prevalence and incidence of glaucoma in different ethnic
backgrounds? Studies clearly indicate a substantially higher prevalence
and incidence of glaucoma in black populations. Prospective studies to
obtain prevalence and incidence data in other ethnic groups, particularly
Hispanics and Native Americans, are needed to assess the public health
impact as it relates to these groups.
How many people have glaucoma and how severe is their visual impairment?
Well-designed studies that use systematically selected samples, that have
high rates of participation, and that use standard ascertainment
procedures are necessary for a more definitive measure of prevalence.
These studies will fill in gaps in knowledge about the natural history and
course of glaucoma.
How is the course of glaucoma affected by the presence of other
diseases/conditions? Prospective studies are called for to resolve
questions of comorbidity. Emphasis should be placed on studies that seek
to define the natural history and progression of glaucoma in the presence
of other diseases associated with aging and/or minority populations, such
as adult-onset diabetes and hypertension.
Are environmental risk factors for glaucoma identifiable? Are there
genetic risk factors for glaucoma? Prospective studies should be
implemented to identify any additional risk factors or physiological
correlates associated with the disease to verify the effect of known risk
factors and to determine the relative contribution of each risk factor to
the etiology of glaucoma. As susceptibility genes are identified, genetic
epidemiological studies will be required to sort out the interaction of
genetics and environment to understand the role each plays in the etiology
of the disease.
What is the impact of visual impairment on health-related quality of
life? Future epidemiological studies must incorporate quality-of-life
measurements to provide researchers with a complete picture of the natural
history of this disease.
What are the best methods of screening for glaucoma? Screening
strategies should center on population-based procedures that are simple,
inexpensive, portable, and effective. Implementing these screening methods
include testing populations that historically have limited access to
formal healthcare systems, determining more accurately the incidence and
prevalence of glaucoma in epidemiologic studies, and screening large
populations in remote regions of the world.
What is the role of ocular blood flow and microcirculation of the optic
nerve in glaucoma, and how does it relate to visual function? Longitudinal
studies that incorporate both blood flow and visual field measurements are
necessary to better understand the role of ocular blood flow in glaucoma.
What factors explain why many individuals with high intraocular pressure
do not develop glaucoma, while some individuals with normal pressures do
develop glaucoma? Epidemiologic studies focused on cohorts of ocular
hypertensive individuals and normal-tension glaucoma patients should be
implemented to identify potential risk factors and other physiological
correlates associated with the development of glaucoma in these
Objective 6: Develop improved diagnostic techniques
encompassing measures of visual function, optic nerve, and nerve fiber
layer structure, in situ and for clinical applications of
Research Needs and Opportunities
In recent years, the diagnosis of glaucoma has emphasized the presence
of visual field loss and observable glaucomatous optic neuropathy, with
recognition of high intraocular pressure as a risk factor rather than an
essential disease characteristic. Researchers have achieved a greater
ability to identify early functional and structural abnormalities caused
by glaucoma. With new statistical analysis packages for visual field and
imaging devices, there is more agreement and certainty regarding the
presence of abnormal findings. However, the large variability inherent in
these measures continues to hamper the identification of disease
progression. Developing reliable methods to quantitatively distinguish
progression of glaucomatous visual field loss from long-term variability
is of critical importance. Such techniques are needed for better outcome
measures in clinical treatment trials in glaucoma, for the clinical
management of patients, and for clinical research studying the underlying
basis of glaucomatous optic nerve damage. Because of the variability of
optic nerve topography in normal eyes, well-designed longitudinal studies
are needed to learn whether the new diagnostic instruments providing
real-time measurements of the optic nerve will improve the ability of
clinicians to detect glaucoma and monitor its progression.
The availability of more sensitive visual function tests and new methods
of quantifying the topography of the optic nerve head and the retinal
nerve fiber layers have provided an opportunity to define the relationship
between visual function losses and structural changes in glaucoma.
Characterizing these relationships will improve understanding of the
clinical course of glaucomatous damage and help to identify the most
effective methods for detecting and monitoring pathologic changes.
Advances in genetics may be useful in classifying different subtypes of
glaucoma and assist in improving diagnosis and treatment. With these
opportunities to characterize pathology at a molecular genetic level comes
a need for prospective longitudinal studies to expand the search for risk
factors in these diseases and improve diagnostic techniques.
At this time, there is little information concerning the impact of
visual function loss produced by glaucoma on a person's ability to perform
various daily activities. Researchers need to answer a number of questions
related to visual loss and quality of life to optimize intervention
strategies, such as: At what level of visual field loss is there an
impairment of task performance or a negative impact on a person's quality
of life? What are the changes in quality of life associated with
progression of glaucomatous loss? With visual loss, what other factors
influence a person's ability to perform daily activities of living? Will
improved diagnostic and monitoring techniques provide true benefit to the
patient in terms of vision or quality of life? The NEI's Visual
Functioning Questionnaire (NEI-VFQ) can provide the instrument for some of
New clinical measures for early detection of glaucoma have improved
specification of the changes found in visual function and optic nerve
topography. When correlated with newly identified genetic markers, these
clinical measures may help identify the subclasses of glaucoma. The
combination of epidemiological, clinical, and laboratory research is
fundamental to a better understanding of the disease in humans, which in
turn will lead to the development of more effective therapies and improved
designs for prospective intervention studies. Clinical studies
encompassing visual function, optic nerve and nerve fiber layer structure,
and quality-of-life measurements should improve the detection of disease
progression and the effects of glaucoma on vision and quality of life.
Strategic Research Questions
What is the best method for determining progression of visual loss in
glaucoma? Reliable methods to distinguish progression of visual field loss
from long-term variability are needed. Longitudinal studies that directly
compare techniques should help scientists discern the most sensitive and
specific methodology for determining disease progression.
What is the relationship between visual function loss and structural
changes to the optic nerve and retinal nerve fiber layer in glaucoma? To
characterize the pathology of glaucomas more comprehensively, prospective
longitudinal studies that incorporate existing measures of visual
function, optic nerve, and nerve fiber layer structure are needed.
Strategies to define the relationship between visual function losses and
structural changes in glaucoma should include standard visual function
tests, SWAP, and new methods of quantifying the topography of both the
optic nerve head and the retinal nerve fiber layers.
What is the relationship of visual loss to task performance,
occupational demands, and quality-of-life measures? There is a growing
recognition of the importance of evaluating the health outcomes and
quality-of-life changes imposed by glaucoma and its treatment. Clinical
studies should include quality-of-life measurements to determine the
effects of glaucoma and its treatment on a person's ability to carry out
daily tasks. Such information will help clinicians devise more effective
What is the genetic basis for the different etiologies of glaucomatous
optic nerve damage? As glaucoma genes are identified, phenotype
descriptions should include detailed optic nerve structure and nerve
function assessments to determine if there is a correlation between
structural and functional damage with specific genotypes. Correlation of
optic nerve damage with genetic markers may assist in classifying subtypes
of glaucoma and help predict the course of the disease.
What is the effect of aging on visual function and optic nerve/retinal
nerve fiber layer structure? Prospective longitudinal studies to determine
optic nerve/retinal nerve fiber layer changes as a function of aging are
needed. In addition to improved baseline data against which glaucomatous
loss can be measured, this information may provide insight into why aging
increases the risk for glaucoma.
Objective 7: Identify neuroprotective strategies that
could prevent retinal ganglion cell death, promote survival, or stimulate
Research Needs and Opportunities
There is a growing realization that treating glaucoma solely by lowering
intraocular pressure is not a comprehensive therapeutic approach. Over the
last 5 years, there has been a burgeoning interest in developing agents
that will protect neuronal cells from glaucomatous damage. Neuroprotection
can be broadly envisioned as a pharmacological means to prevent or slow
retinal ganglion cell degeneration or promote regeneration of damaged
retinal ganglion cells. Neuroprotection encompasses classic
pharmacologic-type molecules, biologics, and gene therapy approaches. To
begin thinking about these types of approaches, glaucomatous
neurodegenerative processes must first be established and characterized in
animal models to identify target pathways where neuroprotective agents can
Molecular mechanisms that define the neuroprotective and survival
effects of neurotrophic factors and their receptors currently under study
in a variety of in vivo and in vitro models need to be
expanded to include retinal ganglion cells. Altering cellular homeostasis
in the retina or in the optic nerve has been suggested to result in
retinal ganglion cell apoptosis and modulation of the apoptotic pathway.
This points to a number of targets to investigate. For example, disruption
of homeostasis may include glutamate excitotoxicity, production of
reactive oxygen species, depletion of intracellular antioxidants, or
increase in intracellular calcium. This disruption may, in turn, induce
the expression of a number of apoptotic genes/pathways including bcl-2 and
the interleukin-1 beta-converting enzyme protease. Ongoing research in
neurodegenerative disorders in which apoptosis plays a central pathogenic
role should provide new approaches to study the mechanisms of retinal
ganglion cell death and neuroprotective strategies in glaucoma.
Glutamate is likely to play an excitotoxic role in the death of retinal
ganglion cells, as it does elsewhere in the CNS. Within the retina,
photoreceptors and bipolar cells contain high concentrations of glutamate,
which they use as a neurotransmitter. Müller cells are actively
involved in maintaining extracellular glutamate levels by taking up the
released transmitter. Many retinal glutaminergic receptors have been
identified: metabotropic receptors, AMPA receptors, kainate receptors, and
NMDA receptors. Stimulation of the NMDA receptors in particular leads to
activation of a variety of calcium-dependent processes intracellularly and
is important for glutamate excitotoxicity and neuronal damage. Several
noncompetitive NMDA antagonists and NMDA open-channel blockers have been
shown to limit neuronal loss in animal models of neural ischemia and
chronic glutamate intoxication and are currently being tested in human
neuronal degenerative diseases. Other antagonists that prevent glutamate
release from presynaptic storage may also be useful in blocking
excitotoxicity. However, glutamate is an essential neurotransmitter. Thus,
complete blockade of all glutamate activity seems not to be a viable
therapeutic approach. Identifying agents that primarily interfere with the
neurotoxic effects of elevated glutamate levels may be pharmacologically
Another molecule that can play a key role in neuronal degeneration in
the CNS is nitric oxide. Although at physiological concentrations the
molecule acts as a neurotransmitter and vasodilatory agent, nitric oxide
is neurodestructive at excessive levels. Since nitric oxide synthase, the
biosynthetic enzyme for nitric oxide, is present in the retina and the
optic nerve, nitric oxide may contribute to cell death and glaucomatous
pathology. Pharmacological inhibitors of the various forms of nitric oxide
synthase are being developed for treating other diseases in which nitric
oxide has been implicated and may also prove useful for accomplishing
neuroprotection in glaucoma.
Because elevated calcium has been implicated in neuronal cell death,
calcium channel blockers have been tried for the treatment of ischemic
injury. Adenosine agonists and drugs that increase adenosine appear to
reduce neuronal damage in cerebrovascular disease. Experiments have
demonstrated that adenosine reduces neuronal damage in reperfusion injury
and causes vasodilation of retinal vessels. Conceivably, adenosine
agonists could improve blood flow to a compromised optic nerve in
glaucoma. To the extent that compromised vascular perfusion of the optic
nerve may occur in glaucoma, antagonists at the receptors of these
mediators may prove useful in restoring optic nerve blood flow. Production
of neurotoxic free fatty acids, such as platelet-activating factor (PAF)
from endogenous phospholipids, may occur in the glaucomatous optic nerve.
PAF antagonists reduced neuronal damage in experimental models of retinal
injury. They may prove to be relevant to glaucoma.
Since neurotrophic factors enhance the survival of retinal ganglion
cells and other neurons, these agents or their mediators are interesting
candidates for gene therapy approaches. Experiments using transgenic
animals and knockout animals have demonstrated that overexpression or
underexpression of certain gene products can interfere with the apoptotic
mechanism in retinal ganglion cells. Thus, a therapy based on
vector-targeted gene transfer to retinal ganglion cells, perhaps through
intravitreal administration, may eventually prove useful as a novel
therapeutic approach for glaucoma. An example of this therapeutic approach
would be to supply retinal ganglion cells with neurotrophic factors that
may be in limiting concentration, thereby resulting in activation of the
cell death cascade.
Strategic Research Questions
Can the cascade of events leading to retinal ganglion cell death be
identified, and can pharmacological interventions that are neuroprotective
be identified? Glaucomatous neurodegenerative processes must be
established and characterized in animal models in order to identify target
pathways where neuroprotective agents can act. Candidates for
neuro-protection being tested to determine their ability to halt or slow
the degenerative process in other diseases suggest possible candidate
therapeutics that can be tested in glaucoma models.
Can suitable approaches to monitor retinal ganglion cell viability and
function in animal models be developed to study the efficacy of
neuroprotective agents? Reliable, reproducible endpoints are needed to
determine the efficacy of neuroprotective agents in animal models.
Ultimately, it must be demonstrated over time that the neuroprotective
agent preserves retinal ganglion cells and, hence, visual function.
Therefore, inherent in the development of models is developing a way to
test cell viability and visual function in the animal.
Can in vitro systems used to screen neuroprotective agents for
glaucoma be identified? Developing in vitro screening systems
would facilitate the identification of candidate molecules for
How can researchers devise strategies to deliver pharmacological agents
locally to the retina and optic nerve? A confounding factor in developing
neuro-protection strategies for glaucoma is the difficulty in delivering
drugs to the retina and optic nerve. Coupled with developing
neuroprotective therapies is the need to develop delivery strategies to
introduce therapeutics to their target sites.
How can side effects of neuroprotective drugs be minimized? Because it
is very likely that any useful neuroprotective drugs may also interfere
with normal processes, specificity must be optimized either by modifying
the agent or using a targeted drug delivery system. Further complicating
the use of these agents is the chronic nature of glaucoma, thus
necessitating the need for long-term local exposure of the retinal
ganglion cells and increasing the probability of unattended side effects.
These confounding factors must be factored into the development of any
drug design strategies.