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Back To Vidyya Report On Glaucoma

Information From The National Eye Institute

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 characteristic.

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 $29,935,000.

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.

  1. Latanoprost—Initial 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.
  2. Dorzolamide—Although 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 synthesis—mitomycin-C and 5-fluorouracil—are 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 opportunity.

PROGRAM OBJECTIVES

Following are the objectives of the Glaucoma Program over the next 5 years.

  • 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 populations.
  • 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 products.

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 the study.

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 addressed.

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 glaucomatous process.

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 in glaucoma.

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 molecular level.

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 candidate proteins.

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 outflow.

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 open-angle glaucoma.

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 glaucomatous tissue.

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 segment immunology.

Research Needs and Opportunities

The immune system protects the eye from destructive infections. (Also see Corneal 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 African-American populations.

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 populations.

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 function.

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 subpopulations.

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 genetics.

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 these investigations.

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 intervention strategies.

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 regeneration.

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 act.

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 useful.

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 neuroprotection strategies.

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.


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Editor: Susan K. Boyer, RN
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