National Plan for Eye and Vision Research
Corneal Diseases Program
The cornea is the clear tissue at the front of the eye that serves two specialized functions: It forms a protective barrier that shields the eye from the external environment and serves as the main refractive element of the visual system, directing incoming light through the lens for precise focusing on the retina. Vision depends on the cornea acquiring transparency during development and maintaining clarity throughout adult life. In the United States, corneal diseases and injuries represent some of the most painful ocular disorders and are the leading cause of visits to eye care clinicians. In addition, 60 percent of the U.S. population have refractive errors that need correction for sharper vision. Worldwide, corneal infectious diseases have compromised the vision of more than 250 million people and have blinded over 6 million of them.
After a thorough evaluation of the entire Program, the Corneal Diseases Panel recommends the following goals for the Program for the next 5-year period:
- Explore the biology of the ocular surface as a physiological system, consisting of the tear film, cornea, conjunctiva, lacrimal and meibomian glands, eyelids, and their innervations, to gain a better understanding of the interaction and regulation of these components under normal and pathological conditions.
- Investigate corneal infectious and inflammatory processes and immunological responses to develop treatments to reduce keratitis and prevent blindness.
- Apply the knowledge acquired from discoveries in the basic science of the cornea and other tissues of the ocular surface to the diagnosis, prevention, and treatment of ocular injury and disease.
Recent NEI-funded research has led to significant progress in defining the composition and function of the tear film and the role of its components in maintaining the health of the ocular surface. It is now recognized that the tear film is a complex, dynamically regulated fluid. Scientists have identified over 500 components in tears. These include innate defense molecules, such as antimicrobial peptides, growth factors, proteases and their inhibitors, and a variety of cytokines. Also found in tears are novel molecules whose functions are beginning to unfold—including lipocalin, which regulates the outermost lipid layer of the tear, and lacritin, a modulator of tight junction permeability. While many of these substances are derived from lacrimal or meibomian gland secretions, the cornea and conjunctiva also contribute a variety of components to the tear film, such as mucins, which are essential for innate defense, surface hydration, and refraction. The actions of these compounds do not occur in isolation and may well be modulated by association with other tear components. New molecular and spectroscopic techniques have been developed and are beginning to unravel the protein-protein and protein-lipid interactions that occur in the tear film.
Recent studies of the causes and mechanisms involved in tear deficiency have led to the suggestion that dry eye syndromes may involve inflammatory processes. Translational research has led to the development of therapeutic strategies that target ocular inflammatory responses and increase tear production as a means of managing dry eye diseases. The importance of hormonal influences in maintaining lacrimal and meibomian gland function is emerging. Studies of altered protein trafficking in the lacrimal gland suggest that the dry eye in Sjogren syndrome may involve autoantigens misdirected to the plasma membrane from intracellular sites where they are attacked by regulatory lymphocytes.
Significant progress has been made in understanding the pathophysiology of blinding corneal infections. The molecular genetic characteristics of herpes simplex virus type 1 (HSV-1) and the role of the host tissue during the acute and latent periods of infection are being vigorously explored. The NEI-sponsored Herpetic Eye Disease Study demonstrated the efficacy of oral acyclovir in reducing HSV-1 recurrences by 40 percent. River blindness, or onchocerciasis, is a parasitic infection transmitted by black flies. In this immune-mediated disease, Th2 lymphocytes respond not only to the parasite but also to symbiotic bacteria that are released in the cornea from larvae of the parasitic microfilaria. This knowledge likely will lead to more precise diagnoses and more effective treatments for this globally blinding disease. Studies also continue on the immunological response to trachoma, a blinding chlamydial disease prevalent in the tropics. Antibiotic treatment of entire villages over the past 5 years has been proven to be an effective trachoma eradication strategy.
Knowledge about inherited corneal diseases has increased considerably over the past 5 years and will lead to better diagnosis and therapy. The NEI-funded Collaborative Longitudinal Evaluation of Keratoconus Study established that keratoconus is a slowly progressing, asymmetric disease, but when patients are treated with rigid contact lenses, surprisingly good vision is achieved. Along with the discovery of new corneal dystrophies, molecular genetic studies have identified gene loci for more than 30 of these disorders, and a variety of gene mutations are associated with distinctive clinical and histopathological characteristics. For example, more than 20 mutations of the TGFBI (BIGH3) gene have been found in 14 clinically distinct disorders, including various types of granular and lattice corneal dystrophies. Similarly, a number of phenotypes of macular corneal dystrophy have been attributed to over 70 distinct mutations in the CHST6 gene. Defects in this sulfotransferase gene alter the processing of proteoglycans in the stroma, such as lumican and keratocan, which are essential for optical clarity.
Substantial progress has been made in using a variety of gene knockout models to examine the role of specific stromal molecular components, such as small, leucine-rich proteoglycans, in corneal transparency. Transgenic and knockout studies have established the essential role of the Pax-6 gene during corneal and lacrimal gland development. Proper development of the lens and its signals is required for normal corneal development. Ongoing studies of gene expression changes during development will expand our knowledge of the specific contribution of these molecules in developing and maintaining transparency.
Corneal trauma, chemical burns, and refractive surgery induce changes in epithelial and stromal cells to repair the wound. Considerable basic knowledge has been acquired regarding regulation of cell-cell and cell-matrix adhesion properties, cell death, signaling molecules invoked during epithelial and stromal cell migration and proliferation, and production of new extracellular matrix by activated stromal cells. The epithelial cells on the corneal surface are continuously replaced by new cells derived from stem cells located in the corneoscleral limbus (corneal periphery). Efforts to identify molecular markers and morphological characteristics of these cells are ongoing. Recent evidence suggests that stem cells exist in a variety of adult tissues, and current studies are examining ocular surface tissues for this possibility. Epithelial stem cells grown on membranes outside the body have been successfully transplanted to restore transparency to the ocular surface damaged by diseases such as Stevens-Johnson syndrome and chemical burns. Unlike most other cells, human corneal endothelial cells generally do not proliferate. However, recent studies of endothelial cell cycle regulation suggest that it may be possible to coax these cells to divide, thus opening a promising avenue for repair of diseased or injured endothelial tissue.
NEI-funded research has contributed to the development of technological innovations that have had a significant impact on clinical care. Silicone hydrogel contact lenses, which allow physiological levels of oxygen to reach the ocular surface, have improved the safety of continuous-wear contact lenses. Progress continues in correcting refractive error by laser-assisted in situ keratomileusis and in understanding the biological consequences of this procedure. Ongoing development of tools to measure higher order aberrations will lead to better vision after refractive surgery. Recent development of the femtosecond laser has encouraged researchers to study partial-thickness keratoplasty, a less invasive surgical procedure that will likely reduce the need for corneal transplantation. Advances in imaging the cornea in vivo, including wavefront imaging, optical coherence tomography, and confocal microscopy, have provided new methods for studying postsurgical and pathological changes in the optical and biomechanical properties of the cornea.
Corneal transplantation has a success rate greater than 90 percent for first-time grafts and remains the most widespread and successful form of solid-tissue transplantation. However, immune rejection remains the leading cause of corneal graft failure. Studies over the past 5 years have revealed the importance of both donor and host antigen-presenting cells and the critical role of minor histocompatibility antigens in provoking corneal graft rejection. Donor age requirements and tissue quality limit the availability of donor corneas. The NEI-funded Cornea Donor Study is a prospective study to determine the graft failure rate over a 5-year followup period by comparing tissues obtained from donors older than 65 years of age with those of younger donors. The NEI also supports tissue bioengineering studies to generate corneal replacements in vitro, thereby supplanting the need for donor eye tissue.
After carefully considering research progress and current research needs and opportunities, the Corneal Diseases Panel recommends the following objectives to increase knowledge of the ocular surface system and translate this knowledge into clinical practice for the prevention and treatment of corneal disorders:
With respect to the goal of understanding the biology of the ocular surface system:
- Characterize the genes and proteins expressed in tissues of the ocular surface system; determine the functional consequences of changes in expression and molecular interactions; and determine the epigenetic, hormonal, neural, and environmental influences under both normal and pathological conditions.
- Describe intercellular signaling between layers of the cornea as well as between various tissues of the ocular surface system to understand its function as a unified physiological system.
- Elucidate the intracellular pathways and diverse effector mechanisms activated by extracellular inputs such as neurotransmitters, hormones, cytokines, and growth factors.
- Probe changes of gene and protein expression in the developing and mature cornea, including the changes in response to signals derived from the lens and other sources.
- Identify and characterize the stem cells of each tissue that make up the ocular surface system, define the ocular stem cell niches, and determine the molecular and structural attributes that maintain stem cells and promote their differentiation.
With respect to the goal of understanding infectious, inflammatory, and immunological processes affecting the cornea:
- Elucidate the pathophysiology of the ocular surface tissues in response to infection, investigate the defensive mechanisms invoked by infectious diseases, and determine the factors that compromise these mechanisms.
- Investigate interactions of the innate and adaptive immune systems with the tissues of the ocular surface system and characterize the impairment of thesesystems in autoimmune and other corneal diseases.
- Explore, characterize, and analyze the causes of corneal graft rejection and neovascularization and determine the signals that disrupt the immunoregulation of the anterior chamber of the eye.
With respect to the goal of translating discoveries into the prevention and treatment of ocular surface disorders:
- Gain an understanding of the epidemiology of and risk factors for infectious and inflammatory corneal and ocular surface diseases to develop preventive strategies.
- Develop vaccines and other novel therapeutic interventions for blinding viral, bacterial, fungal, and parasitic corneal and ocular surface diseases.
- Develop new technologies for drug delivery, gene therapy, surgery, and tissue bioengineering for treating disorders of the ocular surface system.
- Address the consequences of interventions such as wound healing after refractive surgery and tear film function after drug treatment.