Cornea Research Takes Center Stage

Highlights of the 25th Biennial Cornea Research Conference.

BY MARK B. ABELSON, M.D., GEORGE OUSLER, STEPHANIE LEUNG AND CIERA MAFFEI

The research presented at this year's Cornea Research Conference, held at the Schepens Eye Research Institute in Boston, included a breadth of new data on the basic science of infection, angiogenesis and the ocular surface. Although all of the information presented is valuable, it would be impossible to report the details of every presentation and poster. In this article, we will share the findings we think were especially relevant to clinical applications.

Infection

Research on ocular infection focused on the recent rise of Acanthamoeba keratitis (AK) cases, as well as the epidemiology and basic science of the disease. Acanthamoeba — which can be found in water or soil — can attack the cornea and cause keratitis. A history of trauma to the cornea, direct contact with contaminated water, improper contact lens care and the use of contact lenses while swimming or showering can increase the risk for Acanthamoeba infection.¹

Charlotte E. Joslin, O.D., discussed the recent AK epidemic originating in Chicago, which had prompted the Centers for Disease Control (CDC) to begin a multistate investigation in March 2007. Preliminary results of both the CDC and Dr. Joslin's group implicated Complete MoisturePlus (CMP) Multi-Purpose Solution (Advanced Medical Optics [AMO]) as an independent risk factor of AK. The product was recalled internationally on May 25, 2007. Dr. Joslin and colleagues additionally found a 38.8% AK rate among individuals who did not use AMO-CMP, suggesting that this solution was not the only cause of AK. It was hypothesized that minimized disinfection of the domestic water supply, as ordered by the Environmental Protection Agency, might have been responsible for the increased prevalence of AK. Other results demonstrated that poor contact lens hygiene contributed to the risk of AK, but was most likely not a primary issue.² Considering the multi-factorial nature of this condition, soft contact lens users should take preventative steps to avoid contraction of AK, despite its generally low incidence. Individuals who wear soft contact lenses should adhere to recommended guidelines of contact lens use, as well as avoid wearing their lenses while swimming and showering.¹

Fu-Shin X. Yu, Ph.D., lectured on the use of bacterial flagellin as a vaccine against Pseudomonas aeruginosa (PA) keratitis in mice (presented in a different section of the conference), which also pertains to ocular infection. According to the study Dr. Yu presented, the injection of different dosages of PA flagellin — the protein component of the flagellum — into the eyes of mice elicited a dose-dependent protection against Pseudomonas infection. Improvement of PA keratitis occurred with the pre-treatment of 100 ng flagellin per eye, and notably, the disease was prevented when each eye was pre-treated with 500 ng flagellin.

Because toll-like receptors in conjunctival cells recognize pathogens that enter the epithelium, Dr. Yu and his colleagues speculated that flagellin pre-treatment played a role in upregulating antimicrobial genes, downregulating PA-induced cytokine expression and suppressing proinflammatory cytokine production in mice. As corneal protection was found to last for up to 24 hours, these findings represent a possible control of bacterial flora, which can cause serious complications during wound healing. PA is a major pathogen that causes corneal infection, especially in contact lens wearers; therefore, further investigation of the prophylactic therapy of PA will shed light on the feasibility of its clinical use.³

Angiogenesis/Transplantation

The second section of the conference focused on corneal angiogenesis and therapeutic approaches. Normally void of both blood and lymphatic vessels, the cornea can be invaded by these vessels under some inflammatory conditions.

Claus Cursiefen, M.D., discussed the recent strides made in research into the mechanisms of neovascularization of the eye, as well as the need to apply these findings to the development of novel topical treatments to modulate neovascularization. Dr. Cursiefen presented the antiangiogenic treatment options used in the management of age-related maculopathy and diabetic retinopathy, and went on to demonstrate novel ways to treat angiogenesis at the cornea. He discussed topical agents — such as VEGF-antibody bevacizumab (Avastin, Genentech), and antisense oligonucleotides that work against the gene IRS1 — that demonstrated efficacy in preventing progressive corneal neovascularization in patients. Dr. Cursiefen further explained that newly available topical antiangiogenic drugs will improve the management of corneal neovascularization.⁴

Reza Dana, M.D., M.S.c., M.P.H., addressed "The Interface of Inflammation, Angiogenesis and Lymphangiogenesis-Lessons From the Cornea." Dr. Dana presented the similarities between the mechanisms inducing the vascular processes in the cornea and also clarified the differential regulation in the immunity of each of the processes. Dr. Dana further discussed his group's study of VEGFR-3 as a sink in the corneal epithelium for proangiogenic factors, a finding that has promising implications not only in ophthalmology, but other fields as well, such as oncology.⁵

Ocular Surface

By far the most thoroughly represented portion of the conference was that pertaining to the ocular surface. Central themes of the section included novel research into dry eye and its clinical endpoints. Researchers presented data ranging from the physiology of the mucins at the ocular surface to new techniques in clinical diagnostics and surgery. Ilene K. Gipson, Ph.D., presented compelling information on the functioning of membrane-associated mucins, MUC1, -4, and -16, present in the glycocalyx. Through the use of siRNA (small interfering RNA) knockdown and bacterial and cell adherence, Dr. Gipson found MUC16 to be an important part of the protective barrier at the corneal surface. And through dye-penetrance assays and reagent-induced shedding, she showed inflammation-related surface damage in dry eye to result from the loss of mucin.

These findings have promising implications in furthering understanding of the role of the different membrane-associated mucins in dry eye disease, as well as potential for new targets in future treatment strategies.⁶

Mark Abelson, M.D., presented on the need to apply meaningful diagnostics for dry eye disease in order to identify the subgroups of the disease population, as well as the necessity of matching these subgroups with the appropriate treatments. Dr. Abelson emphasized the interaction between blink rate and tear film break-up time (see Figure) and the critical implication of this interaction on visual function. He also presented findings on specific patterns of tear film break-up and suggested that these may be correlated with the etiology of the disease. Finally, Dr. Abelson explained the importance of understanding the progression of dry eye and the precise role of clinical models like the controlled adverse environment (CAE, ORA Clinical Research and Development, North Andover, Mass.) in the development of emerging agents.⁷

Figure. The interaction between blink and tear film break-up time plays a critical role in ocular surface protection.

Stephen C. Pflugfelder, M.D., presented intriguing results on the response of ocular surface epithelia to desiccating stress. He explained his murine model of desiccating stress and human corneal epithelial cultures exposed to osmotic stress in vitro. Through Dr. Pflugfelder's study, MAPK and NF_B pathways were activated by desiccating/osmotic stress; this activation of the pathways stimulated a cascade of inflammatory mediators and ocular surface inflammation.

The production of matrix metalloproteinases (MMPs) by the ocular surface epithelia was increased in the tear due to desiccating stress (MMP 3, 9 in humans and MMP 1, 3, 9 in mice). Dr. Pflugfelder suggested that therapies to prevent or inhibit this response would need to either protect the epithelia from dessication and osmotic stress or inhibit various components of the response via pharmacologic action.⁸

Concluding Thoughts

While the findings presented at the Cornea Research Conference pertain to clinical treatments further down the pipeline, they also provide insight into the roots of ophthalmic conditions and the potential for future therapeutic agents to address these mechanisms. Overall, the conference supplied the attendees with a concise update of recent research on the cornea and a bolstered understanding of where basic science and clinical research must convene to provide patients with the best therapies possible. OM

References

1. Cohen EJ. The resurgence of contact lens-related infections. Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.
2. Joslin CE, Tu EY. Acanthamoeba keratitis — where do we stand? Paper presented at: 25th Biennial Cornea Research Conference; October 12-13; 2007, Boston.
3. Kumar A, Zhang J, Hazlett LD, Yu FX. Flagellin-induced reprogramming and protection against pseudomonas infection in the cornea (and in lung). Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.
4. Cursiefen C. Novel options for topical antiangiogenic treatment at the cornea. Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.
5. Dana R. The interface of inflammation, angiogenesis and lymphangiogenesis-lessons from the cornea. Paper presented at: 25th Biennial Cornea Research Conference; October12-13, 2007; Boston.
6. Gipson IK, Blalock TD, Spurr-Michaud S, Tisdale A. Membrane associated mucins at the ocular surface. Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.
7. Abelson MB. Novel diagnostic techniques for diagnosing and treating dry eye. Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.
8. Pflugfelder SC, Stern ME, de Paiva C, Li DQ, Yoon KC. Ocular surface epithelia— first responders to desiccating stress. Paper presented at: 25th Biennial Cornea Research Conference; October 12-13, 2007; Boston.

Mark Abelson, M.D., an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. George Ousler is the Director of the Dry Eye Department and Ms. Leung and Ms. Maffei are medical writers with Ophthalmic Research Associates in North Andover, Mass.