Ophthalmology News From Mayo Clinic Vol. 1, No. 1, 2011

Uveal Research and Treatment at Mayo Clinic

INSIDE THIS ISSUE Mayo Clinic in Rochester, Minnesota, has a long research at Mayo Clinic history in the treatment of uveal . In and other institutions. the early 1980s, Dennis Robertson, MD, was one 2 New Glaucoma of the first to use iodine-125 plaques, the form of Treatment for Large Research Increases most commonly used for treatment Uveal Melanomas Understanding of Human of uveal melanomas in the United States today. Although COMS Conventional Outflow The plaques used in the Collaborative Ocular recommended enucle- Melanoma Study (COMS), a multicenter study ation for large uveal initiated in 1985 to evaluate therapeutic interven- melanomas, recently Photography tions for patients with choroidal melanoma, used such tumors have been 3 Jose S. Pulido, MD Project Ensures Early gold shells made at Mayo Clinic. COMS showed treated with larger Detection and Treatment that treatment of medium-sized choroidal melano- radioactive plaques, especially if the patient has of Diabetic Retinopathy mas (Figure 1) with radioactive plaque brachyther- type 2 melanoma with a poor prognosis. Despite apy was at least 90% successful in local control of a higher risk of local recurrence and poor vision the melanoma and had no increase in metastatic from radiation retinopathy, local treatment may 4 Research Confirms risk compared with enucleation. Unfortunately, be a reasonable option because the eye and useful Association Between TCF4 radiation retinopathy ultimately limits vision in vision are retained for some time. Gene and Fuchs Corneal these patients. Radiation retinopathy has been a considerable Dystrophy “The question now, however, is what to do problem with brachytherapy. Methods of obtain- with small, medium, and large melanomas in light ing good local control by combining treatment of COMS data and new molecular information,” methods may decrease the development of this said Jose S. Pulido, MD, of the Department of complication. Intraoperative ultrasound for precise Ophthalmology. At least 50% of uveal melano- localization of the plaque in association with mas have a mutation in a protein called GNAQ. combination therapy may be helpful in this regard. Unfortunately, this mutation occurs early on, even Research is in progress to find methods of main- in what are considered choroidal nevi. Of more taining local control while minimizing vision loss. importance is that there appear to be 2 forms of uveal melanomas: • Class 2, a uveal melanoma associated with of and with mRNA that confers a high metastatic risk • Class 1, a uveal melanoma with disomy 3 or mRNA testing that has a low metastatic risk “Patients are attuned to these distinctions. Many wish to undergo prognostic testing. It is important to carefully discuss the results and use of the data with patients because at this time there is no prophylactic treatment for clinically undetect- able but high-risk uveal melanomas,” according to Dr Pulido. These questions are a focus of intense

Figure 1. Choroidal melanoma. New Research Additional studies conducted with the A study conducted by Dr Pulido in collab- Department of Molecular Medicine and the oration with the Department of Radiation Department of Immunology aim to induce evaluated a new plaque design that autoimmunity for the treatment of ocular allows for in situ radiation of an melanoma melanomas. Initial animal studies have shown (Figure 2). This innovation precludes removal promise, and methods to adapt this approach of the melanomas, yet decreases the amount for human trials are in progress. Figure 2. Iris melanoma. of radiation to other portions of the eye.

New Glaucoma Research Increases Understanding of Human Conventional Outflow

In 1873, German ophthalmologist Theodor Leber Prostaglandin Analog Cell Signaling postulated that elevated intraocular pressure Prostaglandin analogs such as latanoprost are (IOP) in the glaucomatous eye resulted from among the first-line treatments for lowering increased outflow resistance to aqueous humor IOP, but their mode of action at the molecular drainage. It is widely accepted that the likely site level is unknown. Until recently it was thought of outflow resistance resides between the juxta- that prostaglandin analogs acted solely through canalicular region of the trabecular meshwork the uveoscleral pathway. (TM) and the inner wall of the Schlemm canal, Using an ex vivo anterior segment human but identification of the regulatory mechanisms eye culture model developed at Mayo Clinic, and molecules within this area has been elusive. researchers have demonstrated that prostaglan- Michael P. Fautsch, PhD Increase in TM cell contractility, perme- din analogs increase outflow facility through the ability, and different forms of stress are a few of conventional or trabecular outflow pathway in the mechanisms believed to increase outflow addition to the uveoscleral pathway (Figure). facility in primary open-angle glaucoma (POAG). Using several prostaglandin analogs, multiple Understanding the pathophysiology of outflow primary TM cell lines, and different treatment resistance in normal and POAG eyes is essential durations, Dr Fautsch’s research team has identi- for the identification of key molecules that can be fied several proteins involved in prostaglandin used as novel therapeutic targets. analog signaling. One of these proteins is cal- Michael P. Fautsch, PhD, of the Department cipressin, an inhibitor of calcineurin, a serine– of Ophthalmology at Mayo Clinic in Rochester, threonine phosphatase protein involved in several Minnesota, and his laboratory team are conducting calcium-dependent cellular signaling pathways. several innovative studies to identify the molecular Treatment with cyclosporine, an inhibitor of events involved in IOP modulation, including calcineurin activity, increased outflow facility in identification of novel prostaglandin analog cell the ex vivo anterior segment culture signaling targets and aqueous humor flow through model, suggesting a role for calcipressin and the conventional outflow pathway. calcineurin in IOP control. Ongoing studies aim to identify regulatory proteins Ex Vivo Anterior Segment Human Culture Model downstream to calcipressin and calcineurin. The goal is to Monitor pressure identify these molecules and develop therapeutics to regulate their activity, leading to better control of IOP. Perfuse media Aqueous Humor Outflow Pathway Figure. Schematic of an ex vivo anterior segment human eye culture model. Briefly, the Classical understanding of the human eye is bisected at the equator. The anterior portion of the eye minus the lens, iris, aqueous humor outflow path- and aqueous humor is clamped into a modified Petri dish. Media is perfused into the way focuses on homogenous anterior chamber at the normal human flow rate of 2.5 μL/min. The only exit for fluid is fluid movement through the through the trabecular outflow pathway. Pressure is monitored in real time. TM. This focus is partly due to lack of human models and the

2 MAYO CLINIC | ClinicalUpdate ability to visualize fluid movement in real time. whether the change in orifice size is a cause or Mayo Clinic researchers have found that effect in glaucoma is a new direction for aqueous flow through the TM is not uniform but Dr Fautsch’s research team. is increased in regions of the TM underneath the collector channels. These preferential fluid flow New Ideas, Approaches, and Questions regions are associated with expanded TM (specifi- It has been more than 130 years since Dr Leber’s cally the juxtacanalicular tissue) found directly astute recognition that elevated IOP is the result under collector channels. of increased outflow resistance to aqueous Mayo researchers are using 3-dimensional drainage. New approaches are beginning to dis- micro–computed tomography to study the con- sect the molecular and anatomic features associ- ventional outflow pathway as a functional unit. ated with POAG. Many questions, however, still This imaging modality enables identification of require answers. Researchers at Mayo Clinic the collector channel location, size, and associated currently work to episcleral veins down to 2-micrometer resolution. • Determine the effect of prostaglandin Preliminary work has indicated that the analogs in normal and POAG eyes. orifice size of collector channels in POAG eyes • Identify the molecular mechanisms respon- may be reduced by as much as 50% compared sible for coupling prostaglandin analog to with normal collector channel orifices. This increased trabecular outflow facility. finding is important because the reduction in • Understand how changes in the trabecular collector channel orifice size would have a pro- outflow pathway, such as collector channel found effect on outflow resistance. Determining orifice size, affect outflow facility.

Retina Photography Project Ensures Early Detection and Treatment of Diabetic Retinopathy

Despite the availability of effective treatment for part of each patient’s electronic medical record. diabetic retinopathy for nearly 3 decades, early detection is still critical to prevent vision loss. The Goal: 100% Participation Annually The Department of Ophthalmology and the Nationwide, less than 50% of people with diabetes Mayo Employee Health Service in Rochester, have yearly eye examinations, often because eye Minnesota, have teamed to ensure that Mayo care is not controlled by the primary care physi- Clinic employees with diabetes keep watch on cian or diabetes specialist. Project leaders hope their vision. that by providing convenient access to retinal The retina photography project alerts diabetic photographs in the primary care setting, they can patients to signs of eye disease so that they can increase the rate of annual eye examinations for Andrew J. Barkmeier, MD receive early treatment and avoid potential vision Mayo employees with diabetes to 100%. loss. At selected Mayo primary care clinics, tech- The retina photography project is directed nicians use cameras to provide a retinal photo- at diabetic patients who have relatively good graph that can detect the earliest signs of diabetic control of their diabetes and may not feel a need eye disease. Photographs may be obtained when to schedule annual eye examinations. Rajeev employees are seeing their primary care physi- Chaudhry, MBBD, a primary care physician, and cians for regular diabetic management. Dr Barkmeier agree that patients today are gener- Following an established dilation protocol ally well educated about diabetes and the need that includes visual acuity testing and applana- to monitor blood glucose levels. Many patients, tion tension, technicians acquire 30º color fundus however, do not appreciate the seriousness of photographs centered on both the macula and diabetic retinopathy and do not see an ophthal- the optic nerve. The retinal scans are transferred mologist until they have symptomatic vision loss. electronically through a secure portal to the The cost of a fundus camera and associated Department of Ophthalmology, where they are hardware and software is approximately $25,000 interpreted by Andrew J. Barkmeier, MD, a vitreo- per site. Photographic screening for diabetic eye retinal specialist. If Dr Barkmeier sees any indica- disease is not reimbursed by Medicare, Medic- tion of diabetic eye disease, the patient is offered aid, or most commercial payers. Project leaders a complete eye examination and transferred from anticipate, however, that task transfer associated the photographic screening program to a periodic with new technology, convenient access, and examination area in the ophthalmology depart- ophthalmology oversight will improve diabetic ment. The retinal scans also become a permanent retinopathy screening efficacy and reduce costs.

MAYO CLINIC | ClinicalUpdate 3 Mayo Clinic Ophthalmology Update Research Confirms Association Between Medical Editor: TCF4 Gene and Fuchs Corneal Dystrophy Jay C. Erie, MD

Fuchs corneal dystrophy (FCD) accounts for E2-2 Protein the majority of corneal grafts performed at Function Varies Ophthalmology Update is written for physicians and Mayo Clinic in Rochester, Minnesota and TCF4 encodes the should be relied upon for medical education purposes only. It does not provide a complete overview of the is the most common indication for corneal E2-2 protein, which topics covered and should not replace the independent transplantation in the United States (Figure). is in the class of basic judgment of a physician about the appropriateness or Corneal guttae, the hallmark of FCD, are pres- helix-loop-helix pro- risks of a procedure for a given patient. ent in approximately 5% of individuals over teins. These proteins the age of 40 years. regulate the expres- Until recently, sion of other genes, Keith H. Baratz, MD investigations into controlling tissue the genetic causes differentiation and differential expression of FCD revealed a of tissue-specific proteins. Contact Us few genes that are The function of E2-2 in the eye is not rare causes of the known, but in other tissues, the protein partici- You don’t need to request a consult from a dystrophy. A research pates in diverse biochemical pathways. E2-2 has specific physician to refer a patient. We’ll team that includes been implicated both as a tumor suppressor, by William L. Brown, OD help you reach the most appropriate contact. Keith H. Baratz, MD, inhibiting the cyclin-dependent kinase pathway, and William L. Brown, OD, of the Mayo Clinic and as a tumor promoter, through E2-2 control Arizona Department of Ophthalmology and collabora- of epithelial-to-mesenchymal transition. 866-629-6362 tors at the University of Oregon and University Tumor promoters involve a complex array of Michigan, however, has discovered a strong of pathways that influence the balance between Florida association between the transcription factor 4 tissues with an epithelial phenotype, includ- 800-634-1417 gene (TCF4) on chromosome 18 and FCD. ing apicobasal polarity, basement membrane A genome-wide association study production, and strong intercellular junctions, Minnesota (GWAS) compared 100 affected study partici- and tissues with a mesenchymal phenotype. 507-284-2744 pants with 200 controls. GWAS techniques Mesenchymal characteristics, which are typical identify genetic variation of individual alleles, of invasive tumors, include a loss of polarity or single nucleotide polymorphisms, at thou- and a disorganized growth pattern. www.mayoclinic.org/medicalprofs sands of sites along the entire genome. Dr Baratz notes: “One of the causes of “This study allowed a simultaneous cancer may also play a role in FCD. The disease comparison of 330,000 alleles between the may result from a complex alteration in the affected and unaffected subjects. The strength differentiation or phenotypical expression of of the association between FCD and variation corneal endothelial at the TCF4 gene was unprecedented. The cells. This process is TCF4 gene may be responsible for 75% of a lot more inter- FCD,” says Dr Baratz. The results of the initial esting than the GWAS were confirmed in an additional 160 simple equation Mayo patients affected by FCD. of 1 gene result- “This finding is a major advance in under- ing in 1 abnormal standing the cause of FCD. Once the primary protein. It also gene is known, research can elucidate the presents a much pathophysiology and treatment of the disease. bigger challenge in Newer corneal transplantation techniques are defining FCD on a Figure. Fuchs corneal very good, but not perfect. It would be great molecular level. Eye dystrophy is the most to have an alternative to halt progression in research doesn’t get common indication for patients identified with an early stage of the any more exciting corneal transplantation in disease,” according to Dr Baratz. than this.” the United States.

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