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Faulty Gene Predictive of Fuchs' Dystrophy

It could be responsible for as much as 75% of cases.

■ Mayo Clinic and University of Oregon researchers have confirmed that a genetic factor called a repeating trinucleotide is a strong predictor of an individual's risk of developing Fuchs' dystrophy. The findings were presented at the recent ARVO meeting.

Until recently, the cause for most Fuchs' cases was unknown, but Mayo researchers showed a variation in the gene for transcription factor 4 (TCF4) was a major cause of this condition.

The findings are based on an initial genome-wide association study that revealed a link between Fuchs' dystrophy and the TCF4 gene. Mayo researchers further defined the association with Fuchs' to be due to unusually long segments of repeated DNA nucleotides in the gene. In this case, three nucleotide residues (aka trinucleotide) repeat more than 40 times, some as high as several thousand repeats.

“Those long repeats of trinucleotides cause havoc, impacting the coding of the TCF4 protein,” says lead researcher Keith Baratz, MD, a Mayo Clinic ophthalmologist.

Characteristics of trinucleotide repeat diseases include later onset of the condition and progressive degeneration. The study showed that a particular repeating trinucleotide, TGC in the TCF4 gene, is a strong predictor of disease. Researchers say that while Fuchs' dystrophy has other causes, TCF4 repeat expansion is a major cause of the condition in the patients in the Mayo study, accounting for about three-quarters of cases.

Fuchs' dystrophy can only be successfully cured with a corneal transplant procedure, either full-thickness penetrating keratoplasty (PK), or with newer and more effective partial-thickness transplant procedures such as DSAEK and DMEK.

Injector Cartridges Preserve DSAEK Grafts

Endothelial cell damage is greatly reduced.

■ Research conducted by the Lions Eye Institute for Transplant & Research found that pre-loading corneal buttons for DSAEK grafts into injector cartridges and shipping them that way lead to far less endothelial cell damage than if they had not been injector-loaded. The research was presented at the recent ARVO meeting.

The eight pre-loaded buttons demonstrated an average of 9.07% damage to endothelial cells, while the control group sustained a 36.2% damage rate.

“These initial findings look very promising for the future of corneal transplants,” says David C. Gritz, MD, MPH, director of Cornea and Uveitis Divisions in the Department of Ophthalmology & Visual Sciences, Montefiore Medical Center. “Allowing eye banks to handle the tissue preparation and injector preloading may allow for increased precision and reproducibility that would result in decreased surgical time and better patient outcomes. More studies with larger sample sizes are needed to confirm these results.”

Punctal Plugs Promising in Sustained-release

Four-week delivery of latanoprost proves effective.

The ongoing effort by QLT, Inc. to deliver the glaucoma medication latanoprost in a sustained-release format using punctal plugs appears to be making significant progress, as documented in a detailed study presented at the recent ARVO meeting.

Damien F. Goldberg, MD, of Torrance, Calif., in conjunction with QLT, conducted a phase 2 study to evaluate the safety and efficacy of the Latanoprost Punctal Plug Delivery System (L-PPDS) in subjects with ocular hypertension or open-angle glaucoma.

As Dr. Goldberg reported, approximately 95 subjects had four weeks of treatment with simultaneous bilateral L-PPDS placement in both the upper and lower puncta. The trial used a proprietary punctal plug in the lower punctum and an early-stage prototype punctal plug based on a modified commercially available plug in the upper puncta, with a combined latanoprost amount of 141 µg. Subjects were followed up for assessment of safety and IOP effect. Analysis of IOP effect was based on change from baseline. Adverse events and adverse device events were monitored.

After four weeks of L-PPDS treatment, mean IOP change from baseline was statistically significant at -5.7 mmHg, with 60% of subjects showing an IOP reduction vs. baseline of 5 mmHg or greater and 47% of subjects showing a reduction of 6 mm Hg or greater. The mean percentage change in IOP from baseline at four weeks was also statistically significant at 22.3%.

The L-PPDS was well tolerated over the testing period with adverse events (AEs) similar to those reported for commercial punctal plugs. The majority of AEs were ocular, with tearing reported as the most frequent. No associated AEs were serious.

Few subjects experienced any discomfort related to the punctal plugs, with most patients having either no awareness or mild awareness of the punctal plugs by week four.

Dr. Goldberg concluded that this is the first reported demonstration of a clinically significant, prolonged (four weeks) reduction in IOP in glaucoma with an extraocular, minimally invasive sustained release ophthalmic drug delivery system. He believes these results have significant implications for maintaining compliance for patients.

The results reported at ARVO appear to demonstrate significant progress from previous studies in which plug retention was a major issue. Bilateral plug placement and modified plug design appear to have overcome the retention problem.

Another company, Ocular Therapeutix, is also conducting a trial using punctal plugs to deliver the glaucoma medication travoprost.

For more discussion of potential new pathways for delivery of glaucoma medications, please see our cover article, beginning on page 24.

Glaucoma Meds: Eyedrops or Implants?

Survey: Most patients would welcome a sustained-release format.

With anticipation building regarding the commercialization in the near future of a sustained-release implant for delivering glaucoma medications, researchers from the University of Singapore and the University of Melbourne in Australia wanted to know if glaucoma patients would welcome the opportunity to eliminate the negative issues associated with eye-drops for a tiny implant that would deliver their medication accurately and regularly over a period of months.

The researchers noted that though topical medication is the mainstay of treatment for most patients with glaucoma, non-adherence remains a critical issue. They pointed out that “novel methods of ocular drug delivery are increasingly being considered although little is known about the associated patients' attitudes and perceptions of such techniques.” The researchers examined the patients' acceptance of a subconjunctival injectable implant as a possible alternative to topical anti-glaucoma medication and identified a subgroup willing to accept this alternate form of drug delivery.

Patients with primary open-angle or angle-closure glaucoma and currently on topical anti-glaucoma medication for a minimum of six months, from specialist glaucoma clinics were recruited. Socio-demographic data and information about patients' general and ocular health were collected from medical records. Beliefs about medicines, glaucoma, eyedrops and self-reported adherence were assessed by trained interviewers using various validated questionnaires.

Of the 344 patients enrolled, the researchers found that 216 (62.8%) would accept the implant as a replacement for their current eye drops. Regarding the cost of this alternate delivery system, 162 (47.1%) were willing to accept it provided it was similar to the cost of their current medication, and 53 (15.4%) and 30 (8.7%) patients were willing to pay one-and-a-half and twice the cost of their present medication, respectively.

Survey data showed that patients who accepted the implant tended to have more severe glaucoma and rated the implant's helpfulness more highly. There was also a trend suggesting that a shorter duration of diagnosis of glaucoma was associated with greater implant acceptance. Beliefs towards medicines, glaucoma, eyedrops, self-reported adherence and socio-demo-graphic factors did not have a significant impact on the patients' decisions.

The researchers concluded that a commercially available ocular drug implant would be an acceptable alternative to topical eyedrops for a clearly defined subgroup of glaucoma patients.

The research was presented at the recent ARVO meeting.

Research Digest

New & Noteworthy Journal Articles

Compiled by Andrew E. Mathis, PhD, Medical Editor

► Keratoconus and sleep apnea. Noting the sparseness of post-keratoplasty patients among their elderly patients, ophthalmologists at the Duke Eye Center in Durham, NC, undertook a study to determine whether there was any correlation between keratoconus and mortality, looking specifically at sleep apnea as a primary symptom. They report their findings in the June 2012 issue of Cornea.

The authors conducted telephone interviews with 101 patients diagnosed with keratoconus over a 14-year period. Items specifically focusing on a diagnosis of sleep apnea were asked, as well as symptoms suggesting risk for sleep apnea for those patients without diagnoses.

Of the 101 patients enrolled in the study, 18 had previous diagnoses of obstructive sleep apnea diagnosed with sleep studies. Thirty-nine of the remaining 83 patients were determined to be at high risk for sleep apnea based on their responses to the questionnaire. Other common, potentially life-threatening comorbidities among the patients interviewed included high blood pressure (37%) and diabetes (20%). The mean BMI of the patients was 31.2, greater than the obesity cutoff of 30 (the median was 28.4 — overweight but not obese).

As the prevalence of obstructive sleep apnea is only between 1% and 5%, the Duke study team concludes that sleep apnea is significantly more common in the population of keratoconus patients, suggesting that ophthalmologists include screening for sleep apnea in the workups of patients with keratoconus.

► Avastin injections and retrobulbar blood flow. With the majority of wet AMD patients now being treated with intravitreal injections of anti-VEGF drugs, an obvious area of research interest is the effect of these repeated injections over time. A team of retinal physicians collaborating between UCLA and several research institutions in Iran looked at the effect of intravitreal injections on retrobulbar blood flow. Their results appear in the May 2012 issue of Retina.

Undertaking a prospective study of patients with wet AMD, the study team examined the retrobulbar hemodynamics of 43 patients using color Doppler ultrasonography. The patients' central retinal and short posterior ciliary arteries were measured for peak systolic velocity, end-diastolic velocity and resistive index value in both injected eyes and uninjected fellow eyes at baseline and at seven days after a single intravitreal injection of Avastin.

The injected and uninjected eyes were not significantly different with regard to the measured outcomes at baseline. However, at seven days following Avastin injections, there were highly statistically significant (P ≤ .006) differences in all three measured parameters in the injected eyes (lower peak systolic and end-diastolic velocities and higher resistive index value). In the uninjected eyes, there were significant decreases in both velocities measured, while there was no significant changes in the resistive index value.

The authors concede that the short follow-up and small number of cases constitute serious limitations to their research, and they urge more studies, including with much longer follow-ups, to determine the ultimate hemodynamic outcomes associated with intravitreal anti-VEGF injections.

► A decade of corneal grafts. The May 2012 issue of Archives of Ophthalmology features an article by doctors from the United Kingdom who studied the trends in indications for keratoplasty in the UK over a 10-year period. Examining records from the National Health Service, files on surgeries for keratoplasty between April 1, 1999, and March 31, 2009 were reviewed to determine the type of graft used and the surgical indication.

A total of 2,511 keratoplasties were performed in the period under study. Among these surgeries, 939 were performed to address endothelial failure, an increase to 37.4% in the final year of the study from 35.6% in the first two years.

Of the procedures undertaken to treat cases of endothelial failure, penetrating keratoplasty fell from 98.3% of the procedures in 1999-2000 to only 46.6% in 2008-2009, while endothelial keratoplasty increased enormously, from 0.3% in 19992000 to a majority of procedures (51.2%) in 2008-2009. The performance of PK for grafts decreased from 88.4% of all grafts in 1999-2000 to 57.1% in 2008-2009, with deep anterior lamellar keratoplasty increasing from 8.8% to 40.1%.

The authors conclude that endothelial failure is the most common indication for keratoplasty in the UK, and endothelial keratoplasty is now the most procedure for this indication. Keratoconus and regraft surgeries are the second and third most common indications, the latter because of endothelial failure in most cases. The sheer size and length of follow-up of the study should contribute to its authority and applicability in practice in the future.

► Strabismus across populations. In a study appearing in the May 2012 issue of the British Journal of Ophthalmology, Taiwanese ophthalmologists compared the insertion positions and outcomes of strabismus surgeries between Han Chinese patients and Western patients. They found that in the Chinese subjects, extraocular muscle insertion locations did not differ between strabismus patients and controls, while the distances from the distances from the insertion location to three extraocular muscles were significantly shorter in Chinese patients compared to Western subjects.

The study's findings contribute to a body of data suggesting that guidelines for certain ocular surgeries should be adjusted for the population being treated. OM