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A New Target for Dry AMD Discovered
Seeking targets for the ever-elusive dry type of macular degeneration, a collaboration of 40 researchers from Kentucky to Korea recently reversed the standard bench-to-bedside approach, gaining new insight into the pathogenesis of geographic atrophy.
Looking for potentially “malevolent” molecules, the researchers searched for endogenous doubled-stranded (duplex) RNAs in the eyes of people with geographic atrophy. They report in Nature1 on what could be a significant source of the disease—a poorly understood element called Alu, which is a repetitive, hitchhiking part of the human genome, sometimes referred to as “junk” DNA. Although Alu RNA sequences are abundant in human DNA, in RNA they normally number only a few dozen in cells—or a few hundred, at most.
While examining reasons why Alu RNA is less common than Alu DNA, the researchers uncovered another clue to dry AMD, said coauthor Jayakrishna Ambati, MD, professor of physiology and professor and vice chairman of ophthalmology and visual sciences at the University of Kentucky. They found that an appropriately dubbed enzyme, Dicer1, typically chops up Alu RNA and degrades it, keeping its numbers in check.
“But in the RPE cells of human donor eyes with geographic atrophy, we found a 65 percent deficit of Dicer1 compared with controls and an increase of Alu RNA, which had been allowed to accumulate,” said Dr. Ambati. “And we showed that this buildup of Alu RNA is toxic to cells.”
To rule out other potential culprits, the researchers looked at a panel of seven other microRNA-processing enzymes, which are also capable of degrading duplex RNA. Dicer1 was the only one that was diminished, but this occurred only in the RPE cells of these diseased eyes, not in other eye tissues, lending credence to its specificity, added Dr. Ambati.
Wondering whether the process of cell death might precipitate the domino effect, the investigators looked at other diseases, such as retinitis pigmentosa and retinal detachment. But here Dicer1 levels remained unchanged. Further subjecting their hypothesis to the stringency of the Koch’s postulates, the researchers re-created—and blocked—the disease with conditional ablation of Dicer1 in mice, taking them another step closer to assigning disease causality.
“This gives us a lot of confidence that we’ve found something very important in our study of geographic atrophy,” said Dr. Ambati, who added that his team is currently testing drugs that can block Alu RNA. “We hope to have a manufacturer of the product by summer and to have regulatory approval to do phase 1 clinical trials by the end of this year.”
Although they’ve been able to block Alu with antisense drugs, these lack durability and potency, he said. “For clinical trials, we can inject drugs, but geographic atrophy is a chronic disease, so ultimately we’ll need to partner with a manufacturer of sustained-release technology.”
Although the cause of RPE-specific Dicer1 deficits is still a mystery, oxidative stress remains a likely suspect, said Dr. Ambati. After subjecting RPE cells to the oxidative stress of hydrogen peroxide, the researchers found that Dicer1 levels did indeed go down.
Dr. Ambati reports that he is named as an inventor on patent applications filed by his employer, the University of Kentucky, related to these technologies.
1 Kaneko, H. et al. Nature
Published online Feb. 6, 2011.
Randomized Controlled Trials
Relevant Research Not Cited in Many Studies
Researchers who studied the citation patterns among randomized controlled trials published over the last four decades have reached a disturbing conclusion: These papers failed to take into account the evidence from three-quarters of the previous trials that address the same question.
“The findings here show not just that the prior evidence is understated but also that it is barely acknowledged,” the Johns Hopkins University researchers report.1
“Just as treatment decisions should be based on the best available evidence, the same principle should apply to the initiation, design and interpretation of randomized clinical trials. At all those stages, a trial should be based on the best available evidence,” said Karen A. Robinson, PhD, lead author of the paper. She added that funding agencies and journals should require investigators to perform a systematic analysis of the previous literature, with citations and context provided either in print or in online supplements. She is an assistant professor of medicine and codirector of the Evidence-Based Practice Center at Hopkins.
She and Steven N. Goodman, MD, MHS, PhD, looked at 1,523 trials and determined that, regardless of the number of previous relevant studies (range: three to 58; mean: 9.7), a median of two of them were cited in the subsequent papers. In a subset of 1,101 studies in which five or more citable trials existed, 23 percent cited only one prior trial, and another 23 percent cited none.
At its most benign, these findings suggest widespread sloppiness in the documentation of how and why researchers are testing their specific hypotheses. At its worst, they suggest that these studies might have led to ethically unjustifiable trials that wasted resources, reached incorrect conclusions and exposed trial participants to unnecessary risks, Dr. Robinson said.
Thomas J. Liesegang, MD, editor-in-chief of the American Journal of Ophthalmology and professor of ophthalmology at Mayo Clinic, Jacksonville, Fla., said, “It’s very disturbing. For researchers to ignore the previous evidence completely, and to not put their new results into context with other trials is just not acceptable. I had no idea the problem was so pervasive.” Dr. Liesegang noted that the study controlled for citation oversights by defining previous studies as “citable” only if they were published at least one year before the subsequent trial was. So the lack of citations suggests “a selective bias on the part of the researchers about which previous clinical trial data they will pay attention to—and that is poor science. You can’t ignore alternative hypotheses or research,” he said.
Andrew J. Schachat, MD, editor-in-chief of Ophthalmology and vice chairman of ophthalmology at Cleveland Clinic Foundation, is more skeptical about the extent of the problem. Factors other than sloppiness or bias are also at work, he said. “I agree that people tend to miss things. But just because it’s not in the paper doesn’t mean that the researchers did not review the study,” Dr. Schachat said. “It is possible some of the citations shouldn’t be there because the questions those trials addressed may not be directly relevant to the question at hand.”
1 Ann Intern Med
Study Flags Risk Factor
Narrow anterior chamber width may be a previously unrecognized risk factor for angle-closure glaucoma, a recent study suggests.1
Recognized risk factors for the disease include a shallow anterior chamber depth and short axial length as well as a thick and anteriorly placed lens. In addition, some studies have identified ethnicity and gender as predisposing factors.
In this study, researchers in Singapore evaluated anterior chamber width (ACW) in a community-based population sample, and then they compared the findings with those taken from a hospital-based sample of patients with primary angle closure.
Of the 1,465 community participants, 54.1 percent were female and 90 percent were Chinese.
The researchers found that a smaller ACW was more likely to be found in eyes with narrow angles. They also found that ACW was significantly smaller in Chinese participants than in those of other ethnic backgrounds.
“These findings could indicate that angle crowding caused by a narrower ACW may be an important factor predisposing Chinese eyes to angle closure,” they note.
Because this was a cross-sectional study, the investigators acknowledge that they were unable to confirm a causal relationship between ACW and angle closure.
Ideally, future research would prospectively study the association, as well as the angle narrowing that tends to occur with age.
“We noticed that patients with angle closure often had smaller eyes, not only axially but also in terms of smaller ‘white-to-white’ corneal diameters. With the availability of anterior segment OCT, we could reliably measure the ACW, and in this study we found that smaller ACW was independently associated with angle closure,” said Tin Aung, MBBS, PhD, coauthor of the study and senior consultant and head of the glaucoma service at the Singapore National Eye Center and deputy director of the Singapore Eye Research Institute.
Most ophthalmologists already are aware that a shallow anterior chamber is linked to angle-closure glaucoma and would assess anterior chamber depth clinically when examining patients, said Dr. Aung. “Now, they should also look out for a smaller ACW.”
What’s next for the research team? “We are exploring further the contribution of different parameters associated with angle closure,” Dr. Aung said. “Our aim is to develop a customized glaucoma risk-assessment model and algorithm for angle-closure risk assessment.”
1 Nongpiur, M. E. et al. Ophthalmology
Diet and the Eye
Carbohydrates May Be Linked to Cataracts
When it comes to cataract development, there’s more evidence that dietary carbohydrate intake matters.
In a cross-sectional analysis of data from the Melbourne Visual Impairment Project, researchers found a link between higher total carbohydrate intake and an increased risk of cortical cataracts in some 1,600 nondiabetic patients.1 No similar association emerged for nuclear cataracts, although there were indications that the type of carbohydrate eaten, as ranked by the glycemic index, might play a role in their development.
The results open the door to a novel method of preventing lens opacities, said researcher Allen Taylor, PhD, director of the Laboratory for Nutrition and Vision Research at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “It’s increasingly clear that dietary carbohydrate intake affects cataractogenesis.”
How might carbs cause cataracts? “Cells have a protein quality-control mechanism. The excess glucose from high-glycemic carbohydrates creates damaged proteins; it also compromises the machinery that recognizes and removes these damaged proteins from the eye,” said Dr. Taylor, who’s also professor of nutrition, biochemistry and ophthalmology at Tufts.
More research needs to be done to clarify any link between high-glycemic index (GI) carbs and cataract development. And the differences between the pathogenesis of cortical and nuclear cataracts need to be teased out, he said. “We see more consistent results with AMD; there’s a clear dose response between intake of high-GI foods and AMD progression.”
1 Chiu, C. J. et al. Invest Ophthalmol Vis Sci
EyeNet thanks Steven I. Rosenfeld, MD, for his help with this issue’s
News in Review.