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FUTURE FILE: Highlighting innovative early-stage and preclinical concepts in retina.

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Bioactive Lipids May Reduce Severity of Wet AMD

■ A compound of specific bioactive products from a major family of enzymes reduced the severity of AMD in a preclinical model, according to a new study led by Massachusetts Eye and Ear researchers. The report was published online in the Proceedings of the National Academy of Sciences, and it suggests that it may be possible to prevent the vision loss resulting from angiogenesis and inflammation observed in wet AMD by increasing the expression of specific bioactive lipid metabolites in the retina.

The research demonstrates that these bioactive lipids can regulate inflammatory immune cells in the retina, key regulators of the angiogenic process in this disease. These molecules show encouraging therapeutic potential not only for AMD, but also for other major conditions that involve angiogenesis and inflammation, such as cardiovascular disease and cancer.

“Given the high prevalence and progressive nature of neovascular eye disease, the ability to stabilize bioactive lipids that mitigate or halt disease is of great and increasingly therapeutic significance,” said corresponding author Kip Connor, PhD, a vision scientist at Mass. Eye and Ear. “It is our hope that emerging technologies and future studies will expand on our work, and ultimately lead to safe, targeted, and cost-effective therapies that markedly improve visual outcomes and quality of life for patients suffering from these debilitating eye diseases.”

Newly Discovered Immune Cell Combats ROP

■ Research at Australia’s Monash University has discovered the existence of a disease-fighting immune cell in the eye that points to potentially new methods for treating eye disorders in premature babies and diabetic adults. The paper was published in Nature Communications.

The scientists, led by Professor Jennifer Wilkinson-Berka, were investigating improved ways of treating ROP. Current standard of care treatment is laser surgery on newborn babies to burn the damaged blood vessels that occur with the disorder, but this also damages healthy cells. The scientists’ major breakthrough was finding that disease-fighting white blood cells known as regulatory T cells (Tregs) are present in the retina.

“People thought you couldn’t actually have Tregs in eye tissue because the eye, like the brain, has a barrier that stopped them from entering. No one had ever described this before,” Professor Wilkinson-Berka said. “I thought there might be a weakness in the barrier.”

The researchers confirmed their theory using animal models. They then boosted the cells to test whether they could repair damaged blood vessels in the retina and found that ROP was significantly reduced.

The research could have far-reaching implications for improving eye disease in people with DR.

“The same set of ideas are applicable,” Professor Wilkinson-Berka said.

Cell Regeneration Potential in Retinitis Pigmentosa

■ Researchers at the University of Louisville Department of Ophthalmology and Visual Sciences have discovered a way to revitalize cone receptors that have deteriorated as a result of retinitis pigmentosa (RP). Working with animal models, researchers discovered that replenishing glucose under the retina and transplanting healthy rod stem cells into the retina restore function of the cones.

The research, conducted by Henry J. Kaplan, MD, chair of the Department of Ophthalmology and Visual Sciences, Douglas Dean, PhD, and Wei Wang, PhD, and published in the journal Cell Reports, could lead to therapies for preserving or recovering central vision in patients with RP.

Retinitis pigmentosa is an inherited disease in which the photoreceptor cells in the retina — rods and cones —deteriorate over time. Photoreceptors absorb and convert light into electrical signals, which are sent through the optic nerve to the brain. Rods, located in the outer regions of the retina, allow peripheral and low-light vision. Cones, located mostly in the central part of the retina, allow perception of color and visual detail.

In RP, rods deteriorate first, causing the peripheral and low-light vision loss typically associated with the disease. In later stages, the cones also deteriorate. Without cone function, RP patients lose the high-resolution daylight vision necessary for reading, facial recognition, and driving. As a result, this stage of RP vision loss is more debilitating than the loss of night-time or peripheral vision. RP affects 1 in 4,000 people globally.

Recent research has shown that as the rods deteriorate, the cones are no longer able to access glucose, which becomes trapped in the retinal pigment epithelium (RPE). As a result of glucose starvation, the cones go dormant and eventually die.

The researchers found that the cones remain dormant for a period of time before they are completely lost, and if the glucose supply can be replenished during dormancy, the cones can be regenerated. The researchers were able to successfully restore cone access to glucose in either of 2 procedures. First, by transplanting rod-specific induced pluripotent stem cells beneath the retina, and second by injecting glucose directly into the subretinal space.

“Following rod stem cell transplant, we observed reassembly of the cone inner segments, regeneration of cone outer segments and increased electrophysiologic function within 1,000 microns from the transplant margin for at least 3 months after the transplantation in all directions,” Kaplan said in a statement. “However, the recognition that glucose starvation of cones occurred because of the trapping of glucose in the RPE provides multiple new possible treatments to restore lost central vision including drug therapy, gene editing, and regenerative medicine.”

This research has the potential to lead to therapies that preserve or restore central vision for individuals with RP.

“If therapy can prevent or reverse the onset of cone degeneration within the macula, most patients would be immeasurably helped and able to live a normal life despite the loss of peripheral vision and decreased dark adaptation,” Kaplan said.

Patient-Derived Cells May Lead to New Retinal Therapies

■ Researchers at the University of Rochester Medical Center (URMC)have found hallmarks of macular degeneration in a new human stem cell model. This new model could make new avenues of macular degeneration research possible and has helped the team hone in on some possible drug targets for the disease. The study was published in the Proceedings of the National Academy of Sciences.

“So far, there has not been a patient-derived model of macular degeneration,” said Ruchira Singh, PhD, assistant professor of ophthalmology in the Flaum Eye Institute at URMC and lead author of the study, in a news release. “It was not known if you can take cells from the human eye and make a cell model that displays the hallmarks of the disease.”

Although macular diseases can vary widely, age-related and similar inherited macular degenerative diseases are all characterized by buildup of debris in the retina. These deposits, called drusen, are specifically found beneath the layer of retinal pigment epithelium (RPE) cells, which are known to be key players in macular degeneration.

For their new model, Singh’s team collected skin cells from patients with genetic forms of macular degeneration, reprogrammed them to stem cells, and used the stem cells to create RPE cells. RPE cells derived from patients mimicked several characteristics of macular degeneration when aged in a dish, like producing the hallmark deposits.

RPE cells carrying macular degeneration-causing mutations developed more deposits with more similar composition to what is seen in the affected human eye than cells from healthy adults or patients’ cells in which disease-causing mutations were corrected using gene editing.

Using this model, Singh’s group showed for the first time that dysfunctional RPE cells can cause specific aspects of macular degeneration on their own — without the help of other cells or components of the retina. This was true for cells derived from patients with 3 different genetic forms of macular degeneration, suggesting RPE cell dysfunction could be central to multiple forms of the disease.

Singh’s new model also allowed her research team to identify a group of molecules in RPE cells that could be targeted by new macular degeneration drugs. These “complement proteins,” which normally boost immune functions in cells, may be affected by genetic alterations that cause macular degeneration. In the study, the expression of genes that encode these proteins was elevated in RPE cells from all of the macular degeneration patients, suggesting they may also play a key role in many forms of the disease.

“Now we can actually identify and test a rational drug therapy in patients’ own cells,” said Singh. “So far, this has not been possible, but now we can actually study macular diseases in parallel and identify what might be the central defect across macular diseases.”

Singh believes this study will help move the field of macular degeneration research toward developing new drugs that target RPE cells, while providing a new and improved model to screen those drugs. Though this work is early, the team hopes it will lead to an effective treatment for macular degeneration in the future.

Cytokines Studied for Combating Effects of Diabetes

■ Researchers at Case Western Reserve University have found that certain cytokines that help cells communicate with each other might be the key to repairing diabetic nerve damage, according to a study that recently appeared in the journal Experimental Neurology. Diabetes damages nerve cells, which can lead to impaired circulation, muscle weakness, blindness, and other harmful side effects. The new study demonstrated that diabetic mice can’t repair nerve cells after damage due to low levels of specific cytokines.

In a mouse model of type 1 diabetes, the researchers measured cytokine responses in mice with damaged sciatic nerves. Diabetic mice responded with unusually low levels of the cytokines that notify other cells of injury, which in turn hampered activation of reparative genes. These results offer a new explanation for the irreversible nerve cell damage seen in diabetic patients.

Replenishing the missing cytokines could help improve symptoms for diabetics, said study lead Richard Zigmond, PhD, professor of neurosciences at Case Western Reserve University School of Medicine, “Our results indicate that targeting this cytokine pathway might alleviate some of the neural complications from diabetes.” Dr. Zigmond added that pilot animal studies toward this aim are under way. RP