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FUTURE FILE: Data and research that could impact how retina specialists treat patients.

Highlighting innovative early-stage and preclinical concepts in retina

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Future File is a Retinal Physician feature designed to highlight new and innovative early-stage and preclinical concepts that could one day help to advance the everyday practice of retina specialists.

Innovation to Achieve Full 3D OCT

■ Researchers at the Technical University of Denmark say they have invented a swept light source technology that makes it possible to take full 3D OCT images of the eye. The technology is currently being developed for commercial use by the university spin-out company Octlight ApS.

Octlight says it is now manufacturing these light sources to be used by medical technology companies in full 3D OCT imaging devices. According to Octlight, this innovation will enable physicians to take an image of the eye 10 times faster and more than 10 times longer range than before, dramatically improving their ability to comprehensively assess the condition of the eye.

“The field of vision and depth is critical to diagnosing diseases of the retina. Our technique allows you to image the whole eye from front to back in 3D. It scans faster so you can image a larger part of the retina. It allows you to image 150 degrees of the retina, and penetrates the eye, allowing you to see all the layers of the retina,” said Thor Ersted Ansbæk, PhD, CEO of Octlight, in a news release. “It’s a big leap forward for this type of technology and specially tailored for use in the devices that are used for diagnosing and treating eye diseases.”

Individual RPE Cells May Be Clue to Disease

■ Cells of the retinal pigment epithelium (RPE) form unique patterns that can be used to track changes in this important layer of tissue in the back of the eye, researchers at the National Eye Institute (NEI) have found. Using a combination of adaptive optics imaging and a fluorescent dye, the researchers used the RPE patterns to track individual cells in healthy volunteers and people with retinal disease. The new finding could provide a way to study the progression and treatment of blinding diseases that affect the RPE. The study was published in the journal JCI Insight.

“Studying cells of the retinal pigment epithelium in the clinic is like looking into a black box. RPE cells are difficult to see, and by the time signs of disease are detectable with conventional techniques, a lot of damage has often already occurred,” said Johnny Tam, PhD, the lead author of the study. “This study is proof-of-concept that we can use a fluorescent dye to reveal this unique fingerprint of the RPE, and to monitor the tissue over time.”

High-Dose Statins and Dry AMD

■ An early clue to the possible therapeutic effect of high-dose statins on dry AMD has emerged from a 10-year retrospective, large-scale study of the small number of patients who had dry AMD and also took high-dose statins. The researchers from Stanford University School of Medicine presented their findings at the recent ARVO meeting.

The research effort, made possible by a large database of commercially insured patients, was spurred by the hypothesis that high-dose statins could reduce drusen volume in dry AMD. This hypothesis has been supported by early, small-scale clinical studies.

Of the 174,716 individuals who met the inclusion criteria for the study, only 0.46% (797) had filled a high-dose statin prescription (atorvastatin 40 mg or greater or an equivalent statin) within 6 months of diagnosis of dry AMD, while 99.5% (173,919) had no record of statin use.

Progression to wet AMD occurred in 13,484 (7.7%) patients (mean time to diagnosis of wet AMD 585 days). Patients taking high-dose statins had no significant difference in odds of progressing to wet AMD as compared to patients not taking statins before or after controlling for age, sex, smoking, and obesity. Kaplan-Meier estimates demonstrated no significant difference between conversion to wet AMD over time by high-dose statin use as compared to no statin use.

The researchers found no significant association between the use of high-dose statins and the progression of dry to wet AMD. But given the devastating effects of wet AMD and limited options for prevention, further exploration of subgroups for whom statins may be effective in preventing progression is warranted.

Ellex 2RT Laser Slows Progression of Intermediate AMD

■ Clinically proven to delay the rate of intermediate AMD (iAMD) progression in suitable patients, as demonstrated in the LEAD study, 2RT Retinal Therapy represents a new treatment approach, with more than 10,000 patients treated worldwide. Ellex has regulatory clearance to market 2RT for iAMD in Europe and will be seeking FDA approval in the United States.

The randomized placebo-controlled LEAD trial showed that more than three-quarters of patients with intermediate AMD (without coexistent reticular pseudodrusen) had a 77% reduction in progression rate to late-stage AMD following treatment with 2RT.

2RT technology features a proprietary nanosecond laser, teamed with a unique pixelated beam profile that targets the monocytes in RPE cells. Ellex says this begins a cascade of healing events that cause RPE cells to replicate (blood markers confirmed) and migrate into the diseased areas, thinning Bruch’s membrane and renewing retinal structures and functions, thereby delaying the risk of vision-threatening complications associated with late-stage AMD.

Premature Infants May Benefit From Therapeutic Light

■ Scientists at Cincinnati Children’s Hospital Medical Center have discovered a light-dependent molecular pathway that regulates how blood vessels develop in the eye. The findings, published in Nature Cell Biology, suggest it may be possible to use light therapy to help premature infants whose eyes are still developing avoid vision problems.

Called the opsin 5-dopamine pathway, the novel molecular process helps ensure blood vessel development in the eye is appropriately balanced to prepare it for visual function. The process can be thrown out of balance in medically fragile premature babies. Researchers are looking for ways to prevent or treat the retinopathy of prematurity and myopia that can result.

“Our study indicates opsin 5-dopamine pathway is probably part of a light-dependent disease process for conditions like myopia, which is now a worldwide epidemic,” said Richard A. Lang, PhD, director of the Visual Systems Group at Cincinnati Children’s and study senior author. “It raises the interesting possibility that we might be able to use light exposure to treat conditions like retinopathy of prematurity after a premature infant is born or in people with myopia.”

Interrupted TGF-Beta Signals and AMD Progression

■ A signaling pathway controlled by transforming growth factor beta (TGF-beta) could be involved in AMD progression, say researchers at the National Eye Institute (NEI). In an animal study, the researchers found that interrupting TGF-beta signals to immune cells called microglia causes the cells to enter an activated, inflammatory state. These activated microglia damage the retina, causing damage similar to cellular effects observed in AMD. The study was published in the journal eLife.

Prior research has shown that individuals with certain variations in genes in the TGF-beta pathway may be more at risk for advanced AMD, which suggests that TGF-beta might contribute to disease progression. In a healthy retina, neurons continuously emit a variety of signaling molecules, including TGF-beta, which communicate to neighboring cells that all is well, or conversely, let those cells know if something is wrong. When microglia sense normal levels of these molecules, they adopt a branched shape connected with and maintaining the health of their neuron neighbors. But when the signals change, microglia can enter an activated state, where they move to sites of injury to remove damaged or dead cells.

“Communication between neurons and microglia in the retina is going on all the time. Neurons tell the microglia how to behave and how to be of service to the rest of the retina,” said Wai Wong, MD, PhD, chief of the NEI section on neuron-glia interactions in retinal disease, who led the study, in a news release. “We wanted to know whether there was a connection between this genetic risk involving TGF-beta and abnormal retinal microglia, which are often found in AMD.”

To study this connection, Wong and his team genetically modified mice in order to turn off the microglial cells’ ability to sense TGF-beta. When cells stopped sensing TGF-beta, they immediately changed shape, moved to incorrect locations, and began to proliferate. The microglia also decreased their expression of their “sensome,” a collection of proteins that the microglia use to sense their environment. Instead, they started expressing proteins used in their activated state.

While microglia are critical for maintaining healthy neurons, decreased TGF-beta activity switches microglia to a proinflammatory mode, which is worse than having no microglia at all, said Wong.

Lab Creates Retinas That Explain Color Vision

■ Biologists at Johns Hopkins University grew human retinas from scratch to determine how cells that allow people to see in color are made. The work, published in the journal Science, lays the foundation to develop therapies for eye diseases such as color blindness and macular degeneration. It also establishes lab-created “organoids” as a model to study human development on a cellular level.

“Everything we examine looks like a normal developing eye, just growing in a dish,” said Robert Johnston, PhD, a developmental biologist at Johns Hopkins. “You have a model system that you can manipulate without studying humans directly.”

Johnston’s lab explores how a cell’s fate is determined — or what happens in the womb to turn a developing cell into a specific type of cell. He and his team focused on the cells that allow people to see blue, red and green — the 3 cone photoreceptors in the human eye.

While most vision research is done on mice and fish, neither of those species has the dynamic daytime and color vision of humans. Johnston’s team created the human eyes they needed — with stem cells.

“Trichromatic color vision delineates us from most other mammals,” said lead author Kiara Eldred, a Johns Hopkins graduate student. “Our research is really trying to figure out what pathways these cells take to give us that special color vision.”

Over months, as the cells grew in the lab and became retina organoids, the team found the blue-detecting cells materialized first, followed by the red- and green-detecting ones. They found the key to the molecular switch was the ebb and flow of thyroid hormone. Importantly, the level of this hormone wasn’t controlled by the thyroid gland, but entirely by the retinal tissue itself.

Wave Life Sciences to Target IRDs

■ Wave Life Sciences, a biotechnology company focused on genetically defined diseases, plans to design and advance stereopure oligonucleotide therapeutics for the potential treatment of rare inherited eye diseases (IRDs). Wave Life Sciences’ research in ophthalmology will initially focus on 4 IRDs that commonly lead to progressive vision loss, typically starting in childhood or adolescence: retinitis pigmentosa due to a P23H mutation in the RHO gene, Stargardt disease, Usher syndrome type 2A, and Leber congenital amaurosis 10.

“We have long believed that oligonucleotides have the potential to be particularly effective and durable in the eye and are energized by our latest research that provides additional validation of our precisely designed stereopure oligonucleotides,” said Paul Bolno, MD, MBA, president and CEO of Wave Life Sciences, in a news release. “Our aim is to move quickly to develop long-acting, intravitreally injected, disease-modifying therapies to address the enormous need across a spectrum of rare, genetically defined eye diseases.”

ElsaLys Retina Drug Shows Preclinical Efficacy

■ ElsaLys Biotech, announced the publication of 2 studies validating the potential of its first-in-class anti-CD160 antibodies for the treatment of neovascular diseases of the eye. The French company plans to begin an initial clinical trial in the near future.

The first study reveals that in patients, CD160 endothelial expression in retinal vessels is higher and correlates with a wide range of ocular neovascular diseases, while the second reports the safety of the antibody and demonstrates, in relevant animal models, its therapeutic benefit alone and in combination with anti-VEGF agents, the current standards of care for retinal vascular pathologies.

Published in Investigative Ophthalmology & Visual Science, the results of these 2 studies confirm ElsaLys Biotech’s preclinical data in ophthalmology: CD160 antibodies could be used for additive or synergistic effect with the current standard of care, or they could be used as alternative therapies in patients with anti-VEGF-resistant or refractory neovascular diseases.

Previous studies have shown that the engagement of CD160 by an activating antibody induces cell death of endothelial cells that surround newly formed blood vessels, thereby blocking their formation, both in vitro and in vivo. Researchers have also assessed the efficacy of this antibody as a monotherapy or as a combination therapy with bevacizumab (Avastin; Genentech). They show that administration of an anti-CD160 has an antiangiogenic effect in vivo in a relevant model of corneal neovascularization. This effect is equivalent to that seen with bevacizumab or with aflibercept (Eylea; Regeneron).

The antiangiogenic effect of the combination treatment (anti-CD160 and bevacizumab) was significantly higher than either antibody alone, and this result strongly supported that the anti-CD160 may act independently of the VEGF pathway and could be a good alternative for patients who respond poorly to an anti-VEGF treatment. RP