Future File is a new 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.

The Octopus and Screening for AMD

■ Shelby Temple, PhD, from the University of Bristol’s School of Biological Sciences in the United Kingdom, has been recognized for his groundbreaking work into polarization and its potential for early detection of macular degeneration.

The Biotechnology and Biological Sciences Research Council (BBSRC) award recognizes Dr. Temple’s work in developing a device that can rapidly screen people at increased risk of AMD.

The innovation arose from research that looked at the ability of octopi, cuttlefish, and coral reef fish to see polarized light — an aspect of light that humans aren’t typically aware they can see. Dr. Temple invented a series of unique devices to display polarized light to animals, and in doing so, realized he could see a pattern as well.

“What I was seeing was an effect known as Haidinger brushes, which happens within the eye when people perceive polarized light. The ability to see this phenomenon is linked to an aspect of eye health and can be an early indicator of disease … the tools I had developed for octopi and cuttlefish could be the foundation for a novel ophthalmic device that could rapidly screen people for susceptibility to AMD,” said Dr. Temple in a news release.

Dr. Temple has been awarded an InnovateUK Aid for Start-Up grant of half a million pounds to commercialize his research on polarized light sensitivity in humans into an optical device for assessing macular pigments in the eye as a tool in the prevention of eye disease.

What We Can Learn From the Zebrafish

■ Researchers have discovered that in zebrafish, decreased levels of the neurotransmitter gamma-aminobutyric acid (GABA) cue the retina, the light-sensing tissue in the back of the eye, to produce stem cells. The finding sheds light on how the zebrafish regenerates its retina after injury and informs efforts to restore vision in people who are blind. Early studies in zebrafish led to the idea that dying retinal cells release signals that trigger support cells in the retinal called Muller glia to dedifferentiate and proliferate. The research was funded by the National Eye Institute (NEI), part of the National Institutes of Health, and appeared online in Stem Cell Reports.

“This work opens up new ideas for therapies for blinding diseases and has implications for the broader field of regenerative medicine,” said Tom Greenwell, PhD, NEI program officer for retinal neuroscience, in a news release.

Recent studies in the mouse brain and pancreas have suggested that GABA might also regulate the activity of stem cells. Based on these findings, James Patton, PhD, Stevenson Professor of Biological Sciences at Vanderbilt University and his student Mahesh Rao hypothesized that GABA was involved in the zebrafish retina’s regeneration response. To test their idea, Patton and Rao injected GABA inhibitors into undamaged zebrafish eyes and found that the fish developed a regenerative response; that is, Muller glia in the retina dedifferentiated and proliferated. Conversely, increasing GABA levels after inducing retinal damage suppressed proliferation of dedifferentiated Muller glia. These findings supported the hypothesis that decreased GABA signaling is a cue for regeneration in the zebrafish retina.

“This is the first report to show a regenerative role for GABA in the zebrafish retina,” said Patton in a news release. The researchers are conducting ongoing work to determine if the dedifferentiated Muller glia can turn into functional retinal cells, such as photoreceptors. They are also exploring whether altering GABA signaling might coax a regenerative response in the retina of other species, such as mice.

A “Bicycle” for DME

■ Bicycle Therapeutics, a biotechnology company pioneering a new class of therapeutics based on its proprietary bicyclic peptide product platform (Bicycle), has announced the receipt of a preclinical milestone in connection with the advancement of a Bicycle into preclinical development for the treatment of diabetic macular edema, under its ophthalmology alliance with ThromboGenics, a biopharmaceutical company focused on developing treatments for back-of-the-eye disease.

Bicycles are a novel class of small-molecule medicines designed to overcome many of the limitations of existing drug modalities. They can be used as standalone therapeutic entities or coupled to deliver a variety of therapeutic payloads, and exhibit the affinity and exquisite target specificity usually associated with antibodies, but in a small-molecule format enabling rapid tissue penetration and flexible routes of administration.

A Device to Combat RP Progression

■ Retinal Implant AG this year merged with its former subsidiary Okuvision to begin European marketing of the Okuvision OkuStim system for slowing the progression of retinitis pigmentosa (RP) in patients with early and intermediate RP. The therapy, which has attained the CE mark, uses transcorneal electrical stimulation (TES) to extend the functional ability of retinal cells.

After an initial consultation and first therapy session with their doctor, patients can learn to administer the 30-minute-per-week treatment at home using a proprietary OkuStim headset and frame that positions extremely thin 100-micron electrode filaments on the eye below the pupil.

According to the company, “Research results show that the activation of several so-called neuroprotective growth factors on the retina — by means of electrical stimulation — can have a retention effect on the dying retinal cells. Thus, the degeneration of affected cells can also be reduced. Both contribute to enabling longer cellular function of the remaining cells. The retention can, for example, be measured or examined by a so-called electroretinography (ERG). This represents the electrical activity of the cells in response to light stimuli.”

Retinal Implant says the OkuStim concept has proven safe and effective in 3 clinical trials involving approximately 150 patients. The trials include both a pilot and a longer-term 1-year study at the University of Tuebingen, Germany, and the 24-week observational TESOLA study that took place at 11 sites with a total of 105 patients.

“The ability to delay the progression of a disease like RP is incredible,” said Andre Messias, MD, of Ribeirao Preto, Brazil, a trial investigator, in a news release. “Our results show an increased cell activity in the retina. We are very encouraged by these results as they demonstrate that TES could make a big difference in the many lives impacted by RP.”

Retinal Implant is also the developer of the Alpha AMS subretinal, 160-electrode retinal prostheses for patients with end-stage RP, which achieved the CE mark in 2016.

Newly Discovered Mediators Protect Retinal Cells

■ The Louisiana State University (LSU) Health Sciences Center reports that research led by Nicolas Bazan, MD, PhD, director of the Neuroscience Center of Excellence at LSU Health New Orleans, has discovered a new class of mediators, or biochemical triggers, that he named elovanoids (ELVs). Elovanoids are the first bioactive chemical messengers made from omega-3 very-long-chain polyunsaturated fatty acids that are released in response to cell injury or when cells are confronted with adversities for survival.

The report states that this discovery provides the first evidence of the existence of elovanoids and of their significant role in protecting and sustaining RPE and photoreceptor cell survival. The research was recently published online in Nature Research’s Scientific Reports.

“We believe this discovery represents a new concept of biology that will be transformative in medicine,” said Dr. Bazan.

The research uncovers a mechanistic breakthrough in the understanding of how cells are protected from impending damage. Uncompensated oxidative stress is often an early event associated with retinal, neuronal, or cardiac cell death, and the RPE and retina are under continuous stress.

“We found that elovanoids have unique structures and that they enhance the expression of prosurvival proteins in cells undergoing uncompensated oxidative stress,” said Dr. Bazan.

Dr. Bazan’s lab discovered, identified, and structurally characterized this new class of molecules in human RPE cells. Due to their biology, they are classified as mediators and are derived from docosahexaenoic acid (DHA). DHA is present abundantly in the retina and also serves as a precursor of signaling molecules called docosanoids that promote cell stability and equilibrium and act to protect the cell. The DHA- or eicosapentaenoic-acid-derived 26-carbon fatty acid is a molecule acted upon by the elongating enzyme ELOVL4, which is expressed in photoreceptor cells. ELOVL4 mutations are linked to vision loss and neuronal dysfunction. This has implications for developing new therapies for conditions such as Stargardt disease and other forms of retinal degeneration.

Fractal Geometry Studied for Retinal Implants

■ Researchers at the University of Oregon believe that electrodes whose shapes are based on fractal geometry can provide a higher level of functional vision than has thus far been achieved in currently available retinal prostheses.

The idea behind the implant is to use electrodes that have the same fractal shapes as the neurons with which they will interact. Fractal objects in nature have repeating patterns such as those easily seen in tree branches, rivers, snowflakes, blood vessels, and neurons. Current retinal implants use shapes based on traditional Euclidean geometry, such as squares.

So far, the concept has only been tested in computer simulations. RP