Future File highlights new and innovative early-stage and preclinical concepts that could one day help to advance the everyday practice of retina specialists.

Researchers Use Adaptive Optics to Make a Correct Diagnosis

■ Researchers from New York Eye and Ear Infirmary of Mount Sinai used adaptive optics that allow clinicians to examine microscopic structures of the eye in living patients with extreme detail in real time to analyze and better understand the rare retinal disease fundus albipunctatus. This inherited condition negatively affects the photoreceptor cells, which typically results in poor night vision. In late stages of the disease, color vision and central vision can also be impaired. There is currently no cure or effective treatment for this disease.

The case study focuses on a 62-year-old patient who was misdiagnosed with Stargardt disease and lived with that diagnosis for more than a decade. He came to New York Eye and Ear Infirmary for further evaluation, where genetic testing and adaptive optics led doctors to properly diagnose him with fundus albipunctatus. These 2 genetic conditions can appear similar but have very different prognosis.

Patients with Stargardt disease typically progress to worse vision, whereas fundus albipunctatus is associated with night vision issues that typically don’t change. With adaptive optics, ophthalmologists went on to find that in the later stages of fundus albipunctatus, some structures of photoreceptor cells were preserved, which implies that future treatments, including gene therapy, may play a role in reversing or preventing vision loss.

New Inhibitor May Prevent Vascular Retinal Disease

■ Unity Biotechnology announced preclinical data demonstrating that UBX1325, a novel senolytic small molecule inhibitor of Bcl-xL, improves retinal vasculature and is differentiated from anti-VEGF agents in preclinical models. Researchers showed that inhibition of retinal Bcl-xL by UBX1325 selectively promotes apoptosis of diseased senescent cells of the retina, thereby restoring healthy vasculature and improving retinal function — important distinctions from anti-VEGF treatments. The research was presented during the ARVO 2021 Virtual Annual Meeting.

“The data presented provide important preclinical support for the potential of UBX1325 as a differentiated treatment for prevalent vascular diseases of the eye,” Przemyslaw (Mike) Sapieha, PhD, chief scientific advisor of Unity, said in a news release. “By targeting the senescent cells that promote inflammation and compromise vascular integrity in the eye, we aim to provide an effective therapeutic option that selectively eliminates diseased and leaky cells within blood vessels while potentially stimulating vascular repair.”

Potential Therapeutic Approach to AMD

■ Runt-related transcription factor 1 (RUNX1) has been linked to retinal neovascularization and the development of abnormal blood vessels, which result in vision loss in diabetic retinopathy. Now, scientists have found that RUNX1 inhibition presents a new therapeutic approach in the treatment of AMD. Their results are reported in The American Journal of Pathology.

Researchers at Mass Eye and Ear induced CNV lesions in mice. Immediately thereafter, the mice received a single intravitreal injection of saline, aflibercept (Eylea; Regeneron), the RUNX1 inhibitor Ro5-3335, or a combination of Ro5-3335 and aflibercept. A single intravitreal injection of Ro5-3335 alone significantly decreased the CNV lesion size 7 days after induction of the CNV lesions. The combination of Ro5-3335 and aflibercept reduced vascular leakage more effectively than aflibercept alone.

“RUNX1 inhibitors hold significant promise to complement or replace anti-VEGF therapies for patients in which anti-VEGF therapy is no longer effective, and with the potential to be administered topically it could be transformative in the field,” said co-lead investigator Joseph F. Arboleda-Velasquez, MD, PhD, assistant scientist, Schepens Eye Research Institute of Mass Eye and Ear, in a news release.

Researchers May Have Found Key to Retinal Fibrosis

■ New research from the laboratory of John A. Moran Eye Center physician-scientist Mary Elizabeth Hartnett, MD, reveals how an oxidized form of cholesterol can change choroidal endothelial cells into cells that become scars and may wreak havoc in the eyes of AMD patients. The oxysterol 7-ketocholesterol (7KC) builds up in the body as a person ages, and in diseases, including cancer and heart disease. In the eye, 7KC accumulates in Bruch’s membrane with age and in AMD.

Examining the effects of 7KC in the eyes of mice, Hartnett lab researchers found evidence that the oxysterol can effectively change choroidal endothelial cells (CECs) into cells that then invade the neural retina and lead to fibrosis. The transformed cells become enlarged lesions and fibrosis similar to those seen in poorly responsive forms of neovascular or wet AMD, which account for 40% of poor vision in neovascular AMD. The transformed CECs may be less responsive to anti-VEGF.

“Of [patients who do not respond to anti-VEGF], 40% have fibrosis or scars,” said Dr. Hartnett, a vitreoretinal surgeon and principal investigator of the study, in a news release. “These findings provide a potential explanation for fibrosis and suggest that if we can interfere with this process, we might be able to improve outcomes in many more patients with neovascular AMD.”

The research was supported by the National Institutes of Health and an unrestricted grant from Research to Prevent Blindness.

An Advance in Imaging the Human Eye

■ Researchers have developed a noninvasive technique that can capture images of rod and cone photoreceptors with unprecedented detail. The advance could lead to new treatments and earlier detection for retinal diseases such as macular degeneration, a leading cause of vision loss.

In Optica, the researchers showed that their new imaging method overcomes resolution limitations imposed by the diffraction barrier of light. The researchers accomplish this feat while using light that is safe for imaging the living human eye.

“The diffraction limit of light can now be routinely surpassed in microscopy, which has revolutionized biological research,” said research team leader Johnny Tam from the National Eye Institute, in a news release. “Our work represents a first step toward routine subdiffraction imaging of cells in the human body.”

Achieving high-resolution images of photoreceptors in the back of the eye is challenging because the eye’s optical elements (such as lens and cornea) distort light in a way that can substantially reduce image resolution. The diffraction barrier of light also limits the ability of optical instruments to distinguish between 2 objects that are too close together. Although there are various methods for imaging beyond the diffraction limit, most of these approaches use too much light to safely image living human eyes.

To overcome these challenges, researchers improved upon a retinal imaging technique known as adaptive optics scanning laser ophthalmoscopy, which uses deformable mirrors and computational methods to correct for optical imperfections of the eye in real time.

“One might think that more light is needed to get a better image, but we demonstrate that we can improve resolution by strategically blocking light in various locations within our instrument,” said Tam. “This approach reduces the overall power of light delivered to the eye, making it ideal for live imaging applications.”

After demonstrating that imaging resolution was improved in theoretical simulations, the researchers confirmed their simulations using various test targets. They then used the new method to image rod and cone photoreceptors in 5 healthy volunteers at the National Institutes of Health’s Clinical Center. The new approach yielded about a 33% increase in transverse resolution and 13% improvement in axial resolution compared to traditional adaptive optics scanning laser ophthalmoscopy.

Replacement Photoreceptors from Stem Cells

■ New advances by medical researchers and engineers at the University of Wisconsin-Madison may provide hope for those suffering from vision loss from permanently damaged photoreceptors. The work was published in the journal Science Advances. The researchers made new photoreceptors from human pluripotent stem cells; however, it remains challenging to precisely deliver those photoreceptors within the diseased or damaged eye so that they can form appropriate connections, says Dr. David Gamm, director of the McPherson Eye Research Institute and professor of ophthalmology and visual sciences at the UW School of Medicine and Public Health.

The UW team developed a micromolded scaffolding photoreceptor “patch” designed to be implanted under a damaged or diseased retina. In 2018, the team developed its first biodegradable polymer scaffolding with wine-glass-shaped pores to hold the photoreceptor cells in place. However, that design wasn’t optimal because it could not fit many photoreceptors in each pore.

In this second-generation scaffold, the team opted for an “ice cube tray” design, which can hold 3 times as many cells while reducing the amount of biomaterial used for the scaffolding to facilitate faster degradation of the synthetic material within the eye.

New Gene Variants Unlocking Key to MacTel

■ An analysis of thousands of genomes from people with and without the rare eye disease macular telangiectasia type 2 (MacTel) has turned up more than a dozen gene variants that are likely causing the condition to develop and worsen for a significant share of patients. The discovery by a team of scientists from Scripps Research and the Lowy Medical Research Institute, in collaboration with Columbia University in New York and UC San Diego, provides a new avenue to pursue for diagnosis and treatment. It also sheds light on fundamental aspects of metabolism in the retina. Findings appear in the journal Nature Metabolism.

MacTel is a progressive and debilitating eye disease that occurs in roughly 1 out of 5,000 people, or about 2 million people worldwide. A disease of the retina, the light-sensing tissue at the back of the eye, MacTel causes a gradual deterioration of central vision, interfering with critical tasks such as reading and driving.

One gene, PHGDH, had significantly more variants in MacTel patients than those without the disease. The team identified 22 rare variants in PHGDH which, together, account for approximately 3% to 4% of MacTel cases. Many more variants likely exist but haven’t been found yet — a challenge considering the small patient population with diverse genetic causes.

PHGDH is a key enzyme that enables the body to make serine, and these studies provided the long-sought link to low serine observed in MacTel patients. Its function is essential for the health of neurons in the eye and elsewhere in the body. RP