Week in Review: Number 13

Single Injection of RNA Therapy Improved Vision with Lasting Effect in LCA Patient
This study presents an unexpected case of sustained visual improvement at 15 months following a single injection of RNA therapy. The case study was part of a 2018 clinical trial involving eleven patients with Leber congenital amaurosis (LCA) due to a mutation in the CEP290 gene, one of the more common variants of the disease. People with this form of LCA suffer from severe visual impairment, typically beginning in infancy, due to abnormal development of the cilia of their photoreceptors. Specifically, the researchers investigated intravitreal injection of the RNA antisense oligonucleotide sepofarsen at three-month intervals for improvement of foveal structure and visual function. Unlike the other ten patients in the clinical trial, the patient in question elected to forgo quarterly maintenance doses after the initial injection due to concerns of cataract development. Surprisingly, however, more than a dozen measurements of visual function and retinal structure showed marked improvement, which peaked between 2 and 3 months and were sustained with mild reduction at 15 months. The researchers suggest that the success of antisense oligonucleotide therapy, which works to increase normal protein levels in the eye's photoreceptors, is due to the fact that these RNA molecules are tiny enough to get into the cell nucleus and have a slow natural rate of degradation, both contributing to their lasting effect. What is interesting about this case is that it inadvertently provides a comparison between two dosing schedules. One of the researchers notes, “The unexpected stability of the ciliary transition zone noted in the patient prompts reconsideration of dosing schedules for sepofarsen, as well as other cilium-targeted therapies.”

LCA Gene Therapy Restores Vision in Canines
Veterinary ophthalmologists and vision scientists studying a severe form of the rare eye disease Leber congenital amaurosis (LCA) have developed a gene therapy that restored vision in a canine model of the disease. Specifically, the variant of LCA they studied is caused by a mutation in the NPHP5 gene, resulting in abnormal or incomplete development of the cilia of photoreceptors. Among the spectrum of LCA vision disorders, the one caused by the HPHP5 gene is one of the rarest, affecting about 5,000 people worldwide. It is also one of the most severe and children with this form of LCA are not visual. In people with NPHP5 LCA, the rod photoreceptors degenerate early in the disease and the cones survive, albeit abnormally structured and without function. The fact that the cone photoreceptors persist in this form of LCA led the researchers to consider a gene therapy that would not only prevent early degeneration of photoreceptors but possibly even reverse vision loss. Investigating this hypothesis in dogs with a nearly identical naturally occurring form of the disease showed incredible promise. The researchers used gene augmentation therapy, in this case delivering a normal copy of either the canine or the human version of the NPHP5 gene via intravitreal injection in one eye of nine five-week-old dogs with the vision disorder. They then used electroretinography (ERG) and optical coherence tomography (OCT) to determine the effectiveness of the treatment. OCT imaging showed that the outer segments of the cones in treated eyes regrew. Even more encouraging were the functional visual outcomes. At six months, the dogs' vision was tested using an obstacle-avoidance course. When the dogs' treated eye was blindfolded, they had difficulty navigating, but when that eye was not covered, the ability to avoid obstacles was notably improved. As the researchers are keen to point out, these results show not only halting disease progress but also restoring visual function. Although affecting only a small number of people, the fact that a large animal model of NPHP5 disease very closely parallels the disease in humans lends support for clinical trials to investigate the potential benefit in children with this form of LCA.

Consistency of Visual Perception of Constellations
This small study was an abstract presented at the March 2021 meeting of the American Physical Society. Though it has yet to be published in a journal, the findings were intriguing enough to catch the attention of two general science news sources. The study relates to eyes in its topic of saccades and how human visual perception of random points of light, in this case the constellations of the night sky, show a level of consistency across cultures. Why does the perception of one constellation comprise a particular group of stars rather than another? For example, the Greco-Roman constellation Orion is exceedingly similar to the constellation Baiame in Aboriginal Wiradjuri traditions in Australia. Moreover, in both myths, Orion and Baiame chase seven young women, whether known as the Plaeiades or the Yugarilya sisters, respectively. The presenters used a simulation that incorporated information about the lengths of saccades and the apparent distances between neighboring stars and their brightnesses to generate groupings of stars. They reported that their simulation tended to align with the 88 modern constellations recognized by the International Astronomical Union. What is intriguing about this study is that it provides a simple explanation for the naming practices of constellations in the night sky across different cultures. That explanation is all the more exciting in locating these similarities in the consistency of human visual perception.

We Choose Things We Spend More Time Looking At
Researchers in psychology and economics conducted a study using eye-tracking technology to investigate how people decide when given many options. They found that people tended to choose items, snacks in this case, that they spent more time looking at, sometimes even over snacks that they rated more highly. This study in particular involved 49 participants, who were tasked with choosing a snack from a total of 80 snacks shown on a computer screen in sets of varying numbers from 9 to 36 items. One finding was a peripheral screening process that depended on the items' location and how much they were liked. Results showed that participants didn't look carefully at all the items before making a choice, but instead avoided looking directly at snacks they don't really like. This peripheral screening only happens when there are many options presented, as compared to a binary choice. Another finding correlated final choice with the amount of time spent looking at the chosen snack. People would look through the items, often going back and forth among them, until one item stood out from the others, often the item they looked at the most. Though this is a small study, the findings are interesting in connecting decision-making with duration of visual input.

Anti-Apoptotic Protein Inhibitors as Potential Treatment for Retinal Neovascularization
Understanding the molecular basis of angiogenesis is a foundation to developing therapies for eye diseases due to abnormal neovascularization, eye diseases such as diabetic retinopathy. A team of researchers in Canada and the U.S. discovered that in contrast to healthy blood vessels, pathological blood vessels engage in pathways of cellular senescence, or accelerated aging. They then induced senolysis, the selective destruction of senescent cells, by either genetically eliminating the senescent cells (specifically p16^INK4A-expressing cells) or by using small molecule inhibitors of the anti-apoptotic protein BCL-xL. BCL-xL is a molecular target present in defective blood vessels. Senolysis was found to suppress pathological angiogenesis, consequently providing a better environment for physiological vascular repair. As the news article states, Phase 1 clinical trials are underway to test the potential of this new class of drug for treatment of diseases of retinal neovascularization.

In the News: Edition 3
There is a place for ophthalmic imaging devices, from small clinics to large medical centers, where their use is appropriate for the setting. Research in so-called DICOM compliant devices should work toward increasingly rigorous standards, though they are optional at this point. Transparency in research progress, as a safety measure, is a voluntary objective for some projects that are currently in development in eye care, though that development will take many years to fully realize. For systems that interface with a variety of devices and networks, compliance to privacy protocols must be followed to ensure patient confidentiality. [These reasons are even clearer now than previously.] Recognizing that there is no easy way to standardize all ophthalmic imaging devices, ample testing is conducted before implementing any new standard. Any change will be based on clear evidence, a prudent strategy that is adopted by even large organizations. Thank you to the NEI for this piece.

In Other News
(1) How sign language exposure impacts infants
(2) FDA approval of BRIMOCHOL for presbyopia correction
(3) The best contact lenses of 2021