Citicoline Oral Supplementation as Neuroprotection Independent of IOP in a Rat Model of Glaucoma

Article: Citicoline Protects Against Glaucoma Without Reducing Fluid Pressure in Eye
Source: NYU Langone Health, via NEI
Published: April 14, 2021

Citicoline is a major source of choline, a building block of cell membranes, including those of the nerve cells that transmit information from the eye to the brain. The authors note that previous studies in humans and rodent models of glaucoma showed lower levels of choline in the brain, but there has been little research into the effectiveness of choline supplementation as a glaucoma therapy. The present study in rats found that ingesting citicoline restored optic nerve signals between the eye and the brain independent of intraocular pressure (IOP). As such, citicoline is of particular interest as a novel mechanism for the treatment of glaucoma. In the vast majority of cases, elevated eye pressure is a risk factor for damage to the optic nerve, resulting in glaucoma. However, many studies have shown that glaucoma progression continues despite good eye pressure control, suggesting additional mechanisms of the disease. Despite hints of alternative mechanisms, contributing to normal tension glaucoma, for example, eye pressure has been the only variable that can be modified clinically. Neural protection and reversal of optic nerve damage are the holy grails of glaucoma research. The fact that citicholine can reduce vision loss in mice independent of eye pressure is intriguing. In particular, the research team induced glaucoma in several dozen rats using a clear gel. For rats with mildly elevated IOP, optic nerve and other tissues decayed for up to five weeks after injury. In rats treated with oral doses of citicoline over a three-week period, nerve degradation was reduced by 74%, suggesting a neuroprotective effect. Furthermore, reduced vision loss was sustained for another three weeks after treatment was stopped. The researchers caution that there are several steps between lab research and commercial development of an effective drug. They next intend to further investigate the connection between choline and neural protection.

My rating of this study: ⭐⭐

Van der Merwe Y, Murphy MC, Sims JR, et al. "Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control." Neurotherapeutics. 13 April 2021. https://doi.org/10.1007/s13311-021-01033-6

Txnip Gene Therapy for Three Types of RP in Mice

Article: Gene therapy shows promise in treating rare eye disease in mice
Source: eLife, via ScienceDaily  and NEI
Published: April 13, 2021

Effect of Txnip on ATP:ADP levels in RP cones
in media with different carbon sources

Retinitis pigmentosa (RP) is a genetic eye condition that results in progressive dysfunction or loss of the photoreceptors in the retina, beginning with loss of rod photoreceptors and later also affecting cone photoreceptors. Currently, more than 100 gene loci for retinitis pigmentosa have been mapped or identified. However, targeted gene therapies have only been able to treat specific gene defects rather than wider sets or families of the disease. As the lead author states, “A gene therapy that would preserve photoreceptors in people with retinitis pigmentosa regardless of their specific genetic mutation would help many more patients.” To find a gene-agnostic therapy that could apply more broadly, the researchers screened 20 potential therapies in mouse models of RP, selecting for therapies that target sugar metabolism based on the theory that cone photoreceptor degeneration in RP was due to loss of glucose supply. Their experiments found that a gene called Txnip, especially an allele called C247S, was most effective in treating RP across three different mouse models. C247S in particular helped the cone photoreceptors switch to alternative sources of energy and improved mitochondrial health. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), suggesting that this therapy improves cone photoreceptor health by enhancing lactate catabolism. Combining Txnip gene therapy with additional gene therapies that reduced oxidative stress and inflammation provided additional cellular protection. The researchers intend to further their studies in animal models beyond mice before starting clinical trials in humans.

My rating of this study: ⭐⭐

Xue Y, Wang SK, Rana P, et al. "AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa." eLife.  10:e66240. 13 April 2021. https://doi.org/10.7554/eLife.66240

Microgravity Manufacturing of Artificial Retina

Article: An artificial retina engineered from ancient protein heads to space
Source: National Eye Institute
Published: April 12, 2021

Layers of bacteriorhodopsin generate a proton gradient across an ion-permeable membrane

Industry researchers are exploring the development of an artificial retina using bacteriorhodopsin, with intended manufacturing in the microgravity environment of space on the International Space Station. A representative for one of the companies explains, “When gravity is nearly eliminated, so too are forces such as surface tension, sedimentation, convection driven buoyancy, all of which can interfere with the orientation and alignment important in the creation of crystalline structures, nanoparticles, or improved uniformity in layering processes." Similar to rhodopsin in human photoreceptors, bacteriorhodopsin is a light-sensing protein found in extremomophile microorganisms of the Archaea domain of life. When activated by light, bacteriorhodopsin pumps hydrogen ions across a membrane, generating an ion gradient. Additionally, bacteriorhodopsin's molecular structure is highly ordered and thermally stable for nanotechnology applications. In the artificial retina, layers of purified bacteriorhodopsin generate an ion gradient across a permeable membrane, acting in place of photoreceptors, to stimulate bipolar cells and retinal ganglion cells. From there, the signal is relayed via the optic nerve to the brain as usual. The microgravity environment of space facilitates layering the bacteriorhodopsin in a more precise orientation to create a unidirectional ion gradient, which the companies anticipate would persist when returned to gravity on Earth. The companies are working toward FDA approval for the use of their artificial retina for retinitis pigmentosa, with preclinical data still underway prior to clinical trials.

My rating of this study: ⭐⭐

Complement Factor H in C. Elegans Model of AMD

Article: Study Identifies New Mechanism that May Cause Blindness in Older Adults
Source: University of Maryland School of Medicine, via NEI
Published: April 12, 2021

Photoreceptor (green) and inversin (red) proteins are
compartmentalized in healthy retinas (top), but overlap (yellow)
in mouse and human retinas with CFH mutations (bottom)

Researchers working with a laboratory model of C. elegans have found a potential new mechanism for age-related macular degeneration (AMD). Specifically, they looked at the contribution of protein complement factor H (CFH), after previous research showed that mutations related to it are seen in a large number of AMD patients. The role of complement factor H is to mark cells in the body as self to protect them from an immune attack. This link between CFH and AMD led some researchers to hypothesize that AMD is due to the immune system attacking the body's cells that were not marked as self. The researchers were curious to explore new mechanisms of the disease using nematode lab models. Roundworms in particular have a version of CFH in the middle of their antennas, specifically in the cilia, which are responsible for sensing the environment. The CFH proteins are located next to another important antenna protein called inversin. In roundworms bred to lack CFH, inversin is spread throughout the antennas rather than located in the middle. Roundworm antennas have some structural similarities to the photoreceptors of the human eye. For example, CFH and inversin have the same positioning in the cilia of photoreceptors in healthy human retinal tissue. However, in people with CFH mutations, inversin was spread around rather than located in neat bands. The authors state, "The role of CFH in cilia compartment boundaries is conserved in vertebrate photoreceptors, suggesting that structural defects in photoreceptor cilia make a contribution to AMD progression in patients with CFH mutations that has not been appreciated previously."

My rating of this study: ⭐

Acker N, Smith H, Devine C, et al. "A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans cilia." PNAS.  118(16):e2016698118. April 2021. https://doi.org/10.1073/pnas.2016698118

Models for Precision & Color in Argus II Retinal Implant

Article: Computer model fosters potential improvements to ‘bionic eye’ technology
Source: USC Keck School of Medicine, via NEI
Published: April 9, 2021
Article: USC research coalition uses computer models to advance benefits of ‘bionic eye’
Source: USC Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics
Published: February 10, 2021 [Added November 15, 2021]

Fundus photo of the electrode array

The present pair of studies explored improvements to the Argus II retinal implant using electrical simulation wavefront models for greater precision of target stimulation as well as the encoding of basic color. The Argus II retinal prosthesis uses a camera mounted on special glasses to detect patterns of light. These signals are then relayed to an array of 60 electrodes that stimulate retinal ganglion cells (RGCs). The implant is used in patients whose photoreceptors no longer detect light, such as in severe cases of retinitis pigmentosa, by stimulating retinal ganglion cells downstream of the photoreceptors. The axons of retinal ganglion cells together form the optic nerve that relay the signal to the brain for visual perception. In some patients, off-target stimulation of the axons rather than the cell body results in the perception of elongated phosphenes rather than the intended dots of light. To address this issue, the researchers used a computer model of two types of retinal ganglion cells, D1-bistratified and A2-monostratified, at the single-cell level and in large networks. They identified a pattern of short pulses that preferentially targets the cell bodies with less off-target activation of axons. In a more recent study, the same team of researchers applied the same computer models to study the encoding of color by retinal ganglion cells. Prior tests in patients revealed that the perception of color depended on the frequency of electrical stimulation. The second study uses computer models to predict eliciting color perception, specifically by stimulating small bistratified cells that contribute to blue-yellow color opponency, i.e., blue and yellow color perception. These two studies provide information to guide improvements in the Argus II retinal prosthesis toward more precise and colorful visual perception for the blind.

My rating of these studies: ⭐⭐

Paknahad J, Loizos K, Humayun M, et al. "Targeted Stimulation of Retinal Ganglion Cells in Epiretinal Prostheses: A Multiscale Computational Study." IEEE Transactions on Neural Systems and Rehabilitation Engineering.  28(11):2548-2556. 29 September 2020. https://doi.org/10.1109/TNSRE.2020.3027560 [PDF]

Paknahad J, Loizos K, Yue L, et al. "Color and cellular selectivity of retinal ganglion cell subtypes through frequency modulation of electrical stimulation." Scientific Reports.  11(5177). 4 March 2021. https://doi.org/10.1038/s41598-021-84437-w

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

We Choose Things We Spend More Time Looking At

Article: How people decide when they have so many choices
Source: Ohio State University, via ScienceDaily
Published: April 8, 2021

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.

My rating of this study: ⭐

Thomas AW, Molter F, Krajbich I. "Uncovering the computational mechanisms underlying many-alternative choice." eLife. 10:e57012. 6 April 2021. https://doi.org/10.7554/eLife.57012

Case Study: Single Injection of RNA Therapy Improved Vision with Lasting Effect in LCA Patient

Article: A Single Injection Reverses Blindness in Patient with Rare Genetic Disorder
Source: Penn Medicine News, via ScienceDaily
Published: April 1, 2021
Article: Mutation-Specific RNA Therapy Can Improve Vision with Lasting Effects
Source: Genetic Engineering & Biotechnology News
Published: April 5, 2021

Sustained visual improvement at 15 months
with single injection of sepofarsen

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.”

My rating of this article: ⭐⭐

Cideciyan AV, Jacobson SG, Ho AC, et al. "Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report." Nature Medicine.  27:785-789. 1 April 2021. https://doi.org/10.1038/s41591-021-01297-7

Consistency of Visual Perception of Constellations

Article: Here’s why humans chose particular groups of stars as constellations
Source: Science News Magazine, via ScienceAlert
Published: March 29, 2021
Article: There Could Be a Beautiful Reason Why Constellations Are The Same in Many Cultures
Source: ScienceAlert
Published: April 2, 2021

The stars of constellation Sagittarius

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.

Personal commentary: It is sometimes difficult to literally see how some constellations could be perceived the way they are, such as that of Sagittarius above depicting the Greco-Roman centaur archer. My perception does not align with illustrations of the constellation, but I suppose I can make out a line of stars forming an arm to an arc of three stars forming the archer's bow.

My rating of this study: ⭐🌸

David S, Smith LM, Lynn C, et al. "Free Energy Model of the Human Perception of a Starry Sky." Bulletin of the American Physical Society. Abstract S16.00006 at the American Physical Society Meeting. Presented 18 March 2021. http://meetings.aps.org/Meeting/MAR21/Session/S16.6

LCA Gene Therapy Restores Vision in Canines

Article: Turning back the clock on a severe vision disorder
Source: University of Pennsylvania, via ScienceDaily  and NEI
Published: March 30, 2021

Photoreceptor regrowth (red) in the retinas
of canines with NPHP5-related LCA

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.

My rating of this study: ⭐⭐🌸

Aguirre GD, Cideciyan AV, Dufour VL, et al. "Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis." Molecular Therapy. 27 March 2021. https://doi.org/10.1016/j.ymthe.2021.03.021

Anti-Apoptotic Protein BCL-xL Inhibitors as Potential Treatment for Retinal Neovascularization

Article: Discovery of a new drug for diabetic retinopathy
Source: University of Montreal (Canada), via EyeNet
Published: February 11, 2021

Healthy and pathological retinal vascularization

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.

Personal commentary: Note that this article is from February of this year. I think I had skipped it in the early days of the blog while I decided what kinds of articles to include or comment about. Back then, I hadn't expanded to taking a closer look at the research journal article. The news article from the University of Montreal in this case is on the simpler side, probably contributing to its exclusion from commentary initially. But upon a second round of review, it is still a science news article about eyes, especially from an academic/university news source. So minor commentary is included here.

My rating of this study: ⭐⭐

Crespo-Garcia S, Tsuruda PR, Dejda A, et al. "Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition." Cell Metabolism. 5 February 2021. https://doi.org/10.1016/j.cmet.2021.01.011

In the News: Edition 3

Article: NEI joins call for standardization of ophthalmic imaging devices
Source: National Eye Institute
Published: April 8, 2021

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.

Review of Optology thanks science media and readership and will resume content in one week.

Week in Review: Number 12

3D In Vitro Model of the RPE-Choriocapillaris Complex
To better understanding the underlying pathology of age-related macular degeneration (AMD), researchers at the University of Rochester have engineered a 3D in vitro model of the RPE-choriocapillaris complex of the human retina. In designing a more accurate in vitro model of the human retina, they sought to resolve a debate in the field as to whether the etiology of macular degeneration is due to defects in the retina or due to systemic issues, such as blood supply. Their model combines iPSC-derived retinal tissue from human patients with a hydrogel-based extracellular matrix to better replicate the relationship between the retinal pigment epithelium (RPE) and the underlying vasculature of the choriocapillaris (CC). Notably, their model confirmed that RPE and mesenchymal stem cells play a role in the development of the choriocapillaris layer, showed that blood-derived factors from patients can independently contribute to the development and progression of wet AMD, and identified FGF2 (a fibroblast growth factor) and matrix metalloproteinases as potential therapeutic targets for AMD and other macular dystrophies. In answer to the initiating question regarding AMD etiology, their retinal model strongly points to retinal defects, particularly the RPE, as contributing to AMD. One of the researchers explains, “You can have completely normal choriocapillaris, but if your RPE’s are dysfunctional it will cause the choriocapillaris to dysfunction.” Once the model has been validated in larger sample sizes, they hope it would be useful in testing and developing drug therapies specific to individual patients.

Metabolomic & Proteomic Approaches to Eye Disease
This article provides a commentary on recent scientific approaches in metabolomics and proteomics and how they shed light on the causes of eye diseases such as age-related macular degeneration (AMD) and dry eye disease (DED). For instance, researchers in Finland and Singapore are investigating the mechanisms involved in AMD through advanced liquid chromatography mass spectrometry (LC-MS) with SWATH Acquisition (a more comprehensive method for detecting all the metabolites present in complex samples) to examine the proteomic profiles of tear samples. Their data showed that protein quantities varied with age, and suggest that in healthy aging, cell growth and survival decrease while immune response and inflammation increase. Another research team in Singapore, with collaborators in the U.S., is using LC-MS to examine the metabolic profiles of serum samples in wet AMD patients. As compared to healthy controls, those with wet AMD had higher levels of glycerophospholipids, amino acids, and omega fatty acids. Comparison of sera between anti-VEGF drug responders and suboptimal responders further found that glycerophospholipids, such as lysophosphatidylcholine, were higher in suboptimal responders, implicating glycerophospholipid metabolism as a contributor to suboptimal response.

Mass spectroscopy is also useful in proteomic studies of dry eye disease. For example, LC-MS based proteomic analysis of tears from DED patients undergoing treatment with either flourometholone (FML) or polyvinyl alcohol (PA) revealed protein biomarkers that could be used to predict which patients would respond best to management with either of these drugs. Dry eye disease also affects many glaucoma patients as a side effect of topical glaucoma medications. In such cases, analysis of tear proteomes could help to identify patients who would most benefit from switching to preservative-free eye drops. A metabolomic/proteomic approach to identify biomarkers of disease is useful to both better understand the underlying mechanisms of diseases and to guide treatment that would benefit the right patients at the right time. The author concludes, "This is precision medicine, and you do not get precision medicine without the sensitive and precise quantification of molecules."

Two-Year Data of Preventative Intravitreal Anti-VEGF for Treatment of Diabetic Retinopathy
A randomized clinical trial funded by the National Eye Institute and published in JAMA Ophthalmology  recently provided two-year data of the effect of early treatment with intravitreal anti-VEGF (anti-vascular endothelial growth factor) aflibercept (Eylea) for the prevention of vision-threatening complications of diabetic retinopathy. As part of a four-year randomized clinical trial, this study is conducted at 64 U.S. and Canadian sites and involves 328 adults (399 eyes) with moderate to severe non-proliferative diabetic retinopathy (NPDR), without center-involved diabetic macular edema (CI-DME). Study protocols were followed to ensure that any patient who developed CI-DME with vision loss or high-risk proliferative diabetic retinopathy (PDR) received aflibercept. The results at the halfway mark showed that treatment with periodic aflibercept reduced rates of PDR and DME. In particular, the rate of PDR development was 14% in the treatment group compared to 33% in the control group. Similarly, the rate of development of vision-threatening DME was 4% in the treatment group compared to 15% in the control group. However, change in visual acuity was essentially the same for both groups (6 letters lost) at two years. In other words, preventative treatment did not confer visual benefit compared to the current standard practice of treatment with anti-VEGF only after development of PDR or vision-threatening CI-DME. Just as it is valuable to discover new treatment guidelines that are effective, it is equally important to discover when new treatment strategies do not confer substantial benefit. The four-year results will provide further information on the longer-term effects of preventative treatment in this study.

Depression Affects Visual Perception
Researchers in psychiatry and psychology from Finland investigated the effect of depression on visual perception through optical illusions. In particular, their study explored the difference in subjective brightness and contrast sensitivity (as well as inherent orientation sensitivity with regard to patterns) between 111 people who were experiencing major depressive episodes and 29 people who were not. Their results suggest that while the perception of brightness in the visual illusion was similar in both groups, people suffering from depression perceived the visual illusion in the patterns as weaker, and consequently the contrast as stronger compared to those not experiencing depression. “The contrast was suppressed by roughly 20% among non-depressed subjects, while the corresponding figure for depressed patients was roughly 5%,” one of the researchers explains. They further suggest that the difference in contrast perception in the scenario with patterns, which has an added layer of orientation perception, is due to altered cortical processing rather than altered retinal processing. This interpretation is supported by the data showing that there was little difference between the two groups in perception of the illusion without the patterns. And indeed perception of orientation relies on processing at higher levels than retinal cells. There are several limitations with a small self-reported observational study, which cannot untangle connections at the cellular level or at the level of cerebral visual processing. Nonetheless, the discovery that there are differences in visual perception during depression, which is consistent with studies about other altered mental states, could inform the development of vision testing to identify such disturbances in patients.

Normal Tension Glaucoma and Cognitive Impairment
Researchers in Australia published a small observational study showing an association between normal-tension glaucoma (NTG) and cognitive impairment. Both normal-tension glaucoma, also known as low-tension glaucoma (LTG), and high-tension glaucoma (HTG) are subtypes of primary open angle glaucoma (POAG), with the difference being the elevation of intraocular pressure or lack thereof. In primary open angle glaucoma, the angle at the trabecular meshwork, an angle formed at the intersection of the cornea and the iris, is open. The other angle-related variation of narrow-angle or angle-closure glaucoma (NAG, ACG) would present with a narrow or closed angle, anatomically obstructing drainage of aqueous humor. Normal-tension glaucoma is more common in people of Asian ancestry while high-tension glaucoma is more common in people of European ancestry. All types of glaucoma display optic nerve damage.

Because the etiology of NTG isn't due to anatomical blockage, excessive aqueous production or inadequate aqueous drainage, its pathology is not fully understood. Furthermore, many cases of glaucoma involve mixed mechanisms. The present investigation into neurological connections with NTG was sparked by links between POAG and dementia in some prior studies. This study involved a health questionnaire of 248 patients with NTG and 349 patients with HTG, all of whom were at least 65 years of age. Among these, 144 patients with NTG and 146 patients with HTG received a cognitive screening; both assessment types were conducted over the phone. The small observational study found that cognitive impairment was twice as prevalent in patients with NTG as it was in those with HTG. The investigators acknowledge a range of limitations with their study. Nonetheless, the study adds information to the body of knowledge about the complexity of glaucoma.

In Other News
(1) People with glaucoma at risk for sight loss due to pandemic
(2) Light-activated genetic therapy to treat blindness enters clinic
(3) Could a drug used to treat brain bleeds help patients with optic neuritis?

Two-Year Clinical Data of Preventative Intravitreal Anti-VEGF for Treatment of Diabetic Retinopathy

Article: Preventive treatment reduces diabetic retinopathy complications
Source: National Eye Institute
Published: March 30, 2021

A randomized clinical trial funded by the National Eye Institute and published in JAMA Ophthalmology  recently provided two-year data of the effect of early treatment with intravitreal anti-VEGF (anti-vascular endothelial growth factor) aflibercept (Eylea) for the prevention of vision-threatening complications of diabetic retinopathy. As part of a four-year randomized clinical trial, this study is conducted at 64 U.S. and Canadian sites and involves 328 adults (399 eyes) with moderate to severe non-proliferative diabetic retinopathy (NPDR), without center-involved diabetic macular edema (CI-DME). Study protocols were followed to ensure that any patient who developed CI-DME with vision loss or high-risk proliferative diabetic retinopathy (PDR) received aflibercept. The results at the halfway mark showed that treatment with periodic aflibercept reduced rates of PDR and DME. In particular, the rate of PDR development was 14% in the treatment group compared to 33% in the control group. Similarly, the rate of development of vision-threatening DME was 4% in the treatment group compared to 15% in the control group. However, change in visual acuity was essentially the same for both groups (6 letters lost) at two years. In other words, preventative treatment did not confer visual benefit compared to the current standard practice of treatment with anti-VEGF only after development of PDR or vision-threatening CI-DME. Just as it is valuable to discover new treatment guidelines that are effective, it is equally important to discover when new treatment strategies do not confer substantial benefit. The four-year results will provide further information on the longer-term effects of preventative treatment in this study.

My rating of this study: ⭐⭐⭐

Maturi RK, Glassman AR, Josic K, et al. "Effect of Intravitreous Anti–Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy." JAMA Ophthalmology.  Published online 30 March 2021. https://doi.org/10.1001/jamaophthalmol.2021.0606