Week in Review: Number 38

Alu cDNA Strongly Implicated in Geographic Atrophy
Geographic atrophy (GA) is often considered an advanced form of nonexudative age-related macular degeneration (dry AMD), and although the etiology of centrifugal (outward) spread of the disease from the midperiphery of the retina to the central retina is well studied, the underlying mechanism of pathophysiology is poorly understood. New research strongly suggests that toxic levels Alu complementary DNA (cDNA) at the active leading edge of the "geography of atrophy," confirmed for the first time in human eye specimens (n=20), is responsible for the expansion of the lesion that gradually leads to vision loss. The Alu cDNA, a cytoplasmic self-priming retrotransposon reverse-transcribed from noncoding RNA, triggers activation of the inflammasome, a multiprotein complex of the innate immune system found in the cell cytosol that triggers inflammation and ultimately leads to cytotoxicity and damage to the retinal pigmented epithelium (RPE) that supports retinal health and function. The accumulation of Alu RNA repeats in turn is due to age-related decline in an enzyme called DICER1. In terms of mechanism, the Alu RNA leads to Alu cDNA formation via L1 reverse transcriptase. The Alu cDNA engages a DNA sensing enzyme called cGAS to trigger the escape of mitochondrial DNA into the cell’s cytosol, which in turn amplifies cGAS in a feedback loop (due to the presence of two DNA populations) that triggers the inflammasome (specifically the NLRP3 component of this protein), ultimately resulting in RPE and retinal degeneration.

In an earlier obervational study, senior author Jayakrishna Ambati, MD, demonstrated that FDA-approved nucleoside reverse transcriptase inhibitors (NRTIs) are associated with reduced risk of developing advanced dry macular degeneration in people. His company Inflammasome Therapeutics is working on alkylated derivatives called Kamuvudines that are safer (less toxic) in that they inhibit inflammasome activation but not the reverse transcription of Alu RNA. When asked why he chose to target the endpoint of the inflammasome rather than upstream points in this pathway, such as the complement pathway, Ambati replied, “Alu cDNA causes RPE degeneration via the DNA sensor cGAS. However, there are other toxic substances such as amyloid-beta, complement, and iron, which also play a role in Geographic Atrophy. Therefore, we believe that Kamuvudines which block inflammasome activation induced by these various toxic substances are a rational therapeutic approach to block this multipronged assault.” Given the strong data related to NRTIs, Ambati's team plans on starting clinical trials in 2022. He states, "[T]he planned clinical trial will enroll patients who have early stages of Geographic Atrophy, not involving the center of the retina. The goal of Kamuvudine treatment is to stop or reduce the rate of progression of the disease. This has been the typical strategy of most clinical trials to date with other drug candidates." Although limited by pre-clinical studies, Jayakrishna Ambati's meticulous research methodology and astounding findings are a major clinical advance for a devastating disease that thus far as no treatment.

Aquaporin 5 Induction to Treat Corneal Defects
A new study provides evidence that aquaporins play an important role in corneal cell proliferation and nerve regeneration. Aquaporins, or water channels, are transmembrane proteins that facilitate the transport of water (and small solutes), thereby maintaining cell water homeostasis. There are 13 types of aquaporins found in mammals. The study explored induction of aquaporin 5 (AQP5), which is expressed in the cornea, as a potential therapy to accelerate the resurfacing of corneal defects. In previous studies, the researchers found that deficiencies in AQP5 and nerve growth factor (NGF) resulted in delayed repair of corneal epithelial injury in mice. The present study sought to examine the mechanism of AQP5. The investigators engineered 189 male Aqp5 knockout (Aqp5-/-) mice and compared them to 75 normal (Aqp5+/+) male mice after their epithelial cells had been debrided. Corneal epithelial and nerve regeneration rates were significantly delayed in the Aqp5-/- mice, but were significantly increased in Aqp5-/- mice treated with NGF. NGF also improved the recovery of corneal nerve fiber density and sensitivity, and accompanied recovered levels of phosphorylated Akt in the Aqp5-/- mice. Unsurprisingly, when an Akt inhibitor was administered with the NGF, this led to reversal of Akt reactivation and corneal epithelial and nerve regeneration. The lead investigator comments, “It is exciting to find that Aqp5 deficiency can affect the nerve regeneration of mice by affecting the activation of NGF and Akt signaling pathways, which is not found in previous studies. These results need to be confirmed in a clinical setting, but they provide evidence for the involvement of aquaporins in cell proliferation and nerve regeneration and suggest AQP5 induction as a possible therapy to accelerate the resurfacing of corneal defects.”

Systematic Review & Meta-Analysis: Smart Device Exposure and its Associations with Myopia
Researchers in the U.K. conducted a systematic review and meta-analysis investigating smart device exposure and myopia in children and young adults between 3 months and 33 years of age. They report this being the most comprehensive study yet regarding the myopia epidemic. From a database search that yielded over 3,000 articles, the two reviewers assessed 286 full-text articles for eligibility, resulting in 33 articles included in the systematic review and 11 articles included in the meta-analysis. A high heterogeneity between studies was noted, due to factors such as variability in sample size, the mean age of participants (3-16 years), the standard error of the estimated odds of prevalent or incident myopia, and the use of continuous versus categorical screen time variables. Nonetheless, the authors extrapolate that "[s]mart device exposure might be associated with an increased risk of myopia." In particular, they found that high levels of smart device screen time was associated with roughly 30% higher risk of myopia; when combined with excessive computer use, that risk rose to roughly 80%. The researchers caution that "[r]esearch with objective measures of screen time and myopia-related outcomes that investigates smart device exposure as an independent risk factor is required." However, they also note the importance of research in this topic, especially at a time when millions of children and young people around the world are spending substantial amounts of time doing near work and using digital devices during the COVID-19 pandemic.

Alzheimer's Risk Gene APOE4 Could Be Associated with Better Visual Working Memory
To date, scientists have found versions of at least 30 different genes associated with an altered risk of developing Alzheimer's disease, the most common cause of dementia. Of these, the gene APOE, which encodes apolipoprotein E, has the largest effect on Alzheimer's disease risk. APOE  comes in three variants (E2, E3, and E4), and each of us carries two copies of this gene, one from each parent. Individuals who inherit one copy of the E4 version of APOE  (approximately 25% of people) are roughly three times more likely to develop Alzheimer’s disease compared to those who do not carry the E4 version. Individuals with two copies of the E4 version are more than eight times more likely to develop Alzheimer's disease. It is curious, then, that some individuals who possess the APOE4  risk gene demonstrate better performance in visual working memory. Researchers in the U.K. studied 400 volunteers from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth Cohort, this cohort being characterized by being born in the same week in 1946. The researchers assessed the effects of the APOE4  risk gene and beta-amyloid (a hallmark of Alzheimer's disease), as measured by a brain PET scan, on visual working memory, which was measured using a computerized "What was where?" task (recalling identities and locations). The findings showed that having the APOE4  gene and the presence of beta-amyloid in the brain had opposing effects on object identification, with APOE4  predicting better recall (and more precise location recall) and amyloid build-up predicting poorer recall. This suggests that having a copy of the APOE4  gene could confer some benefits in older age, even in the presence of amyloid plaques, and could provide clues as to why this gene variant is so common. Some earlier studies point to APOE4  conferring some benefits in younger age; the researchers suggest that this benefit could persist into older age. Although the connection might be of little comfort to patients living with Alzheimer's, building a more complete picture of the disease, such as why APOE4  might result in better memory, may also help us to understand why it also leads to increased risk for Alzheimer’s.

Reading Performance as a Suitable Indicator of Functional Impairment in Geographic Atrophy
In geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD), reading ability is a functional indicator that is closely related to changes in retinal structure. German researchers, along with U.S. colleagues, are studying how reading speed is a better reflection of functional impairment in geographic atrophy compared to best-corrected visual acuity (BCVA). They argue that even when central visual acuity is still good, retinal imaging can be used to detect changes that affect reading performance. While conventional assessments are important to guide therapeutic decisions, "conventional functional tests such as visual acuity do not capture all the dismal functional consequences of the disease," one of the authors states. These limitations can be severe enough to affect everyday quality of life. The study involved 85 participants with geographic atrophy, with reading ability assessed using Radner charts and retinal assessment performed with longitudinal fundus autofluorescence and infrared reflectance images. According to their findings, reading acuity was most strongly associated with BCVA and structural biomarkers; reading speed was most strongly associated with BCVA, low-luminance visual acuity, and structural biomarkers. The binocular inhibition phenomenon, a negative influence of the worse-seeing eye in binocular vision (in this case, reading), was not observed, leading the researchers to recommend that clinical and low-vision care be focused primarily on the better-seeing eye. They conclude that both reading ability and reading speed can be suitable functional tests (endpoints) for clinical studies.

In Other News
(1) Smartphone use associated with higher myopia in teenagers
(2) Intraocular epidermal growth factor concentration, axial length, and high axial myopia
(3) Myopia in the news: Article#1, Article#2, Article#3, Article#4, Article#5
(4) Millions with eye conditions at higher risk of dementia