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?