Week in Review: Number 47

Vuity: First FDA-Approved Eye Drops for Presbyopia
The U.S. Food and Drug Administration (FDA) recently approved Vuity, a daily eye drop indicated for treatment of presbyopia, or age-related decline in near focus due to decreased ability of the eye's crystalline lens to accommodate. Presbyopia onset usually begins in the mid-40s. Available with a prescription, Vuity is a formulation of 1.25% pilocarpine. A direct-acting cholinergic agonist, pilocarpine acts on the smooth muscle muscarinic receptors of the iris sphincter to constrict the pupils in miosis. Its additional mechanism of action to directly stimulate the longitudinal muscles of the ciliary body is thought to affect the mechanics of the scleral spur to widen the spaces in the trabecular meshwork, thereby increasing aqueous outflow; in this capacity, pilocarpine is sometimes used as a treatment for glaucoma. In the context of pupillary constriction in itself, which decreases the "aperture" of the eye's optical system, the effect is an increase in depth of field and depth of focus, respectively, the range of clear vision in object space in front of the eye and in image space on the "screen" of the retina. (Often mentioned together, these two ranges are dioptrically equivalent.)

The increase in range of clear vision means an increase in near vision without sacrificing distance vision, in emmetropic or corrected-to-emmetropic eyes. In a press release, Allergan, the company marketing the drops, reported that clinical trials of participants 40 to 55 years of age with mild presbyopia showed "a statistically significant proportion of participants treated with VUITY gaining three lines or more in mesopic, high contrast, binocular Distance Corrected Near Visual Acuity (DCNVA), without losing more than 1 line (5 letters) of Corrected Distance Visual Acuity (CDVA) at day 30, hour 3, versus placebo." The effect lasts up to 6 hours. Common sides effects mentioned were headache and eye redness. Because pilocarpine constricts the pupils, thereby reducing the amount of light reaching the retina, consideration should be made for low-light settings, such as driving at night. Vuity does not correct refractive error such as myopia or astigmatism, or ocular pathology. Importantly, Vuity is only FDA-approved for once daily use in each eye, and although caution should be exercised in using the drops to "replace" reading glasses entirely, it is nonetheless a valuable addition to the toolbox of options to increase spectacle independence.

Stem-Cell RPE Model & Two AMD Drug Candidates
Researchers at the National Eye Institute developed a stem cell-based model of the eye's retinal pigmented epithelium (RPE) to test therapies for age-related macular degeneration (AMD). In particular, they used fibroblasts (skin cells) or blood samples from AMD patients to produce induced pluripotent stem cells (iPSC), which were in turn programmed to become RPE cells. Using this iPSC RPE model, the researchers tested genetic contributors to AMD development. For example, they tested the hypothesis that AMD is the result of the inability to regulate the alternate complement pathway once it had become activated, resulting in the formation of anaphylatoxins, a protein that mediates inflammation, among other functions. They exposed 10 iPSC-derived RPE cell lines of different genetic variants to anaphylatoxins from human serum, and subsequently observed that these iPSC-derived RPE cells developed drusen deposits and RPE atrophy, two key characteristics of AMD. Furthermore, cell lines from patients with high-risk variants in the alternate complement pathway had worse disease phenotype compared to cell lines from patients with low-risk variants, allowing the researchers to examine the effects of variations in genotype. Secondly, the scientists used the RPE models to screen more than 1,200 drugs from a pharmacologic library of drugs that had been tested for other conditions, which uncovered two candidate drugs that inhibit RPE atrophy and drusen formation: aminocaproic acid (ACA), a protease inhibitor that blocks the complement pathway outside of cells, and L745, a dopamine receptor antagonist that stops complement-induced inflammation indirectly inside the cell by inhibiting the dopamine pathway. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. The scientists hope that the stem cell-based RPE model they developed will be helpful to the research community.

Cataract Surgery Does Not Increase Risk of Progression to Advanced AMD
According to the latest analysis of data from the Age-related Eye Disease Study 2 (AREDS2), a 5-year randomized controlled clinical trial, with up to 10 years of follow up, that tested combinations of dietary supplements for their ability to slow progression of age-related macular degeneration (AMD), no association was found between cataract surgery and progression of AMD to an advanced (late) stage, which is defined as presence of geographic atrophy or neovascularization. The analysis involved a subset of 4,553 AREDS2 participants’ eyes that at baseline did not have signs of advanced AMD and had not undergone cataract surgery. Among this group of AREDS2 participants, eyes that later developed cataracts and had cataract surgery were compared with eyes that did not undergo cataract surgery, with analysis of at least two years of follow-up after cataract surgery. Adjustments were made for many potential confounding factors. Senior author of the study explains, "The standard for removing cataracts, called phacoemulsification, where the lens is broken into tiny pieces, causes less trauma and inflammation than older techniques. This could help explain why past studies saw an association between cataract surgery and progression to advanced AMD and we didn’t." In terms of clinical counseling and decision making, she says, "Our results indicate people don’t need to avoid or delay cataract surgery for fear of worsening their AMD."

A Novel Gut-Eye Connection Explored in Uveitis
About 70% of the human immune system is found in our gastrointestinal tract, where it interacts with the gut microbiome. Scientists are beginning to investigate how this ecosystem of gut microorganisms interact with our immune system in the context of eye health, for example, in inflammatory eye diseases such as noninfectious (chronic) uveitis. This novel angle has produced convincing data in animal models. For example, experiments in mice revealed that severity of inflammation from uveitis is partially related to a reduction of regulatory T cells (Tregs) in the gut, which normally function to prevent inflammation. Furthermore, interventions such as giving these mice organic compounds called short-chain fatty acids or oral antibiotics increased the number of Tregs in the gut and improved intestinal permeability and structure, all of which led to decreased eye inflammation. With funding from several awards and grants from the National Institutes of Health, these researchers next plan to dig deeper into the mechanisms that gut microbes use to protect the eye from inflammatory diseases and lay the foundation for new, targeted medications for uveitis. Motivated by the patients she cares for, the lead researcher of this project states, "We’ve hit on something really novel that has the potential to make a difference for people living with uveitis."

Visuals Enhance Attention via Norepinephrine
To catch a child's wandering attention, parents might use a variety of visual cues, e.g., waving their hands, telling the child to "Look at me!" Neuroscientists have uncovered clues as to why using visual stimuli works to engage our attention, reporting that the neurochemical norepinephrine is locally regulated in the visual cortex. Senior author of the study explains, "Before our study, research suggested the possibility of local regulation of norepinephrine release, but it had never been directly demonstrated." A fundamental chemical for optimal neurological performance in general and for attention in particular, reduced levels of norepinephrine result in conditions like attention-deficit/hyperactivity disorder (ADHD), while an excess of norepinephrine release results in states such as post-traumatic stress disorder (PTSD). However, even low-intensity visual stimuli can have an effect to trigger attention-specific norepinephrine signally pathways in the visual cortex. Using a mouse model of the visual cortex and various electrophysiological recordings, the investigators found that "When a person makes a movement, such as turning the head to listen to a parent, and that is combined with visual stimulation, then more norepinephrine is released where visual information is processed." In other words, norepinephrine is locally regulated in cortical areas that process the visual stimuli. Secondly, the researchers found that astrocytes, a type of glial cell in the brain, are sensitive to norepinephrine release, and alter their responses accordingly. They conclude, "Understanding norepinephrine release, its local regulation and the astrocyte response may represent a mechanism by which one could enhance sensory-specific attention."

In Other News
(1) FDA approves Vuity eye drops for presbyopia (Related) (Related) (Related)
(2) FDA approves Varenicline solution nasal spray for DED (Related)
(3) Lenstechs contact lens clinical trials for presbyopia
(4) Protecting the ozone layer to prevent cataracts