Week in Review: Number 15

GUCY2D Gene Therapy for LCA Shows Positive Results
Researchers recently published initial results of a gene therapy for a form of Leber congenital amaurosis (LCA). Specifically, this gene therapy is the first-in-human clinical trial to target the GUCY2D gene in LCA, with initial results pertaining to three adult patients followed at nine months at this point. Normal copies of the GUCY2D gene encode an enzyme in the phototransduction pathway of the retina, allowing for light perception and vision. A lack of this enzyme prevents the recovery of this pathway, necessary for further signaling. Consequently, signals from the photoreceptors become very weak, manifesting as vision loss. However, despite weak signals and dysfunction, the photoreceptors often remain alive and structurally intact, spurring research into therapies via AAV viral vectors (injected subretinally in this case) to deliver functional copies of genes to those photoreceptors. The study reports that the first patient experienced substantial increase in rod sensitivity and improved pupillary response to light. The second patient experienced a smaller but sustained increase in rod sensitivity. And the third patient did not show improved rod sensitivity, although that patient did experience significantly improved visual acuity (a gain of 0.3 logMAR in the treated eye), which the researchers attribute to improved cone sensitivity and function. No toxicity effects were detected. These initial results demonstrate safety and efficacy for improved sensitivity of both rod and cone photoreceptors. The therapeutic dose used for these first three patients was the lowest dose the researchers intend to use in their study, and they hope to see continued safety and even greater efficacy at higher doses.

Vision Loss from Glaucoma in Some, but Not Most, if Untreated or Delayed Treatment
The Ocular Hypertension Treatment Study, a 7-year longitudinal clinical trial, recently published follow-up results 20 years after the initial launch of the trial evaluating the effect of glaucoma eye drops to preserve vision for patients with elevated eye pressure. The study involved 1,600 patients nationally who were at moderate to high risk for glaucoma due to elevated intraocular pressure (IOP). Although treatment was shown to be highly effective, reducing the incidence of glaucoma by 50% to 60% after five to seven years, the study found surprisingly that only 25% of study participants went on to develop vision loss from glaucoma in at least one eye, compared to the prior conventional wisdom that most patients would develop glaucoma if left untreated. This low incidence of vision loss was the case despite 46% of the study participants showing evidence of glaucoma in at least one eye. Furthermore, the risk of delayed treatment was relatively low. Participants who were randomly assigned to the observation group, before being switched to treatment after seven years, had only slightly greater risk of vision loss compared to participants who used eye-pressure-lowering drops from the start of the study. These findings of low incidence of vision loss due to elevated IOP is pertinent in the sense that while eye drops are effective, there can be obstacles due to cost, adverse effects, and adherence. The study also provided information regarding patient demographics. Although one-quarter of the study participants were African-American, a group with a higher incidence of vision loss from glaucoma, the study found that Black individuals had similar outcomes to other racial groups when matched for the same level of risk. The researchers caution that treatment is not a one-size-fits-all approach, and the sample size is small. Nonetheless, studies like these provide a starting point for conversations to arrive at the best approach.

Micromolded Scaffolds for Photoreceptor Transplantation
Scientists and engineers are working to design and fabricate scaffolds to improve photoreceptor transplantation in eyes with retinal diseases. While there are many advances to create photoreceptors from stem cells, the researchers remark that obstacles remain to precisely deliver those photoreceptors to diseased or damaged eyes in ways that would result in forming the appropriate connections so that they can "effectively reconstruct the retina." The research team had previously designed a micro-molded biodegradable polymer scaffolding "patch" with wine-glass-shaped pores to hold the photoreceptors in place. In the current iteration, they designed the shape of the scaffold pores to be more like "ice cube trays," increasing the capacity to hold three times as many cells as well as reducing the amount of biomaterial used. The latter benefit would facilitate faster degradation of the material in the eye. The researchers used poly(glycerol-sebacate), or PGS, a material that is strong, compatible with the retina, and degrades within two months. The process to fabricate scaffolds with microstructures was technically challenging, though the labs discovered that using isopropyl alcohol helped to demount and release the PGS material from the molds cleanly. Using these techniques, they created ice cube tray-shaped scaffolds capable of holding 300,000 photoreceptors in a patch roughly the area of the macula. They next plan to file a patent for the design as well as proceed to testing in large animals. While these designs are early, they provide information for later improvements. As one of the researchers concludes, “We didn’t start out with supercomputers on our wrists and we’re not going to start out by completely erasing blindness in our first attempt. But we’re very excited about taking a significant step in that direction.”

Eye Contact & Attention Influence Perception of Time
Researchers in Switzerland studying the social aspects of eye contact conducted a series of experiments exploring the influence of eye contact on the perception of time, with a focus on exploring connections with emotion and attention. The question they wanted to investigate was whether eye contact with others directly generates an emotional response without passing through attention, or whether eye contact activates attention processing that then generates an emotional response. To differentiate between the two hypotheses, the researchers looked at how either emotion and attention impact our evaluation of time, noting that it has been shown that we overestimate the passage of time (i.e., we perceive that time passes more quickly) when confronted with an unpleasant visual stimulus, such as a large spider. Emotions accelerate our perception of time. Attention, on the other hand, has the opposite and instead slows down our perception of time (i.e., we underestimate the passage of time). Thus, by examining a person's estimation of how long he or she has been looking at an object, we can determine if the eye contact is associated with emotions or with attention.

The experiments involved 22 participants, who observed a series of nearly 300 faces with gazes that either established eye contact (i.e., direct gaze) or did not establish eye contact (i.e., deviated gaze). The participants then subjectively assessed the duration of the social contact. The study found that deviated gazes did not distort the perception of time, whereas gazes where the eyes met, participants underestimated the duration of eye contact. In other words, it is not emotion but attention that distracts our evaluation of time. To further assess this finding, the researchers then carried out the same experiments with other participants using non-social objects that mimicked movements of gaze and with static faces. No distortions in time perception were seen in those situations. Interestingly, however, when the researchers used schematic eyes or stimuli showing parts of eyes without the rest of the face (a similar situation to wearing a mask), both scenarios also making eye movements, the time distortion effect was seen. This finding suggests that not only gaze but also movement elicits the distortion of time perception. The effect was replicated in an online experiment with 100 people. The researchers next plan to study the evolution of this effect at different ages, from childhood to older age. Though these experiments are on the smaller end in terms of sample size, they provide intriguing results to further studies into the connection between eye contact and social cognition, which are clinically relevant to patients suffering from disorders in processing social stimuli. These findings about our preferential processing of eye contact by attention also informs social interactions more broadly. As the lead researcher concludes, “This study gives meaning to the sensation that time stops when we meet another’s gaze.”

Highlights of the NEI's AGI Functional Imaging Consortium
The article summarized here is itself a kind of "Week in Review" highlighting updates to five projects from the National Eye Institute's AGI functional imaging consortium. The highlights include projects in (1) noninvasive methods to record nerve cell firing, (2) retinal camera technologies that compensate for eye movements, (3) two-photon excitation microscopy combined with adaptive optics to noninvasively and dynamically observe the integration of transplanted retinal cells, (4) two-photon excitation microscopy to noninvasively visualize vitamin A metabolic defects in the retina, and (5) diffusion basis spectrum imaging to noninvasively detect and quantify axonal injury and optic nerve damage. These five projects represent examples of advances in functional noninvasive imaging technologies to aid in the diagnosis and treatment of degenerative eye diseases and provide a foundation for enrolling patients in clinical trials for regenerative therapies.

In Other News
(1) In the News: Edition 5
(2) In the News: Supplemental 1
(3) A PhD student's perspective about social media