Week in Review: Number 23

Advancements in Contact Lenses as Theranostics
The Centre for Ocular Research & Education (CORE) published a comprehensive review of upcoming advancements in contact lenses as part of a special edition Contact Lens Evidence-based Academic Reports (CLEAR) series. The review highlights contact lens applications beyond refractive error correction, using diverse technologies such as "novel biomaterials, nanotechnology progress, unique optical designs, biosensing discoveries, antibacterial agents and even battery miniaturization and power transfer," according to the paper's lead author. Applications range from detecting ocular and systemic disease biomarkers in the tear film to monitoring intraocular pressure with progress in integrated circuitry, to microelectronics that monitor corneal gaze direction and adjust in real-time for presbyopia correction. Advancements in fluid dynamics and materials science could also provide alternative therapies for dry eye disease or mitigate color vision deficiencies (by filtering light). Another exciting potential for contact lenses is in theranostics, "the multi-disciplinary medical field that combines therapeutics and diagnostics." For example, contact lenses could act as a drug delivery alternative to eye drops, with advantages such as increasing the residence time of a drug on the ocular surface for more continuous drug regimens. The review ends with highlights of contact lens case designs that mitigate contamination. While many of these projects are in early stages, a review of developments in the field of contact lenses beyond refractive error correction, where contact lenses continue to make ubiquitous impact, is a worthwhile addition to the literature.

Treatment for Herpetic Stromal Keratitis with CRISPR
Herpes stromal keratitis (HSK) is a leading cause of infectious blindness worldwide. Yet, despite its high prevalence, there is as yet no vaccine for herpes simplex virus type 1 (HSV-1). After primary infection and replication in the cornea, HSV-1 is transported via ophthalmic nerves to the trigeminal ganglia (TG) where it can stay dormant and be reactivated in immunocompromised situations. With frequent recurrence and aggravation, the disease can lead to herpetic stromal keratitis (HSK) and potential blindness due to immune-mediated tissue damage. Researchers in China explored using CRISPR-Cas9 to edit HSV-1 in the treatment of HSK in mice, and blocked HSV-1 replication in human corneas. Previous studies using CRISPR-Cas9 or adeno-associated virus (AAV) vector were conducted in vitro, as compared to the present in vivo studies. The Shanghai researchers developed mRNA-carrying lentiviral particles "that simultaneously deliver SpCas9 [CRISPR-Cas9] mRNA and viral-gene-targeting guide RNAs (designated HSV-1-erasing lentiviral particles, termed HELP)." These particles move by retrograde transport to the trigeminal ganglia to target HSV-1 genomes directly. This approach is interesting in the sense that clearing neuronal reservoirs of latent HSV-1 could prevent the recurrence of HSK, as was shown in mice in this case. The researchers reported no significant side effects in the HELP-treated mice, and whole-genome sequencing of human-derived corneas infected with HSV-1 showed inhibited viral replication without causing off-target effects. Current treatments for HSK, such as acyclovir (ACV) and other anti-virals, inhibit DNA replication but do not prevent disease recurrence. The researchers think their findings "could support the potential clinical utility of HELP for treating refractory HSK."

Topical Drops to Close Macular Holes without Surgery
A retrospective multicenter case series explored the use of medicated eye drops to close small full-thickness macular holes (FTMHs). Depending on its size, a macular hole can cause distorted vision or an area of missing vision (scotoma) at the center of a person's field of view. For macular holes that do not close on their own, a vitrectomy can be performed. However, the gas bubble that serves as a temporary bandage to help the edges of the macular hole join and close requires the patient to remain face down for several days and nights so that the gas bubble can float in the correct position at the back of the eye. As with any intraocular surgery, vitrectomy also carries risks, notably cataract formation and retinal detachment. An alternative medical treatment to close macular holes could be attempted prior to considering surgery. The senior author of the study comments, “For certain patients, medicated drops may heal their macular hole by decreasing inflammation and increasing fluid absorption in the retina.” The study involved 14 patients prescribed a daily three-drug regimen of a steroid (prednisolone or difluprednate), an NSAID (ketorolac or bromfenac), and a carbonic anhydrase inhibitor (brinzolamide or dorzolamide). The study reports that 12 of the 14 patients had holes that closed within 2 to 8 weeks, 2-4 times faster than spontaneous closure rates. The treatment was most effective for patients whose macular holes were less than 200 microns in diameter, with treatment duration (including tapering) ranging from 3.5 to 20 months. The two patients who did not experience hole closure during the study duration had multiple missed follow-up appointments, the article noted. The researchers next plan to conduct a prospective randomized trial to definitively determine the benefits of the eye drops compared to the natural history of macular hole closure.

Joint Research in RGC Stem Cell Transplants in Mice
Researchers presented the first successful attempt to transplant retinal ganglion cells (RGCs) derived from induced pluripotent stem cells, tested in mice. The axons of retinal ganglion cells comprise the optic nerve that transmits visual information from the retina to the brain; it is these axons that are damaged in optic neuropathies, including glaucoma, and could lead to irreversible vision loss. The retinal cells were grown using special organoids and transplanted in mice induced to have glaucoma with microbeads as well as chemically induced neurotoxity. The transplanted donor cells exceeded a 65% success rate and survived in the disease-like microenvironments for up to 12 months (a long duration for mice), independent of the donor's age and location of transplantation. The researchers confirmed that the cells could receive signals from other neurons in the retina, but the ability of the cells to transmit signals to the brain was not definitively assessed "due to the relatively low number of cells surviving the procedure." This proof-of-concept technology is many years from clinical applications. However, as an author of the study explains, "This technique will enable countless future studies into the cross talk between transplanted cells and the host microenvironment. This will allow us to find and employ molecular mechanisms which will help transplanted cells to function properly and, as a result, improve visual function when transplanted in the right quantity." Because the eye is an immune-privileged organ, future possibilities could include growing cells in advance from universal donors (as compared to autologous transplants), and storing them in cell banks for the selection of the most suitable cells for transplantation in different patients. They look forward to the research bringing "hope and excitement for cell therapy development."

Depth Perception in Strabismus with Perspective Cues
Colloquially called an eye turn, strabismus is the misalignment of the eyes from the straight forward (orthotropic) position, with one eye turned, for example, outward (temporally) in exotropia or inward (nasally) in esotropia, which can be constant or intermittent. Because the deviation affects normal binocular vision, it is commonly thought that strabismus limits stereopsis or depth perception. Scientists in the U.K. argue that much of what is known about strabismus (in the U.K.) is based on conjecture or on studies that measured motor tasks at near distances. They instead investigated the perception of relative depth from the cue of linear perspective in strabismus using pictorial images and found that "contrary to popular opinion, there is little impact on a major aspect of 3-D vision for a person with a strabismic vision." The senior author of the study explains, “These results support a theory that the brain constructs at least three distinct types of representation that support different competencies in 3-D vision: the perception of distances of objects near the viewer (in personal space), the perception of object distances at walking distances, and the perception of 3-D object shape/layout (relative depth). Our results, combined with a few other studies, suggest that individuals with strabismus may be impaired only in the first component (perception of near distances) but have largely intact perception in the other two.” In other words, although strabismics do experience deficit in depth perception, that limitation applies mostly to near vision, with depth perception of farther distances still largely functional. The study, however, is limited by its very small sample size of 32 individuals, 24 of whom had normal stereovision. A quantitative measure of heterotropia was also not reported in the 8 participants with "no or limited stereovision."

In Other News
(1) Contact lenses: Moving beyond refractive error correction
(2) The scientifically best way to create a photo gallery wall
(3) Increased screen time during pandemic affects eyesight (Related)