March 2022

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Scott HA, Larson A, Rong SS, Mehrotra S, Butcher R, Chao KR, Wiggs JL, Place EM, Pierce EA, Bujakowska KM. A hidden structural variation in a known IRD gene: a cautionary tale of two new disease candidate genes. Cold Spring Harb Mol Case Stud 2022;8(2)Abstract
Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1 in 3500 people. More than 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% of IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with RCD. Family members were given a full ophthalmic exam at the Retinal Service at Massachusetts Eye and Ear and consented to genetic testing. Whole-exome sequencing (WES) was performed and variants of interest were Sanger-validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function. WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187 + 3A > C and c.1568-8C > A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G > A (p.Glu1290Lys) and c.4603G > A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins); however, the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94-bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant. Our study demonstrates the importance of thorough functional characterization of new disease candidate genes and the value of reanalyzing next-generation sequencing sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.
Sobrin L, Yang JY. Not All Genes Are Created Equal in Age-Related Macular Degeneration. JAMA Ophthalmol 2022;140(3):260-261.
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Tam EK, Laver NV, Thakore-James M, Mooney MA, Daly MK, Lefebvre DR. ARHGEF-10 gene mutation presenting as orbital inflammatory syndrome. BMJ Case Rep 2022;15(3)Abstract
Rho guanine nucleotide exchange factor 10 (ARHGEF-10) is a RHO GTPase that has a role for neural morphogenesis, however its effect on the eyes remains unknown. Here, we report a 44-year-old man who presented with eyelid swelling along with a history of bilateral hand contractures, high-arched feet and muscle wasting, who was found to have an ARHGEF-10 mutation. Neuroimaging was significant for numerous nerve-based cystic abnormalities in the bilateral orbits and throughout the neuraxis, and an orbital biopsy revealed S-100 and SOX-10 positive lesion consistent with pseudocysts. While the role of ARHGEF-10 remains unclear, further research is warranted to further describe its clinical manifestations.
Tran JA, Jurkunas UV, Yin J, Davies EC, Sola-Del Valle DA, Chen TC, Lin MM. Netarsudil-associated reticular corneal epithelial edema. Am J Ophthalmol Case Rep 2022;25:101287.Abstract
Purpose: To describe 8 cases of reversible reticular corneal epithelial edema of the cornea that developed after use of the topical Rho-kinase inhibitor netarsudil. Methods: This is a retrospective chart review case series of 8 patients treated with netarsudil at an academic medical center. Observations: Patients had predisposing corneal conditions including penetrating keratoplasty, corneal decompensation after trabeculectomy-associated endophthalmitis, congenital glaucoma with Haab striae, aphakic bullous keratopathy, history of Ahmed valve and silicone oil, and Fuchs endothelial corneal dystrophy undergoing Descemet stripping only. One patient did not have clear predisposing corneal disease other than low endothelial cell density and a history of trabeculectomy. All patients developed reticular corneal epithelial edema, which appeared as collections of moderate sized superficial epithelial bullae arranged in a reticular pattern resembling a honeycomb. Most developed these changes within weeks of initiating netarsudil, but unique to this series are 2 cases in which netarsudil was tolerated by the cornea for months before developing reticular corneal epithelial edema after diode laser cyclophotocoagulation. In cases which underwent anterior segment optical coherence tomography, the imaging demonstrated that the corneal stroma was not edematous, and the reticular corneal epithelial edema involved both host and donor corneal epithelium in cases of penetrating keratoplasty. This fully resolved in all cases upon cessation of netarsudil, and this series is the first to document resolution via a pattern in which the individual bullae become smaller and more widely spaced apart. Conclusion: Netarsudil can cause a reversible reticular corneal epithelial edema.
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Vongsachang H, Fliotsos MJ, Lorch AC, Singman EL, Woreta FA, Justin GA. The impact of COVID-19 on ophthalmology resident surgical experience: a retrospective cross-sectional analysis. BMC Med Educ 2022;22(1):142.Abstract
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused significant disruption to in-office and surgical procedures in the field of ophthalmology. The magnitude of the impact of the pandemic on surgical training among ophthalmology residents is not known. This study aims to quantify changes in average case logs among United States (U.S.) ophthalmology residency graduates prior to and during the COVID-19 pandemic. METHODS: Retrospective, cross-sectional analysis of aggregate, national data on case logs of U.S. ophthalmology residency graduates from 2012 to 2020. The yearly percent change in the average number of procedures performed in the Accreditation Council for Graduate Medical Education (ACGME) ophthalmology resident case logs were analyzed using linear regression on log-transformed dependent variables. The average percent change from 2019 to 2020 was compared to the average yearly percent change from 2012 to 2019 for procedures performed as the primary surgeon, and primary surgeon and surgical assistant (S + A), as well as procedures for which there are ACGME minimum graduating numbers. RESULTS: Across all procedures and roles, average case logs in 2020 were lower than the averages in 2019. While average total cases logged as primary surgeon increased yearly by 3.2% (95% CI: 2.7, 3.8%, p < 0.001) from 2012 to 2019, total primary surgeon case logs decreased by 11.2% from 2019 to 2020. Cataract (-22.0%) and keratorefractive (-21.1%) surgery experienced the greatest percent decrease in average primary surgeon cases logged from 2019 to 2020. Average total cases logged as S + A experienced an average yearly increase by 1.2% (95% CI: 0.9,1.6%, p < 0.001) prior to 2020, but decreased by 9.6% from 2019 to 2020. For ACGME minimum requirements, similar changes were observed. Specifically, the average case logs in YAG, SLT, filtering (glaucoma), and intravitreal injections had been increasing significantly prior to 2020 (p < 0.05 for all) but decreased in 2020. CONCLUSIONS: These findings demonstrate the vulnerability of ophthalmology residency programs to a significant interruption in surgical volume. There is a critical need for development of competency-based, rather than volume-based, requirements to evaluate readiness for independent practice.
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Wang X, Jacobs DS. Contact Lenses for Ocular Surface Disease. Eye Contact Lens 2022;48(3):115-118.Abstract
ABSTRACT: Ocular surface disease can be difficult to manage, causing patients discomfort and vision loss. Therapeutic contact lenses are an important treatment option that is often neglected because it is conventional wisdom that eyes that are dry or irritated are not good candidates for contact lens. In this focused review, we consider the substantial literature on the use of bandage soft contact lenses (BSCL), scleral lenses, and customized prosthetic devices in the management of ocular graft-vs-host disease. Reports on BSCLs for recurrent corneal erosion are reviewed, as is literature on scleral lenses and prosthetic replacement of the ocular surface ecosystem treatment for Stevens-Johnson syndrome. Clinical pearls for fitting BSCLs are presented, and the issue of antibiotic prophylaxis is considered.
Wareham LK, Liddelow SA, Temple S, Benowitz LI, Di Polo A, Wellington C, Goldberg JL, He Z, Duan X, Bu G, Davis AA, Shekhar K, Torre AL, Chan DC, Canto-Soler VM, Flanagan JG, Subramanian P, Rossi S, Brunner T, Bovenkamp DE, Calkins DJ. Solving neurodegeneration: common mechanisms and strategies for new treatments. Mol Neurodegener 2022;17(1):23.Abstract
Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world's leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.
Williams IM, Pineda R, Neerukonda VK, Stagner AM. Reply to Comment on: Mucopolysaccharidosis type I associated corneal disease: A clinicopathologic study. Am J Ophthalmol 2022;235:334-335.
Winter CC, He Z, Jacobi A. Axon Regeneration: A Subcellular Extension in Multiple Dimensions. Cold Spring Harb Perspect Biol 2022;14(3)Abstract
Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional deficits. Thus, developing strategies that promote effective axon regeneration for functional restoration is highly desirable. One fruitful approach is to dissect the regenerative mechanisms used by some types of neurons in both mammalian and nonmammalian systems that exhibit spontaneous regenerative capacity. Additionally, numerous efforts have been devoted to deciphering the barriers that prevent successful axon regeneration in the most regeneration-refractory system-the adult mammalian central nervous system. As a result, several regeneration-promoting strategies have been developed, but significant limitations remain. This review is aimed to summarize historic progression and current understanding of this exciting yet incomplete endeavor.
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Xiong X, Tian S, Yang P, Lebreton F, Bao H, Sheng K, Yin L, Chen P, Zhang J, Qi W, Ruan J, Wu H, Chen H, Breault DT, Wu H, Earl AM, Gilmore MS, Abraham J, Dong M. Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors. Cell 2022;Abstract
Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.
Xu BY, Friedman DS, Foster PJ, Jiang Y, Porporato N, Pardeshi AA, Jiang Y, Munoz B, Aung T, He M. Ocular Biometric Risk Factors for Progression of Primary Angle Closure Disease: The Zhongshan Angle Closure Prevention Trial. Ophthalmology 2022;129(3):267-275.Abstract
PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective, observational study. PARTICIPANTS: Six hundred forty-three mainland Chinese with untreated PACS. METHODS: Participants underwent baseline clinical examinations, including gonioscopy, anterior segment OCT (AS-OCT) imaging, and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. Primary angle closure suspect was defined as an inability to visualize pigmented trabecular meshwork in 2 or more quadrants based on static gonioscopy. Primary angle closure was defined as development of intraocular pressure above 24 mmHg or peripheral anterior synechiae. Progression was defined as development of PAC or an AAC attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Six-year progression from PACS to PAC or AAC. RESULTS: Six hundred forty-three untreated eyes (609 nonprogressors, 34 progressors) of 643 participants were analyzed. In a multivariable model with continuous parameters, narrower horizontal angle opening distance of 500 μm from the scleral spur (AOD500; odds ratio [OR], 1.10 per 0.01-mm decrease; P = 0.03), flatter horizontal iris curvature (IC; OR, 1.96 per 0.1-mm decrease; P = 0.01), and older age (OR, 1.11 per 1-year increase; P = 0.01) at baseline were associated significantly with progression (area under the receiver operating characteristic curve [AUC], 0.73). Smaller cumulative gonioscopy score was not associated with progression (OR, 1.03 per 1-modified Shaffer grade decrease; P = 0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR, 3.10; P = 0.002) and IC (OR, 2.48; P = 0.014) measurements and 59 years of age or older (OR, 2.68; P = 0.01) at baseline showed higher odds of progression (AUC, 0.72). CONCLUSIONS: Ocular biometric measurements can help to risk-stratify patients with early angle closure for more severe disease. Anterior segment OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.
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Yeung V, Zhang TC, Yuan L, Parekh M, Cortinas JA, Delavogia E, Hutcheon AEK, Guo X, Ciolino JB. Extracellular Vesicles Secreted by Corneal Myofibroblasts Promote Corneal Epithelial Cell Migration. Int J Mol Sci 2022;23(6)Abstract
Corneal epithelial wound healing is a multifaceted process that encompasses cell proliferation, migration, and communication from the corneal stroma. Upon corneal injury, bidirectional crosstalk between the epithelium and stroma via extracellular vesicles (EVs) has been reported. However, the mechanisms by which the EVs from human corneal keratocytes (HCKs), fibroblasts (HCFs), and/or myofibroblasts (HCMs) exert their effects on the corneal epithelium remain unclear. In this study, HCK-, HCF-, and HCM-EVs were isolated and characterized, and human corneal epithelial (HCE) cell migration was assessed in a scratch assay following PKH26-labeled HCK-, HCF-, or HCM-EV treatment. HCE cells proliferative and apoptotic activity following EV treatment was assessed. HCF-/HCM-EVs were enriched for CD63, CD81, ITGAV, and THBS1 compared to HCK-EV. All EVs were negative for GM130 and showed minimal differences in biophysical properties. At the proteomic level, we showed HCM-EV with a log &gt;two-fold change in CXCL6, CXCL12, MMP1, and MMP2 expression compared to HCK-/HCF-EVs; these proteins are associated with cellular movement pathways. Upon HCM-EV treatment, HCE cell migration, velocity, and proliferation were significantly increased compared to HCK-/HCF-EVs. This study concludes that the HCM-EV protein cargo influences HCE cell migration and proliferation, and understanding these elements may provide a novel therapeutic avenue for corneal wound healing.
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Zeng R, Garg I, Miller JB. Complete Resolution of Central Soft Drusen without Geographic Atrophy or Choroidal Neovascularization. J Clin Med 2022;11(6)Abstract
The treatment and prevention of dry age-related macular degeneration (AMD) traditionally involve lifestyle modifications and antioxidant supplementation, including the AREDS2 formula. We present a case of a woman with dry AMD in her right eye with several large, confluent central drusen on her exam and optical coherence tomography B-scan. Over the course of a year, the drusen almost completely disappeared, but the retinal layers were preserved without the development of geographic atrophy or choroidal neovascularization. While the exact cause of this phenomenon is unclear, it was thought to be associated with this patient's strict daily use of numerous dietary supplements. This case highlights the potential in exploring alternative medicine supplements in the treatment of AMD.
Zhang C, Owen LA, Lillvis JH, Zhang SX, Kim IK, Deangelis MM. AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets. J Clin Med 2022;11(6)Abstract
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world's leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.
Zheng J, Schjetnan AGP, Yebra M, Gomes BA, Mosher CP, Kalia SK, Valiante TA, Mamelak AN, Kreiman G, Rutishauser U. Neurons detect cognitive boundaries to structure episodic memories in humans. Nat Neurosci 2022;25(3):358-368.Abstract
While experience is continuous, memories are organized as discrete events. Cognitive boundaries are thought to segment experience and structure memory, but how this process is implemented remains unclear. We recorded the activity of single neurons in the human medial temporal lobe (MTL) during the formation and retrieval of memories with complex narratives. Here, we show that neurons responded to abstract cognitive boundaries between different episodes. Boundary-induced neural state changes during encoding predicted subsequent recognition accuracy but impaired event order memory, mirroring a fundamental behavioral tradeoff between content and time memory. Furthermore, the neural state following boundaries was reinstated during both successful retrieval and false memories. These findings reveal a neuronal substrate for detecting cognitive boundaries that transform experience into mnemonic episodes and structure mental time travel during retrieval.
Zolotukhin S, Vandenberghe LH. AAV capsid design: A Goldilocks challenge. Trends Mol Med 2022;28(3):183-193.Abstract
In vivo therapeutic gene transfer has emerged as a novel class of medicines. Its feasibility relies on the safe and efficacious delivery of genetic cargo to the appropriate targets. The adeno-associated virus (AAV) vector manifested itself as a preferred gene delivery vehicle enabling therapeutic gene expression for several clinical indications. Here, we cover the recent trends in AAV capsid engineering to enhance its targeting specificity, safety, and endurance. While each and every desirable trait can be individually remodeled, combining several attributes in one capsid amounts to a significant engineering challenge. Taking advantage of virion structure and phylogenetics, harnessing directed evolution, sequence analyses, and machine learning, researchers develop novel capsid variants to realize the goals of safe and enduring gene therapy.

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