The ocular motility disorder "Congenital fibrosis of the extraocular muscles type 1" (CFEOM1) results from heterozygous mutations altering the motor and third coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knockin mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve's superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a-interacting protein and report that Map1b⁻/⁻ mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1 and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.

PURPOSE: To describe the results of photodynamic therapy (PDT) and/or focal laser photocoagulation in the treatment of serous retinal detachments secondary to lupus choroidopathy. METHODS: The medical records of three patients with serous detachments secondary to lupus choroidopathy who were treated with PDT and/or focal laser photocoagulation were reviewed. Concomitant systemic medical therapy as well as visual acuity and optical coherence tomography (OCT) outcomes were recorded. RESULTS: All patients received systemic immunosuppressive therapy and had control of their extraocular manifestations prior to PDT and/or laser photocoagulation. One patient received only focal laser photocoagulation and had complete resolution of the subretinal fluid on OCT. The two other patients received a combination of PDT and focal laser treatment. One had improvement in vision and resolution of subretinal fluid on OCT. The second patient, who had longstanding lupus choroidopathy and associated subretinal fluid and macular edema, had only a significant decrease in fluid on OCT but no vision improvement. CONCLUSION: In conjunction with control of systemic disease, PDT and/or focal laser photocoagulation can be successful in resolving subretinal fluid secondary to lupus choroidopathy.

For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery, but achieving controlled drug release has been a significant challenge. We have developed a drug-eluting contact lens designed for prolonged delivery of latanoprost for the treatment of glaucoma, the leading cause of irreversible blindness worldwide. Latanoprost-eluting contact lenses were created by encapsulating latanoprost-poly(lactic-co-glycolic acid) films in methafilcon by ultraviolet light polymerization. In vitro and in vivo studies showed an early burst of drug release followed by sustained release for one month. Contact lenses containing thicker drug-polymer films demonstrated released a greater amount of drug after the initial burst. In vivo, single contact lenses were able to achieve, for at least one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with topical latanoprost solution, the current first-line treatment for glaucoma. The lenses appeared safe in cell culture and animal studies. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications.

Glaucoma is a neurodegenerative disorder in which degenerating retinal ganglion cells (RGC) produce significant visual disability. Clinically, glaucoma refers to an array of conditions associated with variably elevated intraocular pressure (IOP) that contributes to RGC loss via mechanical stress, vascular abnormalities, and other mechanisms, such as immune phenomena. The clinical diagnosis of glaucoma requires assessment of the ocular anterior segment with slit lamp biomicroscopy, which allows the clinician to recognize signs of conditions that can produce elevated IOP. After measurement of IOP, a specialized prismatic lens called a gonioscope is used to determine whether the angle is physically open or closed. The structural manifestation of RGC loss is optic nerve head atrophy and excavation of the neuroretinal rim tissue. Treatment is guided by addressing secondary causes for elevated IOP (such as inflammation, infection, and ischemia) whenever possible. Subsequently, a variety of medical, laser, and surgical options are used to achieve a target IOP.

PURPOSE: To investigate biomarker differences in routine preoperative blood tests performed on primary open-angle glaucoma (POAG) case and control patients presenting for anterior segment eye surgery. METHODS: POAG cases and age-related cataract surgery patients (controls) who underwent anterior segment surgery at Massachusetts Eye and Ear from January 2009 through March 2012 were identified by retrospective record review. Patients with diabetes mellitus, secondary glaucoma, and cataract due to trauma or steroid exposure were excluded. Data on demographic features, preoperative ophthalmological and medical diagnosis, blood pressure, anthropometric measures, basic metabolic panel, and complete blood count were extracted from the medical records. Univariate differences in lab values between POAG cases and controls were assessed using unpaired t tests. Multivariate logistic regression analysis was completed to determine the independent associations of biomarkers with POAG. RESULTS: A total of 150 cases and 150 age-related controls were included. In multivariate analysis, higher AG was inversely associated with POAG (odds ratio [OR] = 0.90; 95% confidence interval [CI], 0.80-1.00), and higher Cl- level was positively associated with POAG (OR = 1.15; 95% CI, 1.02-1.29). The lower AG in POAG patients could be explained by higher IgG levels as the available data in post hoc analysis showed a nonsignificant trend toward higher IgG in cases compared to controls (17 vs 23; 1142 ± 284 mg/dl vs 1028 ± 291 mg/dl; P = 0.22). Furthermore, in multivariable analysis, a higher red blood cell count was also associated with POAG (OR = 1.91; 95% CI, 1.11-3.28). CONCLUSIONS: Patients with POAG presenting for anterior segment surgery had a lower AG compared to age-related cataract surgery patients. The etiology of this reduced gap is unclear but the possible contribution of IgG warrants further exploration. The etiology of higher red blood cell counts in POAG cases is unknown and deserves further exploration.

For profoundly blind individuals, navigating in an unfamiliar building can represent a significant challenge. We investigated the use of an audio-based, virtual environment called Audio-based Environment Simulator (AbES) that can be explored for the purposes of learning the layout of an unfamiliar, complex indoor environment. Furthermore, we compared two modes of interaction with AbES. In one group, blind participants implicitly learned the layout of a target environment while playing an exploratory, goal-directed video game. By comparison, a second group was explicitly taught the same layout following a standard route and instructions provided by a sighted facilitator. As a control, a third group interacted with AbES while playing an exploratory, goal-directed video game however, the explored environment did not correspond to the target layout. Following interaction with AbES, a series of route navigation tasks were carried out in the virtual and physical building represented in the training environment to assess the transfer of acquired spatial information. We found that participants from both modes of interaction were able to transfer the spatial knowledge gained as indexed by their successful route navigation performance. This transfer was not apparent in the control participants. Most notably, the game-based learning strategy was also associated with enhanced performance when participants were required to find alternate routes and short cuts within the target building suggesting that a ludic-based training approach may provide for a more flexible mental representation of the environment. Furthermore, outcome comparisons between early and late blind individuals suggested that greater prior visual experience did not have a significant effect on overall navigation performance following training. Finally, performance did not appear to be associated with other factors of interest such as age, gender, and verbal memory recall. We conclude that the highly interactive and immersive exploration of the virtual environment greatly engages a blind user to develop skills akin to positive near transfer of learning. Learning through a game play strategy appears to confer certain behavioral advantages with respect to how spatial information is acquired and ultimately manipulated for navigation.

For individuals who are blind, navigating independently in an unfamiliar environment represents a considerable challenge. Inspired by the rising popularity of video games, we have developed a novel approach to train navigation and spatial cognition skills in adolescents who are blind. Audio-based Environment Simulator (AbES) is a software application that allows for the virtual exploration of an existing building set in an action video game metaphor. Using this ludic-based approach to learning, we investigated the ability and efficacy of adolescents with early onset blindness to acquire spatial information gained from the exploration of a target virtual indoor environment. Following game play, participants were assessed on their ability to transfer and mentally manipulate acquired spatial information on a set of navigation tasks carried out in the real environment. Success in transfer of navigation skill performance was markedly high suggesting that interacting with AbES leads to the generation of an accurate spatial mental representation. Furthermore, there was a positive correlation between success in game play and navigation task performance. The role of virtual environments and gaming in the development of mental spatial representations is also discussed. We conclude that this game based learning approach can facilitate the transfer of spatial knowledge and further, can be used by individuals who are blind for the purposes of navigation in real-world environments.

Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

PURPOSE: The aims of this study were to determine the scleral attenuation of focused neodymium: yttrium-lanthanum-fluoride laser at 1,047 nm applied transsclerally and whether transscleral delivery can close the vascular supply at the base of experimental choroidal melanoma in rabbits. METHODS: Fifty-two New Zealand albino rabbits were included. Scleral laser attenuation was measured across fresh sclera. B16F10 melanomas were established in the subchoroidal space of 49 rabbits. Twenty-one animals were killed immediately after transscleral treatment, 14 were followed for 2 weeks to 4 weeks, and 14 were followed without treatment. Ophthalmoscopy, fundus photographs, and fluorescein angiography were performed before treatment, immediately after, and weekly during the follow-up. Eyes were examined by light microscopy. RESULTS: Sclera attenuated laser energy by 31% ± 7%. Immediately after treatment, angiography showed diffuse hypofluorescence in 71% (15 of 21 rabbits). Light microscopy showed vascular occlusion extending at least two thirds of the tumor thickness from the base. Seven of the 14 tumors followed for 15 days ± 8 days were eradicated. There was no correlation between tumor height and eradication. CONCLUSION: Rabbit sclera attenuated 31% ± 7% of laser energy. A single transscleral treatment causes tumor vascular closure at the base and may serve as an adjuvant therapy to ensure destruction of deep and intrascleral tumor cells.

IMPORTANCE: A phase 1 study has reported that dry eye disease is the most common adverse effect of human exposure to the antibody figitumumab, an anticancer drug that prevents insulin-like growth factor 1 (IGF-1) from binding to its receptor. We hypothesized that the mechanism underlying this effect is the inhibition of IGF-1 action in epithelial cells of the meibomian gland. OBJECTIVES: To test the hypothesis that IGF-1 stimulates meibomian gland function in vitro and to examine whether growth hormone, a closely related hormone of IGF-1, has the same effect. DESIGN, SETTING, AND MATERIAL: Immortalized human meibomian gland epithelial cells were cultured in the presence or the absence of IGF-1, growth hormone, and an IGF-1 receptor-blocking antibody. Signaling pathways, cell proliferation, neutral lipid staining, and a key protein involved in lipid biogenesis were evaluated. INTERVENTION: Application of IGF-1 and growth hormone to human meibomian gland epithelial cells. MAIN OUTCOMES AND MEASURES: Immunoblotting, cell counting, and neutral lipid staining. RESULTS Insulin-like growth factor 1 activated the phosphoinositol 3-kinase/Akt and forkhead box O1 pathways (showing a dose-dependent effect on immunoblotting), stimulated cellular proliferation (about 1.8-fold increase in cell number), increased sterol regulatory element-binding protein 1 expression (about 3-fold increase on immunoblotting), and promoted lipid accumulation in human meibomian gland epithelial cells (about 2-fold increase in lipid staining). These IGF-1 actions, which may be blocked by cotreatment with the anti-IGF-1 antibody, were accompanied by inconsistent effects on extracellular signal-regulated kinase phosphorylation. We were not able to demonstrate activation of Akt, forkhead box O1, extracellular signal-regulated kinase, Janus kinase 2, or signal transducers and activators of transcription 5, induced cell proliferation, or lipid accumulation in these cells by growth hormone application. CONCLUSIONS AND RELEVANCE: Our results support the hypothesis that IGF-1 acts on human meibomian gland epithelial cells and may explain why treatment with figitumumab, the IGF-1 inhibitor, causes dry eye disease. Ophthalmic care for dry eye disease may be needed when patients with cancer undergo treatment with drugs that inhibit IGF-1 action.