Correction of Monogenic and Common Retinal Disorders with Gene Therapy

The past decade has seen major advances in gene-based therapies, many of which show promise for translation to human disease. At the forefront of research in this field is ocular disease, as the eye lends itself to gene-based interventions due to its accessibility, relatively immune-privileged status, and ability to be non-invasively monitored. A landmark study in 2001 demonstrating successful gene therapy in a large-animal model for Leber congenital amaurosis set the stage for translation of these strategies from the bench to the bedside. Multiple clinical trials have since initiated for various retinal diseases, and further improvements in gene therapy techniques have engendered optimism for alleviating inherited blinding disorders. This article provides an overview of gene-based strategies for retinal disease, current clinical trials that engage these strategies, and the latest techniques in genome engineering, which could serve as the next frontline of therapeutic interventions

Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients

Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Although gene-and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials.National Institute of HealthNational Cancer InstituteResearch to Prevent Blindness (RPB)RPB, New York, NY, USARPBInternational Council of Ophthalmology - Retina Research FoundationNIHTistou and Charlotte Kerstan FoundationSchneeweiss Stem Cell Fund, New York StateFoundation Fighting Blindness New York Regional Research CenterCrowley Family FundGebroe Family FoundationColumbia Univ, Dept Ophthalmol, Med Ctr, Jonas Childrens Vis Care, New York, NY 10027 USAColumbia Univ, Dept Ophthalmol, Med Ctr, Bernard & Shirlee Brown Glaucoma Lab, New York, NY 10027 USANew York Presbyterian Hosp, Edward S Harkness Eye Inst, New York, NY 10034 USASuny Downstate Med Ctr, Brooklyn, NY 11203 USAUniv Fed Espirito Santo, Dept Ophthalmol, Vitoria, BrazilUniv Fed Sao Paulo, Dept Ophthalmol, Sao Paulo, BrazilColumbia Univ, Dept Biostat, New York, NY USAUniv Montreal, Dept Ophthalmol, Montreal, PQ, CanadaShanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Dept Ophthalmol, Shanghai, Peoples R ChinaColumbia Univ, Inst Human Nutr, Dept Pathol & Cell Biol, Stem Cell Initiat CSCI,Coll Phys & Surg, New York, NY 10032 USAStanford Univ, Dept Ophthalmol, Om Lab, Byers Eye Inst, Palo Alto, CA 94304 USAUniv Fed Sao Paulo, Dept Ophthalmol, Sao Paulo, BrazilWeb of Scienc

The diverse morphology of pockmarks around Aotearoa New Zealand

Seafloor pockmarks are abundant around Aotearoa New Zealand, occurring across a diverse range of tectonic, sedimentological and geomorphological settings. Globally, the formation and source of pockmarks is widely researched because they: 1) have potential links to subsurface hydrocarbon systems, 2) can provide important habitats for benthic organisms and 3) may be indications of fluid escape pathways or areas of sediment disturbance, which influence seafloor stability and could pose a risk to infrastructure. Pockmarks are widely associated with fluid release (such as gas or water) from subsurface reservoirs. However, the formation of pockmarks, the processes that shape and modify their morphology over time, and the relative timing of these events, remains enigmatic. Here, we compile the first national database of over 30,000 pockmarks around Aotearoa New Zealand, allowing us to begin to comprehend the dynamic processes that shape and affect pockmarks by exploring regional and inter-regional patterns in pockmark geometry and seabed characteristics. This compilation reveals several significant trends, including a distinct lack of correlation between active seafloor seeps and pockmarks, and a strong association of pockmarks with mud-rich seafloor substrate. Furthermore, we highlight key knowledge gaps that require further investigation moving forward, including a lack of constraint on the timing of pockmark formation, and limited modelling of the processes involved in their formation

Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation

D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.We greatly appreciate the assistance of the members of the Bernard & Shirlee Brown Glaucoma laboratory, especially to Chun-Wei Hsu for technical support. SHT is a Burroughs-Wellcome Program in Biomedical Sciences Fellow, and is also supported by the Charles E. Culpeper-Partnership for Cures 07-CS3, Crowley Research Fund, Schneeweiss Stem Cell Fund, New York State N09G-302, Foundation Fighting Blindness [TA-NMT-0116-0692- COLU] (Owings Mills, MD), TS080017 from US Department of Defense, NIH Grants [P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], Research to Prevent Blindness (New York, NY), and Joel Hoffmann Scholarship. CSL is the Homer McK. Rees Scholar. JSP is a BEST2016 awardee (BEST/ 2016/030, Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and his research is supported by a Prometeo Grant (PROMETEO/2016/094; Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and by internal funds from Universidad Católica de Valencia San Vicente Mártir (2018-128-001). VBM is supported by NIH Grants K08EY020530, R01EY016822, The Doris Duke Charitable Foundation Grant #2013103, and Research to Prevent Blindness (New York, NY); GV is supported by NIH Grants [F30EYE027986 and T32GM007337].Author manuscriptMedicin

Gambling Problems Are Associated with Alcohol Misuse and Insomnia: Results from a Representative National Telephone Survey

Gambling has significant costs to the community, with a health burden similar in scale to major depression. To reduce its impact, it is necessary to understand factors that may exacerbate harm from gambling. The gambling environment of late-night licensed venues and 24/7 online gambling has the potential to negatively impact sleep and increase alcohol consumption. This study explored gambling, alcohol, and sleep problems to understand whether there is a relationship between these three factors. Telephone interviews were conducted with a representative sample of Australian adults (n = 3760) combined across three waves of the National Social Survey. Participants completed screening measures for at-risk gambling, at-risk alcohol consumption, insomnia (2015 wave only), and sleep quality. There were small but significant positive correlations between problem gambling and alcohol misuse, problem gambling and insomnia, and problem gambling and poor sleep quality. A regression model showed that gambling problems and alcohol misuse were significant independent predictors of insomnia. A separate regression showed gambling problems (and not alcohol misuse) were a significant predictor of poor sleep quality, but only in one survey wave. Findings suggest that gambling, alcohol, and sleep problems are related within persons. Further research should examine the mechanisms through which this relationship exists

Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy

Background: Autoimmune retinopathy (AIR) is a rare but potentially blinding condition that is often underdiagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies. AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. The goal of this communication is to assess the effects of rituximab infusions on electroretinogram (ERG) responses and visual function outcomes in patients with non-paraneoplastic autoimmune retinopathy (npAIR). Results: Following infusion(s), three out of five patients showed no evidence of disease progression or improved, while two patients continued to progress on ERG. One patient demonstrated improvement in visual acuity (2 lines) in both eyes. ERG responses provided objective monitoring of patients’ visual function and response to immunosuppression over time. Conclusions: These findings suggest that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in our case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients’ progression during treatment

Hearing Loss as a Prognostic Indicator of Visual Function in USH2A-associated Retinal Degeneration.

National Institute of HealthNational Cancer Institute CoreResearch to Prevent Blindness (RPB) Physician-Scientist AwardRPB, New York, NY, USARPB medical student research fellowshipInternational Council of Ophthalmology Retina Research Foundation Helmerich FellowshipNIHTistou and Charlotte Kerstan FoundationSchneeweiss Stem Cell Fund, New York StateFoundation Fighting Blindness New York Regional Research Center GrantCrowley Family FundGebroe Family FoundationColumbia Univ, Ophthalmol, New York, NY USASuny Downstate Med Ctr, Coll Med, Brooklyn, NY 11203 USAUniv Fed Espirito Santo, Ophthalmol, Vitoria, BrazilUniv Fed Sao Paulo, Ophthalmol, Sao Paulo, BrazilColumbia Univ, Biostat, New York, NY USAUniv Montreal, Ophthalmol, Montreal, PQ, CanadaShanghai Jiao Tong Univ, Ophthalmol, Xin Hua Hosp, Sch Med, Shanghai, Peoples R ChinaUniv Iowa, Ophthalmol &Visual Sci, Iowa City, IA USAUniv Iowa, Omics Lab, Iowa City, IA USAColumbia Univ, Inst Human Nutr, Pathol & Cell Biol, New York, NY 10032 USAUniv Fed Sao Paulo, Ophthalmol, Sao Paulo, BrazilNational Institute of Health: 5P30EY019007National Institute of Health: R01EY018213National Institute of Health: R01EY024698National Institute of Health: R01EY026682National Institute of Health: R21AG050437National Cancer Institute Core: 5P30CA013696NIH: R01EY024698NIH: R01EY026682NIH: R21AG050437NIH: R01EY024665NIH: R01EY025225Schneeweiss Stem Cell Fund, New York State: C029572Foundation Fighting Blindness New York Regional Research Center Grant: C-NY05-0705-0312Web of Scienc