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https://www.readbyqxmd.com/read/27874104/identifying-mutations-in-tunisian-families-with-retinal-dystrophy
#1
Imen Habibi, Ahmed Chebil, Yosra Falfoul, Nathalie Allaman-Pillet, Fedra Kort, Daniel F Schorderet, Leila El Matri
Retinal dystrophies (RD) are a rare genetic disorder with high genetic heterogeneity. This study aimed at identifying disease-causing variants in fifteen consanguineous Tunisian families. Full ophthalmic examination was performed. Index patients were subjected to IROme analysis or whole exome sequencing followed by homozygosity mapping. All detected variations were confirmed by direct Sanger sequencing. Mutation analysis in our patients revealed two compound heterozygous mutations p.(R91W);(V172D) in RPE65, and five novel homozygous mutations: p...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27860478/-gene-therapy-for-inherited-retinal-and-optic-nerve-disorders-current-knowledge
#2
Ľ Ďuďáková, B Kousal, H Kolářová, L Hlavatá, P Lišková
The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i...
2016: Ceská a Slovenská Oftalmologie
https://www.readbyqxmd.com/read/27826002/3d-culture-of-human-pluripotent-stem-cells-in-rgd-alginate-hydrogel-improves-retinal-tissue-development
#3
Nicola C Hunt, Dean Hallam, Ayesha Karimi, Carla B Mellough, Jinju Chen, David H W Steel, Majlinda Lako
: No treatments exist to effectively treat many retinal diseases. Retinal pigmented epithelium (RPE) and neural retina can be generated from human embryonic stem cells/induced pluripotent stem cells (hESCs/hiPSCs). The efficacy of current protocols is, however, limited. It was hypothesised that generation of laminated neural retina and/or RPE from hiPSCs/hESCs could be enhanced by 3D culture in hydrogels. hiPSC- and hESC-derived embryoid bodies (EBs) were encapsulated in 0.5% RGD-alginate; 1% RGD-alginate; hyaluronic acid (HA) or HA/gelatin hydrogels and maintained until day 45...
November 5, 2016: Acta Biomaterialia
https://www.readbyqxmd.com/read/27809638/a-recurrence-model-for-laryngeal-cancer-based-on-svm-and-gene-function-clustering
#4
Jili Su, Yanqiu Zhang, Haodong Su, Chuanhai Zhang, Wei Li
CONCLUSION: A prognostic model was obtained for LC. Several critical genes were unveiled. They could be potentially applied for LC recurrence prediction. OBJECTIVE: Gene expression data of laryngeal cancer (LC) were analyzed to identify critical genes associated with recurrence. METHODS: Two gene expression datasets were downloaded from the Gene Expression Omnibus. Dataset GSE27020 is used as the training set, containing 75 non-recurred LC cases and 34 recurred LC cases...
November 4, 2016: Acta Oto-laryngologica
https://www.readbyqxmd.com/read/27768794/fundus-camera-delivered-light-induced-retinal-degeneration-in-mice-with-the-rpe65-leu450met-variant-is-associated-with-oxidative-stress-and-apoptosis
#5
Xin Zhong, Bogale Aredo, Yi Ding, Kaiyan Zhang, Cynthia X Zhao, Rafael L Ufret-Vincenty
Purpose: Oxidative stress, partly due to light, has an important role in many retinal diseases, including macular degeneration and retinal dystrophies. The Leu450Met variant of RPE65 is expressed in C57BL/6 and in many genetically modified mice. It confers significant resistance to light induced retinal degeneration (LIRD). Our goal was to develop an effective and efficient method to induce LIRD in resistant mice that would recapitulate mechanisms seen in known models of LIRD. Methods: The retinas of C57BL/6J mice were exposed to light using a murine fundus camera...
October 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27753762/clinical-progress-in-inherited-retinal-degenerations-gene-therapy-clinical-trials-and-advances-in-genetic-sequencing
#6
Brian P Hafler
PURPOSE: Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies...
October 6, 2016: Retina
https://www.readbyqxmd.com/read/27733811/proinflammatory-cytokines-decrease-the-expression-of-genes-critical-for-rpe-function
#7
R Krishnan Kutty, William Samuel, Kaifa Boyce, Aswini Cherukuri, Todd Duncan, Cynthia Jaworski, Chandrasekharam N Nagineni, T Michael Redmond
PURPOSE: Proinflammatory cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-γ, TNF-α, and IL-1β have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system...
2016: Molecular Vision
https://www.readbyqxmd.com/read/27686653/available-evidence-on-leber-congenital-amaurosis-and-gene-therapy
#8
Maan Alkharashi, Anne B Fulton
Leber congenital amaurosis (LCA) is a group of severe inherited retinal dystrophies that lead to early childhood blindness. In the last decade, interest in LCA has increased as advances in genetics have been applied to better identify, classify, and treat LCA. To date, 23 LCA genes have been identified. Gene replacement in the RPE65 form of LCA represents a major advance in treatment, although limitations have been recognized. In this article, we review the clinical and genetic features of LCA and evaluate the evidence available for gene therapy in RPE65 disease...
September 29, 2016: Seminars in Ophthalmology
https://www.readbyqxmd.com/read/27664291/gene-therapy-and-stem-cell-transplantation-in-retinal-disease-the-new-frontier
#9
Robert E MacLaren, Jean Bennett, Steven D Schwartz
Gene and cell therapies have the potential to prevent, halt, or reverse diseases of the retina in patients with currently incurable blinding conditions. Over the past 2 decades, major advances in our understanding of the pathobiologic basis of retinal diseases, coupled with growth of gene transfer and cell transplantation biotechnologies, have created optimism that previously blinding retinal conditions may be treatable. It is now possible to deliver cloned genes safely and stably to specific retinal cell types in humans...
October 2016: Ophthalmology
https://www.readbyqxmd.com/read/27623928/targeting-iodothyronine-deiodinases-locally-in-the-retina-is-a-therapeutic-strategy-for-retinal-degeneration
#10
Fan Yang, Hongwei Ma, Joshua Belcher, Michael R Butler, T Michael Redmond, Sanford L Boye, William W Hauswirth, Xi-Qin Ding
Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27606349/retinal-pigment-epithelial-cell-expression-of-active-rap-1a-by-scaav2-inhibits-choroidal-neovascularization
#11
Haibo Wang, Xiaokun Han, Colin A Bretz, Silke Becker, Deeksha Gambhir, George W Smith, R Jude Samulski, Erika S Wittchen, Lawrence A Quilliam, Magdalena Chrzanowska-Wodnicka, M Elizabeth Hartnett
To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV), self-complementary adeno-associated virus 2 (scAAV2) with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con) or constitutively active Rap1a (scAAV2-CARap1a) showed strong GFP at the 5 × 10(8) viral particle/µl dose 5 weeks later without altering retinal morphology or function...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27576608/ocular-toxicity-of-auy922-in-pigmented-and-albino-rats
#12
Danielle Roman, James VerHoeve, Heiko Schadt, Axel Vicart, Ursula Junker Walker, Oliver Turner, Terrilyn A Richardson, Suzanne T Wolford, Paul E Miller, Wei Zhou, Hong Lu, Mikhail Akimov, William Kluwe
AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment...
October 15, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27554602/characterization-of-a-spontaneously-generated-murine-retinal-pigmented-epithelium-cell-line-a-model-for-in-vitro-experiments
#13
Ehsan Ranaei Pirmardan, Zahra-Soheila Soheili, Shahram Samiei, Hamid Ahmadieh, Seyed Javad Mowla, Razie Ezzati, Marzieh Naseri
Retinal pigmented epithelium (RPE), the outermost layer of the retina, has a key role in maintaining retinal cells' functions. Severity of the culture of RPE cells has exerted many limitations to both in vitro and in vivo studies and its therapeutic applications. Therefore, establishment of RPE cell lines with high proliferative potential can considerably improve study of RPE cell biology. Here we report generation of a spontaneously immortalized murine RPE cell line in primary mouse RPE cell culture. Founded colonized cells were picked up and expression of RPE and retinal progenitor cells' (RPC) markers were studied using immunocytochemistry (ICC)...
October 1, 2016: Experimental Cell Research
https://www.readbyqxmd.com/read/27537685/tyrosinase-cre-mediated-deletion-of-the-autophagy-gene-atg7-leads-to-accumulation-of-the-rpe65-variant-m450-in-the-retinal-pigment-epithelium-of-c57bl-6-mice
#14
Supawadee Sukseree, Ying-Ting Chen, Maria Laggner, Florian Gruber, Valérie Petit, Ionela-Mariana Nagelreiter, Veronika Mlitz, Heidemarie Rossiter, Andreas Pollreisz, Ursula Schmidt-Erfurth, Lionel Larue, Erwin Tschachler, Leopold Eckhart
Targeted gene knockout mouse models have helped to identify roles of autophagy in many tissues. Here, we investigated the retinal pigment epithelium (RPE) of Atg7f/f Tyr-Cre mice (on a C57BL/6 background), in which Cre recombinase is expressed under the control of the tyrosinase promoter to delete the autophagy gene Atg7. In line with pigment cell-directed blockade of autophagy, the RPE and the melanocytes of the choroid showed strong accumulation of the autophagy adaptor and substrate, sequestosome 1 (Sqstm1)/p62, relative to the levels in control mice...
2016: PloS One
https://www.readbyqxmd.com/read/27488072/clustered-regularly-interspaced-short-palindromic-repeats-challenges-in-treating-retinal-disease
#15
Micah A Chrenek, John M Nickerson, Jeffrey H Boatright
Ophthalmic researchers and clinicians arguably have led the way for safe, effective gene therapy, most notably with adeno-associated viral gene supplementation in the treatment for patients with Leber congenital amaurosis type 2 with mutations in the RPE65 gene. These successes notwithstanding, most other genetic retinal disease will be refractory to supplementation. The ideal gene therapy approach would correct gene mutations to restore normal function in the affected cells. Gene editing in which a mutant allele is inactivated or converted to sequence that restores normal function is hypothetically one such approach...
July 2016: Asia-Pacific Journal of Ophthalmology
https://www.readbyqxmd.com/read/27453555/key-residues-for-catalytic-function-and-metal-coordination-in-a-carotenoid-cleavage-dioxygenase
#16
Xuewu Sui, Jianye Zhang, Marcin Golczak, Krzysztof Palczewski, Philip D Kiser
Carotenoid cleavage dioxygenases (CCDs) are non-heme iron-containing enzymes found in all domains of life that generate biologically important apocarotenoids. Prior studies have revealed a critical role for a conserved 4-His motif in forming the CCD iron center. By contrast, the roles of other active site residues in catalytic function, including maintenance of the stringent regio- and stereo-selective cleavage activity, typically exhibited by these enzymes have not been thoroughly investigated. Here, we examined the functional and structural importance of active site residues in an apocarotenoid-cleaving oxygenase (ACO) from Synechocystis Most active site substitutions variably lowered maximal catalytic activity without markedly affecting the Km value for the all-trans-8'-apocarotenol substrate...
September 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27375040/safety-and-durability-of-effect-of-contralateral-eye-administration-of-aav2-gene-therapy-in-patients-with-childhood-onset-blindness-caused-by-rpe65-mutations-a-follow-on-phase-1-trial
#17
Jean Bennett, Jennifer Wellman, Kathleen A Marshall, Sarah McCague, Manzar Ashtari, Julie DiStefano-Pappas, Okan U Elci, Daniel C Chung, Junwei Sun, J Fraser Wright, Dominique R Cross, Puya Aravand, Laura L Cyckowski, Jeannette L Bennicelli, Federico Mingozzi, Alberto Auricchio, Eric A Pierce, Jason Ruggiero, Bart P Leroy, Francesca Simonelli, Katherine A High, Albert M Maguire
BACKGROUND: Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study...
August 13, 2016: Lancet
https://www.readbyqxmd.com/read/27372654/epithelial-mesenchymal-transition-of-the-retinal-pigment-epithelium-causes-choriocapillaris-atrophy
#18
Andreas Ohlmann, Michael Scholz, Marcus Koch, Ernst R Tamm
Epithelial-to-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is commonly observed at sites of choroidal neovascularization in patients suffering from age-related macular degeneration. To learn in an experimental model how RPE EMT affects the biology of the choroidal vasculature, we studied transgenic mice (βB1-TGF-β1) with ocular overexpression of transforming growth factor-β1 (TGF-β1). RPE EMT was detectable at postnatal day (P)1 and included marked structural and functional alterations such as loss of the outer blood-retina barrier and reduced mRNA expression of the RPE-characteristic molecules Rlbp1, Rpe65, Rbp1 and Vegfa...
July 2, 2016: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/27335025/subretinal-implantation-of-a-monolayer-of-human-embryonic-stem-cell-derived-retinal-pigment-epithelium-a-feasibility-and-safety-study-in-yucat%C3%A3-n-minipigs
#19
Michael J Koss, Paulo Falabella, Francisco R Stefanini, Marcel Pfister, Biju B Thomas, Amir H Kashani, Rodrigo Brant, Danhong Zhu, Dennis O Clegg, David R Hinton, Mark S Humayun
PURPOSE: A subretinal implant termed CPCB-RPE1 is currently being developed to surgically replace dystrophic RPE in patients with dry age-related macular degeneration (AMD) and severe vision loss. CPCB-RPE1 is composed of a terminally differentiated, polarized human embryonic stem cell-derived RPE (hESC-RPE) monolayer pre-grown on a biocompatible, mesh-supported submicron parylene C membrane. The objective of the present delivery study was to assess the feasibility and 1-month safety of CPCB-RPE1 implantation in Yucatán minipigs, whose eyes are similar to human eyes in size and gross retinal anatomy...
August 2016: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/27307694/the-clinical-features-of-retinal-disease-due-to-a-dominant-mutation-in-rpe65
#20
Sarah Hull, Rajarshi Mukherjee, Graham E Holder, Anthony T Moore, Andrew R Webster
PURPOSE: To present a detailed phenotypic and molecular study of two families with autosomal dominant RPE65-related retinal dystrophy. METHODS: Five patients from two families were ascertained from the retinal clinics of a tertiary referral center. Phenotyping included retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of exon 13 of RPE65 and its intron-exon boundaries was performed on all reported patients and segregation confirmed in available relatives...
2016: Molecular Vision
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