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https://www.readbyqxmd.com/read/28754419/evaluation-of-tolerance-to-lentiviral-lv-rpe65-gene-therapy-vector-after-subretinal-delivery-in-nonhuman-primates
#1
Alexandre Matet, Corinne Kostic, Alexis-Pierre Bemelmans, Alexandre Moulin, Serge G Rosolen, Samia Martin, Fulvio Mavilio, Vazrik Amirjanians, Knut Stieger, Birgit Lorenz, Francine Behar-Cohen, Yvan Arsenijevic
Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis...
July 8, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28712537/efficacy-and-safety-of-voretigene-neparvovec-aav2-hrpe65v2-in-patients-with-rpe65-mediated-inherited-retinal-dystrophy-a-randomised-controlled-open-label-phase-3-trial
#2
Stephen Russell, Jean Bennett, Jennifer A Wellman, Daniel C Chung, Zi-Fan Yu, Amy Tillman, Janet Wittes, Julie Pappas, Okan Elci, Sarah McCague, Dominique Cross, Kathleen A Marshall, Jean Walshire, Taylor L Kehoe, Hannah Reichert, Maria Davis, Leslie Raffini, Lindsey A George, F Parker Hudson, Laura Dingfield, Xiaosong Zhu, Julia A Haller, Elliott H Sohn, Vinit B Mahajan, Wanda Pfeifer, Michelle Weckmann, Chris Johnson, Dina Gewaily, Arlene Drack, Edwin Stone, Katie Wachtel, Francesca Simonelli, Bart P Leroy, J Fraser Wright, Katherine A High, Albert M Maguire
BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible...
July 13, 2017: Lancet
https://www.readbyqxmd.com/read/28712536/gene-therapy-for-rpe65-mediated-inherited-retinal-dystrophy-completes-phase-3
#3
Helena Lee, Andrew Lotery
No abstract text is available yet for this article.
July 13, 2017: Lancet
https://www.readbyqxmd.com/read/28697496/spatially-resolved-spectral-sensitivities-as-a-potential-read-out-parameter-in-clinical-gene-therapeutic-trials
#4
Birgit Lorenz, Erika Wegscheider, Christian Hamel, Markus N Preising, Knut Stieger
PURPOSE: Spatially resolved functional assessment of rods and cones under photopic and scotopic conditions is desirable to evaluate the treatment outcome of gene therapeutic applications in inherited retinal disorders, such as early- onset severe retinal dystrophy (EOSRD) or achromatopsia. METHODS: A sample of 3 healthy subjects, 6 patients with RPE65 deficiency (aged 11-45 years), and 3 patients with cone dysfunction disorders underwent spectral sensitivity testing (SST) under conditions of dark and light adaptation using a Humphrey Field Analyzer modified perimeter...
July 12, 2017: Ophthalmic Research
https://www.readbyqxmd.com/read/28691584/fibrin-gel-as-a-scaffold-for-photoreceptor-cells-differentiation-from-conjunctiva-mesenchymal-stem-cells-in-retina-tissue-engineering
#5
Mostafa Soleimannejad, Somayeh Ebrahimi-Barough, Masoud Soleimani, Samad Nadri, Seyed Mohammad Tavangar, Ramak Roohipoor, Meysam Yazdankhah, Neda Bayat, Mohammad Riazi-Esfahani, Jafar Ai
Stem cell-based therapies are attraction approaches for regenerative medicine for treating retinal diseases. One of the limitations in cell therapy is cell death following post-injection whit preventing functional integration with retinal tissue. Fibrin gel, a bio-polymeric material with excellent biocompatibility, provides numerous advantages as a tissue engineering scaffold and a stem cell carrier. Therefore, current research is focusing on developing fibrin hydrogel scaffolds to protect stem cells during delivery and to stimulate endogenous regeneration through interactions of transplanted stem cells and retinal tissue...
July 10, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/28672005/fatty-acid-transport-protein-1-regulates-retinoid-metabolism-and-photoreceptor-development-in-mouse-retina
#6
Aurélie Cubizolle, Laurent Guillou, Bertrand Mollereau, Christian P Hamel, Philippe Brabet
In retinal pigment epithelium (RPE), RPE65 catalyzes the isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol in the visual cycle and controls the rhodopsin regeneration rate. However, the mechanisms by which these processes are regulated are still unclear. Fatty Acid Transport Protein 1 (FATP1) is involved in fatty acid uptake and lipid metabolism in a variety of cell types. FATP1 co-localizes with RPE65 in RPE and inhibits its isomerase activity in vitro. Here, we further investigated the role of FATP1 in the visual cycle using transgenic mice that overexpress human FATP1 specifically in the RPE (hFATP1TG mice)...
2017: PloS One
https://www.readbyqxmd.com/read/28662231/early-onset-progressive-degeneration-of-the-area-centralis-in-rpe65-deficient-dogs
#7
Freya M Mowat, Kristen J Gervais, Laurence M Occelli, Matthew J Annear, Janice Querubin, James W Bainbridge, Alexander J Smith, Robin R Ali, Simon M Petersen-Jones
Purpose: Retinal epithelium-specific protein 65 kDa (RPE65)-deficient dogs are a valuable large animal model species that have been used to refine gene augmentation therapy for Leber congenital amaurosis type-2 (LCA2). Previous studies have suggested that retinal degeneration in the dog model is slower than that observed in humans. However, the area centralis of the dog retina is a cone and rod photoreceptor rich region comparable to the human macula, and the effect of RPE65 deficiency specifically on this retinal region, important for high acuity vision, has not previously been reported...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28632489/the-effects-of-platelet-gel-on-cultured-human-retinal-pigment-epithelial-cells
#8
Sahar Balagholi, Shaban Alizadeh, Abouzar Bagheri, Yashar Amizadeh, Mozhgan Rezaei Kanavi
The positive role of platelet gel (PG) in tissue regeneration is well known, however, other characteristics of PG still remain to be determined. We investigated cellular and molecular changes in cultured human retinal pigment epithelial (hRPE) cells when treated with different concentrations of PG named PG1, PG2, and PG3. hRPE cells were isolated from donor eyes of two newborn children, within 24 hours after their death. The cells were treated with three concentrations of PG for 7 days: 3 × 104/ml (PG1), 6 × 104/ml (PG2), and 9 × 104/ml (PG3)...
June 20, 2017: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28624218/targeted-multifunctional-lipid-eco-plasmid-dna-nanoparticles-as-efficient-non-viral-gene-therapy-for-leber-s-congenital-amaurosis
#9
Da Sun, Bhubanananda Sahu, Songqi Gao, Rebecca M Schur, Amita M Vaidya, Akiko Maeda, Krzysztof Palczewski, Zheng-Rong Lu
Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber's congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC)...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28546339/bmp-induced-reprogramming-of-the-neural-retina-into-retinal-pigment-epithelium-requires-wnt-signalling
#10
Jörg Steinfeld, Ichie Steinfeld, Alexander Bausch, Nicola Coronato, Meggi-Lee Hampel, Heike Depner, Paul G Layer, Astrid Vogel-Höpker
In vertebrates, the retinal pigment epithelium (RPE) and photoreceptors of the neural retina (NR) comprise a functional unit required for vision. During vertebrate eye development, a conversion of the RPE into NR can be induced by growth factors in vivo at optic cup stages, but the reverse process, the conversion of NR tissue into RPE, has not been reported. Here, we show that bone morphogenetic protein (BMP) signalling can reprogram the NR into RPE at optic cup stages in chick. Shortly after BMP application, expression of Microphthalmia-associated transcription factor (Mitf) is induced in the NR and selective cell death on the basal side of the NR induces an RPE-like morphology...
July 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28500718/rpe65-and-the-accumulation-of-retinyl-esters-in-mouse-retinal-pigment-epithelium
#11
Colleen Sheridan, Nicholas P Boyer, Rosalie K Crouch, Yiannis Koutalos
The RPE65 protein of the retinal pigment epithelium (RPE) enables the conversion of retinyl esters to the visual pigment chromophore 11-cis retinal. Fresh 11-cis retinal is generated from retinyl esters following photoisomerization of the visual pigment chromophore to all-trans during light detection. Large amounts of esters accumulate in Rpe65(-/-) mice, indicating their continuous formation when 11-cis retinal generation is blocked. We hypothesized that absence of light, by limiting the conversion of esters to 11-cis retinal, would also result in the build-up of retinyl esters in the RPE of wild-type mice...
May 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28476927/rational-tuning-of-visual-cycle-modulator-pharmacodynamics
#12
Philip D Kiser, Jianye Zhang, Mohsen Badiee, Junzo Kinoshita, Neal S Peachey, Gregory P Tochtrop, Krzysztof Palczewski
Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity...
July 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28474714/-gene-therapy-for-vision-restoration-in-patients-with-leber-congenital-amaurosis-lca-due-to-rpe65-gene-mutations-beginning-the-phase-iv-trial
#13
Óscar Francisco Chacón-Camacho, Juan Carlos Zenteno
This is a significant time moment in the field of gene therapy in humans. Recently, results from a phase III clinical trial were published, demonstrating the first gene therapy success for a genetic disease. A clinical trial was carried out in patients suffering a hereditary blindness disease named Leber congenital amaurosis, caused by mutations in the RPE65 gene. Participating subjects received a subretinal injection of the normal RPE65 gene and one year after exhibited a significant improvement in visual acuity...
March 2017: Gaceta Médica de México
https://www.readbyqxmd.com/read/28428265/inhibition-of-thyroid-hormone-receptor-locally-in-the-retina-is-a-therapeutic-strategy-for-retinal-degeneration
#14
Hongwei Ma, Fan Yang, Michael R Butler, Joshua Belcher, T Michael Redmond, Andrew T Placzek, Thomas S Scanlan, Xi-Qin Ding
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability...
April 20, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28418497/course-of-sodium-iodate-induced-retinal-degeneration-in-albino-and-pigmented-mice
#15
Guy Chowers, Matan Cohen, Devora Marks-Ohana, Shelly Stika, Ayala Eijzenberg, Eyal Banin, Alexey Obolensky
Purpose: To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice. Methods: Single intraperitoneal (IP) injections of SI (25, 50, and 100 mg/kg) were performed in 7- to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28393863/genetic-and-phenotypic-characteristics-of-four-chinese-families-with-fundus-albipunctatus
#16
Guoxing Yang, Zhiqiang Liu, Shipeng Xie, Chengquan Li, Lina Lv, Minglian Zhang, Jialiang Zhao
Fundus albipunctatus (FA) is a rare autosomal recessive form of stationary night blindness characterized by the presence of white or white-yellow dots in the perimacular area and the periphery of the retina, with or without macular involvement. In this study, we examined four Chinese families with FA. Patients were given complete ophthalmic examinations, and blood samples were collected for DNA extraction. Three genes, RDH5, RLBP1 and RPE65, were screened by direct sequencing. Mutations in RDH5 were identified in three families and mutations in RPE65 were identified in one family...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28393043/leber-s-congenital-amaurosis-and-the-role-of-gene-therapy-in-congenital-retinal-disorders
#17
REVIEW
Walid Sharif, Zuhair Sharif
Leber's congenital amaurosis (LCA) and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE, PubMed and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium (RPE) derived retinoid isomerohydrolase (RPE65) to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2...
2017: International Journal of Ophthalmology
https://www.readbyqxmd.com/read/28356702/appropriately-differentiated-arpe-19-cells-regain-phenotype-and-gene-expression-profiles-similar-to-those-of-native-rpe-cells
#18
William Samuel, Cynthia Jaworski, Olga A Postnikova, R Krishnan Kutty, Todd Duncan, Li Xuan Tan, Eugenia Poliakov, Aparna Lakkaraju, T Michael Redmond
PURPOSE: The RPE cell line ARPE-19 provides a dependable and widely used alternative to native RPE. However, replication of the native RPE phenotype becomes more difficult because these cells lose their specialized phenotype after multiple passages. Compounding this problem is the widespread use of ARPE-19 cells in an undifferentiated state to attempt to model RPE functions. We wished to determine whether suitable culture conditions and differentiation could restore the RPE-appropriate expression of genes and proteins to ARPE-19, along with a functional and morphological phenotype resembling native RPE...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28351499/retina-tissue-engineering-by-conjunctiva-mesenchymal-stem-cells-encapsulated-in-fibrin-gel-hypotheses-on-novel-approach-to-retinal-diseases-treatment
#19
Mostafa Soleimannejad, Somayeh Ebrahimi-Barough, Samad Nadri, Mohammad Riazi-Esfahani, Masoud Soleimani, Seyed Mohammad Tavangar, Jafar Ai
BACKGROUND: Retinitis pigmentosa (RP) and age related macular degeneration (AMD) are two retinal diseases that progress by photoreceptor cells death. In retinal transplantation studies, stem and progenitor cells inject into the sub retinal space or vitreous and then these cells can be migrate to the site of retinal degeneration and locate in the host retina and restitute vision. PRESENTATION OF THE HYPOTHESIS: Our hypothesis suggests that using human conjunctiva stem cells (as the source for increasing the number of human stem cells progenitor cells in retina dysfunction diseases) with fibrin gel and also assessing its relating in vitro (cellular and molecular processes) and in vivo (vision tests and pathology) could be a promising strategy for treatment of AMD and RP disorders...
April 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28339981/transcriptome-analysis-of-comb-and-testis-from-rose-comb-silky-chicken-r1-r1-and-beijing-fatty-wild-type-chicken-r-r
#20
Y Wang, J Li, C Feng, Y Zhao, X Hu, N Li
Rose-comb was one of the chicken comb-variants first used by Bateson and Punnet in 1902 to demonstrate Mendelian inheritance in animals. Rose-comb is a monogenic trait that has been widely described in chickens. It is caused by a large structural rearrangement that leads to mis-expression of transcription factor MNR2 on chromosome 7. Rose-comb has pleiotropic effects in homozygous roosters, which is associated with poor sperm mobility. It was postulated that this is caused by the disruption of the CCDC108 gene located at the distal inversion breakpoint...
June 1, 2017: Poultry Science
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