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RPE65

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https://www.readbyqxmd.com/read/28202390/systemic-injection-of-rpe65-programmed-bone-marrow-derived-cells-prevents-progression-of-chronic-retinal-degeneration
#1
Xiaoping Qi, S Louise Pay, Yuanqing Yan, James Thomas, Alfred S Lewin, Lung-Ji Chang, Maria B Grant, Michael E Boulton
Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis...
February 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28130426/genetic-analysis-of-ten-pedigrees-with-inherited-retinal-degeneration-ird-by-exome-sequencing-and-phenotype-genotype-association
#2
Pooja Biswas, Jacque L Duncan, Bruno Maranhao, Igor Kozak, Kari Branham, Luis Gabriel, Jonathan H Lin, Guilio Barteselli, Mili Navani, John J Suk, Michelle Parke, Catherine Schlechter, Richard Weleber, John R Heckenlively, Gislin Dagnelie, Pauline Lee, S Amer Riazuddin, Radha Ayyagari
PURPOSE: To identify causative mutations and characterize the phenotype associated with the genotype in ten unrelated families with autosomal recessive retinal degeneration. METHODS: Ophthalmic evaluation and DNA isolation was carried out in 10 pedigrees with IRD. Exomes of probands from 8 pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The DHDDS gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jews ancestry...
January 27, 2017: Physiological Genomics
https://www.readbyqxmd.com/read/28041994/a-dominant-mutation-in-rpe65-d477g-delays-dark-adaptation-and-disturbs-the-visual-cycle-in-the-mutant-knock-in-mice
#3
Younghwa Shin, Gennadiy Moiseyev, Dibyendu Chakraborty, Jian-Xing Ma
RPE65 is an indispensable component of the retinoid visual cycle in vertebrates, through which the visual chromophore 11-cis-retinal (11-cis-RAL) is generated to maintain normal vision. Various blinding conditions in humans, such as Leber congenital amaurosis and retinitis pigmentosa (RP), are attributed to either homozygous or compound heterozygous mutations in RPE65. Herein, we investigated D477G missense mutation, an unprecedented dominant-acting mutation of RPE65 identified in patients with autosomal dominant RP...
December 30, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#4
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27943290/isolation-characterization-and-establishment-of-spontaneously-immortalized-cell-line-hrpe-2s-with-stem-cell-properties
#5
Hoda Shams Najafabadi, Zahra-Soheila Soheili, Shahram Samiei, Hamid Ahmadieh, Ehsan Ranaei Pirmardan, Maryam Masoomi
The retinal pigment epithelium is a monolayer of highly specialized pigmented cells located between the neural retina and the Bruch's membrane of the choroid. RPE cells play a crucial role in the maintenance and function of the underlying photoreceptors. This study introduces a spontaneously arising human retinal pigment epithelial cell line, HRPE-2S, which was isolated from primary RPE cell culture of 2 days old male donor. We characterized morphology and functional properties of the new cell line. The immortalized cell line was maintained in culture for more than 70 passages and 240 divisions...
December 12, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27874104/identifying-mutations-in-tunisian-families-with-retinal-dystrophy
#6
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
#7
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
#8
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 three dimensional (3D) culture in hydrogels. hiPSC- and hESC-derived embryoid bodies (EBs) were encapsulated in 0...
November 5, 2016: Acta Biomaterialia
https://www.readbyqxmd.com/read/27809638/a-recurrence-model-for-laryngeal-cancer-based-on-svm-and-gene-function-clustering
#9
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
#10
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
#11
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
#12
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
#13
REVIEW
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...
2017: Seminars in Ophthalmology
https://www.readbyqxmd.com/read/27664291/gene-therapy-and-stem-cell-transplantation-in-retinal-disease-the-new-frontier
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
REVIEW
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
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