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gene therapy eye

Junkai Tan, Ning Fan, Ningli Wang, BingKai Feng, Ming Yang, Guo Liu, Yun Wang, Xianjun Zhu, Paul L Kaufman, Iok-Hou Pang, Xuyang Liu
Purpose: We evaluated the effects of lentivirus-mediated exoenzyme C3 transferase (C3) expression on cultured primary human trabecular meshwork (HTM) cells in vitro, and on rat intraocular pressure (IOP). Methods: HTM cells were cultured and treated with lentivirus vectors expressing either green fluorescent protein (GFP) only (LV-GFP) or GFP and C3 together (LV-C3-GFP). Changes in cell morphology and actin stress fibers were assessed. The vectors were also injected into the anterior chamber of rats, and GFP expression was visualized by a Micron III Retinal Imaging Microscope in vivo and a fluorescence microscope ex vivo...
October 1, 2018: Investigative Ophthalmology & Visual Science
Regine Mühlfriedel, Stylianos Michalakis, Marina Garcia Garrido, Vithiyanjali Sothilingam, Christian Schön, Martin Biel, Mathias W Seeliger
Gene therapy for inherited eye diseases requires local viral vector delivery by intraocular injection. Since large animal models are lacking for most of these diseases, genetically modified mouse models are commonly used in preclinical proof-of-concept studies. However, because of the relatively small mouse eye, adverse effects of the subretinal delivery procedure itself may interfere with the therapeutic outcome. The method described here aims to provide the details relevant to perform a transscleral pars plana virus-mediated gene transfer to achieve an optimized therapeutic effect in the small mouse eye...
2019: Methods in Molecular Biology
Juan Yang, Jung Woo Park, Dejin Zheng, Ren-He Xu
Purpose: We generated universal corneal epithelial cells (CEC) from human embryonic stem cells (hESC) by genetically removing human leukocyte antigens (HLA) class I from the cell surface. Methods: The serum-free, growth factor-free, and defined medium E6 was used to differentiate hESC to CEC. Decellularized murine corneas were recellularized with hESC-derived CEC. Using CRISPR/Cas9, β-2-microglobulin ( B2M ) was deleted in hESC to block the assembly of HLA class-I antigens on the cell surface to generate B2M -/- CEC...
September 2018: Translational Vision Science & Technology
Kamal Chamoun, Sanam Loghavi, Naveen Pemmaraju, Marina Konopleva, Michael Kroll, Madeleine Nguyen-Cao, Marisa Hornbaker, Courtney D DiNardo, Tapan Kadia, Jeffrey Jorgensen, Michael Andreeff, Shimin Hu, Christopher B Benton
Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy characterized by neoplastic cells that are positive for CD123, CD4, BDCA2, and TCL1 and aberrant expression of CD56. Historically, patients with BPDCN have an unfavorable prognosis and the optimal treatment is not established due to lack of prospective data. Case report: In this report we describe a patient with Felty's syndrome and myelodysplastic syndrome (MDS) in whom a population of aberrant plasmacytoid dendritic cells emerged while on treatment with decitabine...
2018: Experimental Hematology & Oncology
M Dominik Fischer, G Alex Ochakovski, Benjamin Beier, Immanuel P Seitz, Yousof Vaheb, Constanze Kortuem, Felix F L Reichel, Laura Kuehlewein, Nadine A Kahle, Tobias Peters, Aniz Girach, Eberhart Zrenner, Marius Ueffing, Robert E MacLaren, KarlUlrich Bartz-Schmidt, Barbara Wilhelm
PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0...
October 9, 2018: Retina
Kanmin Xue, Jasleen K Jolly, Alun R Barnard, Anna Rudenko, Anna P Salvetti, Maria I Patrício, Thomas L Edwards, Markus Groppe, Harry O Orlans, Tanya Tolmachova, Graeme C Black, Andrew R Webster, Andrew J Lotery, Graham E Holder, Susan M Downes, Miguel C Seabra, Robert E MacLaren
Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1-5 . Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726 . It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia...
October 2018: Nature Medicine
Josef Finsterer, Stephan Iglseder, Julia Wanschitz, Raffi Topakian, Wolfgang N Löscher, Wolfgang Grisold
Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small-fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilisation and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extra-cellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys...
October 8, 2018: Acta Neurologica Scandinavica
Sneha Singh, Ashok Kumar
Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies, has rejuvenated a significant interest in understanding the pathogenesis of flaviviruses, including ZIKV, in the eye...
September 28, 2018: Viruses
Hualei Zhai, Paulo J M Bispo, Hidenaga Kobashi, Deborah S Jacobs, Michael S Gilmore, Joseph B Ciolino
Purpose: To report the resolution of a fluoroquinolone-resistant Escherichia coli keratitis with use of a prosthetic replacement of the ocular surface ecosystem (PROSE) device for enhanced targeted delivery of moxifloxiacin. Observations: A 62-year-old female presented with a 3-day history of pain, photophobia, and declining vision in left eye. The patient had a 2-year history of binocular PROSE treatment for ocular chronic graft-vs-host disease (cGVHD). A corneal ulcer was diagnosed and treated with topical 0...
December 2018: American Journal of Ophthalmology Case Reports
Yonju Ha, Wei Liu, Hua Liu, Shuang Zhu, Fan Xia, Julia E Gerson, Nisha A Azhar, Ronald G Tilton, Massoud Motamedi, Rakez Kayed, Wenbo Zhang
Purpose: Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). Methods: ONC was induced by a transient crush of optic nerve behind the eye globe...
September 4, 2018: Investigative Ophthalmology & Visual Science
Ayesha Liaqat, Azib Shahid, Hamza Attiq, Atoofa Ameer, Muhammad Imran
Crigler-Najjar syndrome type II is caused by mutations in the UGT1A1 gene resulting in severely reduced hepatic activity of UDP-glucoronyltransferase - an enzyme required to convert bilirubin into a more soluble form that can then be removed from the body. Absence or severe deficiency of this enzyme can lead to bilirubin accumulation in the body resulting in yellow skin and eyes (jaundice). The earliest signs of this disease can be apparent in the neonatal period. Patients with Crigglar-Najjar syndrome type II respond to phenobarbital therapy which decreases their chances of getting bilirubinemia by 60-70% in 3 weeks...
October 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Tanuj Dada, Deepti Mittal, Kuldeep Mohanty, Muneeb A Faiq, Muzaffer A Bhat, Raj K Yadav, Ramanjit Sihota, Talvir Sidhu, Thirumurthy Velpandian, Mani Kalaivani, Ravindra M Pandey, Ying Gao, Bernhard A Sabel, Rima Dada
BACKGROUND: Reducing intraocular pressure (IOP) in primary open angle glaucoma (POAG) is currently the only approach to prevent further optic nerve head damage. However, other mechanisms such as ischemia, oxidative stress, glutamate excitotoxicity, neurotrophin loss, inflammation/glial activation, and vascular dysregulation are not addressed. Because stress is a key risk factor affecting these mechanisms, we evaluated if mindfulness based stress reduction (MBSR) can lower IOP and normalize typical stress biomarkers...
September 25, 2018: Journal of Glaucoma
Pallavi Tyagi, Cynthia Santiago
BACKGROUND: The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors. CASE PRESENTATION: A 71-year-old man presented with 'circular, green patches' in his central vision for 2 weeks...
September 14, 2018: BMC Ophthalmology
Byron L Lam, Janet L Davis, Ninel Z Gregori, Robert E MacLaren, Aniz Girach, Jennifer D Verriotto, Belen Rodriguez, Potyra R Rosa, Xiaojun Zhang, William J Feuer
PURPOSE: To report the final results of a phase 2 high-dose gene therapy clinical trial in choroideremia. METHODS: DESIGN: Phase 2 clinical trial. PARTICIPANTS: Six men (age 32-72 years) with genetically-confirmed advanced choroideremia. Patients received subfoveal injection of AAV2-REP1 (1011 genome particles in 0.1 mL) in the worse-sighted eye. OUTCOME MEASURES: Primary measure was best-corrected visual acuity (BCVA) change from baseline in the treated eye compared to the untreated eye...
September 18, 2018: American Journal of Ophthalmology
Fan Xia, Wenwu Ling, Jing Zhang, Yifan Zhang, Xuelei Ma
RATIONALE: Primary poorly differentiated lacrimal gland adenocarcinoma in the orbital region is an extremely rare type of neoplasm with only 1 related case in the literature. Its high grade of malignancy makes the timely data reported necessary. Hence, we present an extremely rare disease with biopsy results and recommendations on clinical treatment in an elderly male with Chinese descent. PATIENT CONCERNS: A 66-year-old Chinese man presented with swelling in the left ocular region and eyeball proptosis...
September 2018: Medicine (Baltimore)
Catherine Cukras, Henry E Wiley, Brett G Jeffrey, H Nida Sen, Amy Turriff, Yong Zeng, Camasamudram Vijayasarathy, Dario Marangoni, Lucia Ziccardi, Sten Kjellstrom, Tae Kwon Park, Suja Hiriyanna, J Fraser Wright, Peter Colosi, Zhijian Wu, Ronald A Bush, Lisa L Wei, Paul A Sieving
This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations...
September 5, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Angelo Maria Minnella, Valeria Pagliei, Martina Maceroni, Matteo Federici, Gloria Gambini, Aldo Caporossi
BACKGROUND: Von Hippel-Lindau disease is a rare hereditary syndrome caused by germinal mutations in a von Hippel-Lindau tumor-suppressing gene. Retinal hemangioblastoma is the ocular hallmark lesion of von Hippel-Lindau disease. CASE PRESENTATION: A 20-year-old Caucasian woman presented to our institution with painless visual impairment in the right eye. A fundus ophthalmoscopic evaluation and swept-source optical coherence tomographic examination revealed a retinal hemangioblastoma associated with cystoid macular edema...
September 6, 2018: Journal of Medical Case Reports
J Wittmann, J Dieckow, H Schröder, U Hampel, F Garreis, C Jacobi, A Milczarek, K L Hsieh, B Pulli, J W Chen, S Hoogeboom, L Bräuer, F P Paulsen, S Schob, M Schicht
Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a known actin modulator, supports epithelial cell regeneration and apoptosis. The aim of this study was to estimate the potential of recombinant gelsolin (rhu-pGSN) for ocular surface regeneration to establish a novel therapy for delayed or complicated wound healing. We analyzed the influence of gelsolin on cell proliferation and wound healing in vitro, in vivo/ex vivo and by gene knockdown...
September 3, 2018: Scientific Reports
Raaya Ezra-Elia, Alexey Obolensky, Ayala Ejzenberg, Maya Ross, Dvir Mintz, Eyal Banin, Ron Ofri
Recombinant adeno associated viruses (AAV) are the most commonly used vectors in animal model studies of gene therapy for retinal diseases. The ability of a vector to localize and remain in the target tissue, and in this manner to avoid off-target effects beyond the site of delivery, is critical to the efficacy and safety of the treatment. The in vivo imaging system (IVIS) is a non-invasive imaging tool used for detection and quantification of bioluminescence activity in rodents. Our aim was to investigate whether IVIS can detect localization and biodistribution of AAV5 vector in mice following subretinal (SR) and intravitreal (IVT) injections...
August 29, 2018: Experimental Eye Research
Kumari Alka, Joseph R Casey
Purpose: SLC4A11 is a plasma membrane protein of corneal endothelial cells. Some mutations of the SLC4A11 gene result in SLC4A11 protein misfolding and failure to mature to the plasma membrane. This gives rise to some cases of Fuchs' endothelial corneal dystrophy (FECD) and congenital hereditary endothelial dystrophy (CHED). We screened ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) for their ability to correct SLC4A11 folding defects. Methods: Five ophthalmic NSAIDs were tested for their therapeutic potential in some genetic corneal dystrophy patients...
August 1, 2018: Investigative Ophthalmology & Visual Science
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