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gene therapy eye

Giorgia De Lorenzi, Karen Kamphuisen, Giuseppe Biscontini, Maria Pacciarini, Mariagrazia Zanoni, Andrea Luppi
Mycobacterium genavense infection was diagnosed in an adult ferret with ptosis of the left eye, a proliferative lesion of the conjunctiva of the nictitating membrane, conjunctival swelling, and tumefaction of the periorbital tissues with a watery ocular discharge and the presence of a retrobulbar mass. The diagnosis was based on characteristic cytology of the retrobulbar mass and left mandibular lymph node that revealed granulomatous inflammation. Ziehl-Neelsen staining showed the presence of positive acid-fast bacilli in the cytoplasm of the macrophages...
December 2018: Topics in Companion Animal Medicine
Anil Chekuri, Bhubanananda Sahu, Venkata R M Chavali, Marina Voronchikhina, Angel-Soto Hermida, John J Suk, Akhila N Alapati, Dirk-Uwe Bartsch, Raul Ayala-Ramirez, Juan C Zenteno, Astra Dinculescu, Monica M Jablonski, Shyamanga Borooah, Radha Ayyagari
Patients harboring homozygous c.498_499insC mutations in MFRP demonstrate hyperopia, microphthalmia, retinitis pigmentosa, retinal pigment epithelial (RPE) atrophy, variable degrees of foveal edema and optic disc drusen. The disease phenotype is variable however, with some patients maintaining good central vision and cone function till late in the disease. We developed a knock-in mouse model with the c.498_499insC mutation in Mfrp (Mfrp KI/KI) to understand the effects of these mutations in the retina. Our model shares many of the features of human clinical disease including reduced axial length, hyperopia, retinal degeneration, RPE atrophy and decreased electrophysiological responses...
November 30, 2018: Human Gene Therapy
David J Jiang, Christine L Xu, Stephen H Tsang
Recently, there have been revolutions in the development of both gene medicine therapy and genome surgical treatments for inherited disorders. Much of this progress has been centered on hereditary retinal dystrophies, because the eye is an immune-privileged and anatomically ideal target. Gene therapy treatments, already demonstrated to be safe and efficacious in numerous clinical trials, are benefitting from the development of new viral vectors, such as dual and triple adeno-associated virus (AAV) vectors. CRISPR/Cas9, which revolutionized the field of gene editing, is being adapted into more precise "high fidelity" and catalytically dead variants...
November 26, 2018: Genes
Ashkan Faridi, Amir Tavakoli Kareshk, Mehdi Fatahi-Bafghi, Mahsa Ziasistani, Mohammad Reza Kandehkar Ghahraman, Seyedeh Zeinab Seyyed-Yousefi, Noshin Shakeri, Davood Kalantar-Neyestanaki
Background and Objectives: Staphylococcus aureus is the main Gram-positive bacteria isolated from patients with ocular infections. Herein, we describe the pattern of antibiotic resistance, presence of resistance genes including ermA, ermB, ermC, msrA, mecA and the pvl cytotoxin gene in S. aureus isolates collected from patients with external ocular infection. Materials and Methods: In this study, 8 S. aureus isolates were collected from 81 patients that suffered from eye damage...
August 2018: Iranian Journal of Microbiology
Masatoshi Hirayama
The lacrimal glands produce tears to support a healthy homeostatic environment on the ocular surface. The lacrimal gland dysfunction characteristic of dry eye disease causes ocular discomfort and visual disturbances and in severe cases can result in a loss of vision. The demand for adequate restoration of lacrimal gland function has been intensified due to advances in stem cell biology, developmental biology, and bioengineering technologies. In addition to conventional therapies, including artificial tears, tear alternatives (such as autologous serum eye drops) and salivary gland transplantation, a regenerative medicine approach has been identified as a novel strategy to restore the function of the lacrimal gland...
November 1, 2018: Investigative Ophthalmology & Visual Science
Sara E Mole, Glenn Anderson, Heather A Band, Samuel F Berkovic, Jonathan D Cooper, Sophia-Martha Kleine Holthaus, Tristan R McKay, Diego L Medina, Ahad A Rahim, Angela Schulz, Alexander J Smith
Treatment of the neuronal ceroid lipofuscinoses, also known as Batten disease, is at the start of a new era because of diagnostic and therapeutic advances relevant to this group of inherited neurodegenerative and life-limiting disorders that affect children. Diagnosis has improved with the use of comprehensive DNA-based tests that simultaneously screen for many genes. The identification of disease-causing mutations in 13 genes provides a basis for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, and for the development of targeted therapies...
November 20, 2018: Lancet Neurology
Jasmina Cehajic-Kapetanovic, Charles L Cottriall, Jasleen K Jolly, Morag Shanks, Penny Clouston, Peter Charbel Issa, Robert E MacLaren
BACKGROUND: Nuclear hormone receptor gene, NR2E3, plays a critical role in retinogenesis and determination of the rod photoreceptor phenotype. Mutations in NR2E3 typically lead to recessive enhanced S-cone syndrome (ESCS), where affected individuals show higher sensitivity to short wavelength light and early onset rod dysfunction. Patients with ESCS present in early childhood with nyctalopia, enhanced sensitivity to blue light and display a very heterogeneic retinal phenotype with varying degrees of clumped pigmentation and occasional retinoschisis...
November 23, 2018: Ophthalmic Genetics
Kohei Arimizu, Gen Hirano, Chinatsu Makiyama, Mioko Matsuo, Takakazu Sasaguri, Akitaka Makiyama
BACKGROUND: Nuclear protein in testis (NUT) carcinoma (NC) is a rare epithelial malignancy characterized by rearrangement of the NUT gene on chromosome 15. If NC is not suspected, it is often diagnosed as other malignancies. We present the case of NC of the nasal cavity that responded to a chemotherapy regimen for Ewing's sarcoma family of tumors (ESFT). CASE PRESENTATION: A 49-year-old male presented with epistaxis and pain in the left eye. The patient had a tumor in the left nasal cavity at initial visit and it was biopsied...
November 19, 2018: BMC Cancer
Mark C Butler, Jack M Sullivan
HR-SD-OCT is utilized to monitor the progression of photoreceptor degeneration in live mouse models, assess the delivery of therapeutic agents into the subretinal space, and to evaluate toxicity and efficacy in vivo. HR-SD-OCT uses near infrared light (800-880 nm) and has optics specifically designed for the unique optics of the mouse eye with sub-2-micron axial resolution. Transgenic mouse models of outer retinal (photoreceptor) degeneration and controls were imaged to assess the disease progression. Pulled glass microneedles were used to deliver sub retinal injections of adeno-associated virus (AAV) or nanoparticles (NP) via a trans-scleral and trans-choroidal approach...
November 2, 2018: Journal of Visualized Experiments: JoVE
Zhenghuan Zhao, Harini Kantamneni, Shuqing He, Sandra Pelka, Aiyer Sandhya Venkataraman, Mijung Kwon, Steven K Libutti, Mark Pierce, Prabhas V Moghe, Vidya Ganapathy, Mei Chee Tan
Gene therapy is emerging as the next generation of therapeutic modality with United States Food and Drug Administration approved gene-engineered therapy for cancer and a rare eye-related disorder, but the challenge of real-time monitoring of on-target therapy response remains. In this study, we have designed a theranostic nanoparticle composed of shortwave-infrared-emitting rare-earth-doped nanoparticles (RENPs) capable of delivering genetic cargo and of real-time response monitoring. We showed that the cationic coating of RENPs with branched polyethylenimine (PEI) does not have a significant impact on cellular toxicity, which can be further reduced by selectively modifying the surface characteristics of the PEI coating using counter-ions and expanding their potential applications in photothermal therapy...
July 9, 2018: ACS Biomaterials Science & Engineering
Mushfiq H Shaikh, Adi Idris, Newell W Johnson, Sora Fallaha, Daniel T W Clarke, David Martin, Iain M Morgan, Brian Gabrielli, Nigel A J McMillan
OBJECTIVES: Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV-related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells...
November 2018: Oral Oncology
Benjamin Bakall, J Shepard Bryan, Edwin M Stone, Kent W Small
PURPOSE: To report a new family with North Carolina macular dystrophy including a patient with choroidal neovascularization (CNV). METHODS: Diagnostic modalities included fundus imaging, fluorescein angiography, optical coherence tomography, and genetic testing. The CNV was treated with intravitreal anti-vascular endothelial growth factor according to a treat-and-extend protocol in both eyes. RESULTS: A 60-year-old man presented with North Carolina macular dystrophy with decreasing vision in the left eye and persistently deceased central vision in the right eye...
October 31, 2018: Retinal Cases & Brief Reports
Karima Kessal, Hong Liang, Ghislaine Rabut, Philippe Daull, Jean-Sébastien Garrigue, Mylene Docquier, Stéphane Melik Parsadaniantz, Christophe Baudouin, Françoise Brignole-Baudouin
Purpose: In several multicenter clinical trials, HLA-DR was found to be a potential biomarker of dry eye disease (DED)'s severity and prognosis. Given the fact that HLA-DR receptor is a heterodimer consisting in an alpha and a beta chain, we intended to investigate the correlation of inflammatory targets with the corresponding transcripts, HLA-DRA and HLA-DRB1 , to characterize specific targets closely related to HLA-DR expressed in conjunctival cells from patients suffering from DED of various etiologies. Methods: A prospective study was conducted in 88 patients with different forms of DED...
2018: Frontiers in Immunology
Andrea E Dillinger, Michaela Guter, Franziska Froemel, Gregor R Weber, Kristin Perkumas, W Daniel Stamer, Andreas Ohlmann, Rudolf Fuchshofer, Miriam Breunig
Glaucoma is the second leading cause of blindness worldwide, often associated with elevated intraocular pressure. Connective tissue growth factor (CTGF) is a mediator of pathological effects in the trabecular meshwork (TM) and Schlemm's canal (SC). A novel, causative therapeutic concept which involves the intracameral delivery of small interfering RNA against CTGF is proposed. Layer-by-layer coated nanoparticles of 200-260 nm with a final layer of hyaluronan (HA) are developed. The HA-coating should provide the nanoparticles sufficient mobility in the extracellular matrix and allow for binding to TM and SC cells via CD44...
October 23, 2018: Small
Shyamtanu Datta, Marian Renwick, Viet Q Chau, Fang Zhang, Emily R Nettesheim, Daniel M Lipinski, John D Hulleman
Purpose: Temporal and reversible control of protein expression in vivo is a central goal for many gene therapies, especially for strategies involving proteins that are detrimental to physiology if constitutively expressed. Accordingly, we explored whether protein abundance in the mouse retina could be effectively controlled using a destabilizing Escherichia coli dihydrofolate reductase (DHFR) domain whose stability is dependent on the small molecule, trimethoprim (TMP). Methods: We intravitreally injected wild-type C57BL6/J mice with an adeno-associated vector (rAAV2/2[MAX]) constitutively expressing separate fluorescent reporters: DHFR fused to yellow fluorescent protein (DHFR...
October 1, 2018: Investigative Ophthalmology & Visual Science
Charmaine A Ramlogan-Steel, Aparna Murali, Slawomir Andrzejewski, Bijay Dhungel, Jason C Steel, Christopher J Layton
Voretigene neparvovec-rzyl was recently approved for the treatment of Leber Congenital Amaurosis, and the use of gene therapy for eye disease is attracting even greater interest. The eye has immune privileged status, is easily accessible, requires a reduced dosage of therapy due to its size, and is highly compartmentalized, significantly reducing systemic spread. Adeno-associated virus (AAV), with its low pathogenicity, prolonged expression profile and ability to transduce multiple cell types, has become the leading gene therapy vector...
October 21, 2018: Clinical & Experimental Ophthalmology
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
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