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Gene therapy retina

Y J Wu, W S Li
Leber hereditary optic neuropathy (LHON) is a mitochondria hereditary eye disease that involves with retinal ganglion cells (RGCs) resulting eventually in degeneration and atrophy of optic nerve. The three mitochondrial DNA mutations (ND4 G11778A, ND1G3460A, ND6T14484C) have been recognized as the primary mutation locus of LHON. Currently there is no effective therapy for LHON. The result of a clinical trial launched in 2007 indicated that intraocular injection of the recombination of adeno-associated virus and target gene is an effective and safe cure for Leber's Congenital Amaurosis (LCA), which brings hope of treating other hereditary eye diseases with gene therapy...
August 11, 2018: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
Smriti Agrawal Zaneveld, Aiden Eblimit, Qingnan Liang, Renae Bertrand, Nathaniel Wu, Hehe Liu, Quynh Nguyen, Jacques Zaneveld, Keqing Wang, Yumei Li, Rui Chen
Hereditary retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding Receptor Expression Enhancing Protein 6 (REEP6), in multiple families with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with bi-allelic <i>REEP6 </i>mutations, a missense mutation over a frameshift mutation...
August 13, 2018: Human Gene Therapy
Kai Kaarniranta, Jakub Kajdanek, Jan Morawiec, Elzbieta Pawlowska, Janusz Blasiak
PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes...
August 7, 2018: International Journal of Molecular Sciences
Elizabeth Simpson, Andrea J Korecki, Oriol Fornes, Trevor J McGill, Jorge Luis Cueva-Vargas, Jessica Agostinone, Rachelle A Farkas, Jack W Hickmott, Siu Ling Lam, Anthony Mathelier, Lauren M Renner, Jonathan Stoddard, Michelle Zhou, Adriana Di Polo, Martha Neuringer, Wyeth W Wasserman
Retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (rAAV)-based therapies. Importantly, over 50% of those trials are using restricted promoters from human genes. Promoters that restrict expression have demonstrated increased efficacy, and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. Retinal ganglion cells are a critical target in ocular gene therapy; they are involved in common diseases such as glaucoma, rare diseases such as Leber's hereditary optic neuropathy, and in revolutionary optogenetic treatments...
July 31, 2018: Human Gene Therapy
Vitor K L Takahashi, Júlia T Takiuti, Ruben Jauregui, Stephen H Tsang
Hereditary diseases of the retina represent a group of diseases with several heterogeneous mutations that have the common end result of progressive photoreceptor death leading to blindness. Retinal degenerations encompass multifactorial diseases such as age-related macular degeneration, Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa. Although there is currently no cure for degenerative retinal diseases, ophthalmology has been at the forefront of the development of gene therapy, which offers hope for the treatment of these conditions...
July 24, 2018: Ophthalmic Genetics
Jesse D Sengillo, Gabrielle Fridman, Galaxy Y Cho, Christie Buchovecky, Stephen H Tsang
The majority of X-linked retinitis pigmentosa (XLRP) is due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Determining the pathogenicity of novel variants is important for enrollment of patients into gene therapy trials. Sequencing and analysis of RPGR variants in ORF15 is challenging, as it is highly repetitive and rich in purines. Overlapping reading frames and polymorphic insertions / deletions add further complexity to the detection of mutations. Identifying systemic manifestations in affected males and carrier phenotype in related females expedites confirmation of pathogenic variants...
July 1, 2018: Ophthalmic Surgery, Lasers & Imaging Retina
Carina Kelbsch, Archana Jalligampala, Torsten Strasser, Paul Richter, Katarina Stingl, Christoph Braun, Daniel L Rathbun, Eberhart Zrenner, Helmut Wilhelm, Barbara Wilhelm, Tobias Peters, Krunoslav Stingl
The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild-type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20 Hz; envelope frequency constantly kept at 1...
July 10, 2018: Experimental Eye Research
Kumar Abhiram Jha, Mickey Pentecost, Raji Lenin, Lada Klaic, Sally L Elshaer, Jordy Gentry, John M Russell, Alex Beland, Anton Reiner, Veronique Jotterand, Nicolas Sohl, Rajashekhar Gangaraju
Blast concussions are a common injury sustained in military combat today. Inflammation due to microglial polarization can drive the development of visual defects following blast injuries. In this study, we assessed whether anti-inflammatory factors released by the mesenchymal stem cells derived from adipose tissue (adipose stem cells, ASC) can limit retinal tissue damage and improve visual function in a mouse model of visual deficits following mild traumatic brain injury. We show that intravitreal injection of 1 μL of ASC concentrated conditioned medium from cells pre-stimulated with inflammatory cytokines (ASC-CCM) mitigates loss of visual acuity and contrast sensitivity four weeks post blast injury...
July 11, 2018: International Journal of Molecular Sciences
Ivana Trapani, Alberto Auricchio
The retina has been at the forefront of translational gene therapy. Proof-of-concept that gene therapy could restore vision in a large animal led to the initiation of the first successful clinical trials and, in turn, to the recent approval of the first gene therapy product for an ocular disease. As dozens of clinical trials of retinal gene therapy have begun, new challenges are identified, which include delivery of large genes, counteracting gain-of-function mutations, and safe and effective gene transfer to diseased retinas...
August 2018: Trends in Molecular Medicine
Alexandra V Garafalo, Giacomo Calzetti, Artur V Cideciyan, Alejandro J Roman, Supna Saxena, Alexander Sumaroka, Windy Choi, Alan F Wright, Samuel G Jacobson
Purpose: To determine the progression of cone vision loss in patients with recessive disease from NR2E3 gene mutations. Methods: Patients with NR2E3 mutations (n = 37) were studied as a retrospective observational case series clinically and with chromatic static perimetry. Patients were investigated cross-sectionally, and a subset was followed longitudinally. Results: Patients showed a range of visual acuities; there was no clear relationship to age...
July 2, 2018: Investigative Ophthalmology & Visual Science
Omar F Khan, Piotr S Kowalski, Joshua C Doloff, Jonathan K Tsosie, Vasudevan Bakthavatchalu, Caroline Bodi Winn, Jennifer Haupt, Morgan Jamiel, Robert Langer, Daniel G Anderson
Dysfunctional endothelial cells contribute to the pathophysiology of many diseases, including vascular disease, stroke, hypertension, atherosclerosis, organ failure, diabetes, retinopathy, and cancer. Toward the goal of creating a new RNA-based therapy to correct aberrant endothelial cell gene expression in humans, efficient gene silencing in the endothelium of nonhuman primates was achieved by delivering small interfering RNA (siRNA) with 7C1, a low-molecular weight, ionizable polymer that forms nanoparticles...
June 2018: Science Advances
Paula Quintero-Ronderos, Paul Laissue
Transcription factors (TFs) participate in a wide range of cellular processes due to their inherent function as essential regulatory proteins. Their dysfunction has been linked to numerous human diseases. The forkhead box (FOX) family of TFs belongs to the "winged helix" superfamily, consisting of proteins sharing a related winged helix-turn-helix DNA-binding motif. FOX genes have been extensively present during vertebrates and invertebrates' evolution, participating in numerous molecular cascades and biological functions, such as embryonic development and organogenesis, cell cycle regulation, metabolism control, stem cell niche maintenance, signal transduction, and many others...
August 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Anthony Donsante, Nicholas M Boulis
The neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases (LSDs) that cause myoclonic epilepsy, loss of cognitive and motor function, degeneration of the retina leading to blindness, and early death. Most are caused by loss-of-function mutations in either lysosomal proteins or transmembrane proteins. Current therapies are supportive in nature. NCLs involving lysosomal enzymes are amenable to therapies that provide an exogenous source of protein, as has been used for other LSDs. Those that involve transmembrane proteins, however, require new approaches...
July 2018: Expert Opinion on Biological Therapy
Yanmei Qin, Yongfeng Tian, Yang Liu, Dong Li, Hua Zhang, Yeqian Yang, Jianping Qi, Hao Wang, Li Gan
OBJECTIVES: Recent years, gene therapy to treat retinal diseases has been paid much attention. The key to successful therapy is utilizing smart delivery system to achieve efficient gene delivery and transfection. In this study, hyaluronic acid (HA) modified cationic niosomes (HA-C-niosomes) have been designed in order to achieve retinal pigment epithelium (RPE) cells targeted gene delivery and efficient gene transfection. METHODS: Cationic niosomes composed of tween 80/squalene/1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) were prepared by the ethanol injection method...
June 21, 2018: Journal of Pharmacy and Pharmacology
Ron Ofri, Edward Averbukh, Raaya Ezra-Elia, Maya Ross, Hen Honig, Alexey Obolensky, Alexander Rosov, William W Hauswirth, Elisha Gootwine, Eyal Banin
Achromatopsia causes severely reduced visual acuity, photoaversion and inability to discern colors due to cone photoreceptor dysfunction. In 2010, we reported on day blindness in sheep caused by a stop codon mutation of the ovine CNGA3 gene, and began gene augmentation therapy trials in this naturally occurring large animal model of CNGA3 achromatopsia. The purpose of this study was to evaluate long-term efficacy and safety results of treatment, findings that hold great relevance for clinical trials in CNGA3 achromatopsia patients that started recently...
June 21, 2018: Human Gene Therapy
Tian-Zi Zhang, Ting Hua, Li-Kun Han, Yan Zhang, Guang-Yu Li, Qiu-Li Zhang, Guan-Fang Su
OBJECTIVE: Light injury-induced apoptosis of retinal photoreceptor cells can lead to vision loss. The mechanism underlying such injury remains unclear, and there are no effective therapies at present. The aim of this study was to examine the potential antiapoptotic role of the cellular repressor of E1A-stimulated genes (CREG) in retinal cells in a rat model of light-induced retinal damage. METHODS: CREG proteins were injected into the vitreous space of rats in which light retinal injury was induced...
July 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Hanfang Zhang, Farlyn Z Hudson, Zhimin Xu, Rebekah Tritz, Modesto Rojas, Chintan Patel, Stephen B Haigh, Zsuzsanna Bordán, David A Ingram, David J Fulton, Neal L Weintraub, Ruth B Caldwell, Brian K Stansfield
Purpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization...
May 1, 2018: Investigative Ophthalmology & Visual Science
Jennifer A Sullivan, Lisa M Stanek, Michael J Lukason, Jie Bu, Shayla R Osmond, Elizabeth A Barry, Catherine R O'Riordan, Lamya S Shihabuddin, Seng H Cheng, Abraham Scaria
The successful application of adeno-associated virus (AAV) gene delivery vectors as a therapeutic paradigm will require efficient gene delivery to the appropriate cells in affected organs. In this study, we utilized a rational design approach to introduce modifications to the AAV2 and AAVrh8R capsids and the resulting variants were evaluated for transduction activity in the retina and brain. The modifications disrupted either capsid/receptor binding or altered capsid surface charge. Specifically, we mutated AAV2 amino acids R585A and R588A, which are required for binding to its receptor, heparan sulfate proteoglycans, to generate a variant referred to as AAV2-HBKO...
June 2018: Gene Therapy
Si Hyung Lee, Ye Seul Kim, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Jin Young Yang, Keerang Park, Tae Kwann Park
Adeno-associated virus (AAV) vector is a promising platform technology for ocular gene therapy. Recently clinical successes to treat choroidal neovascularization (CNV) in wet type age-related macular degeneration have been reported. However, because pathologic conditions of the retina may alter the tropism of viral vectors, it is necessary to evaluate the transduction efficiency of different serotypes of AAV vectors in the retinas with CNVs. Here, we show the patterns and efficacy of transduction of AAV2, -5, and -8 vectors in a laser-induced CNV mouse model...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Roberta Lugano, Kalyani Vemuri, Di Yu, Michael Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, Anna Dimberg
Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates β1 integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation...
June 25, 2018: Journal of Clinical Investigation
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