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Gene therapy retina

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
T L Edwards, K Xue, H C M Meenink, M J Beelen, G J L Naus, M P Simunovic, M Latasiewicz, A D Farmery, M D de Smet, R E MacLaren
Microsurgery of the retina would be dramatically improved by instruments that offer supra-human precision. Here, we report the results of a first-in-human study of remotely controlled robot-assisted retinal surgery performed through a telemanipulation device. Specifically, 12 patients requiring dissection of the epiretinal or inner limiting membrane over the macula were randomly assigned to either undergo robot-assisted-surgery or manual surgery, under general anaesthesia. We evaluated surgical success, duration of surgery and amount of retinal microtrauma as a proxy for safety...
June 18, 2018: Nature Biomedical Engineering
Andrew Osborne, Tasneem Z Khatib, Lalana Songra, Amanda C Barber, Katie Hall, George Y X Kong, Peter S Widdowson, Keith R Martin
Previous studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improve RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited at least in part due to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery...
September 26, 2018: Cell Death & Disease
Steven F Stasheff
Hereditary retinal degenerations result from varied pathophysiologic mechanisms, all ultimately characterized by photoreceptor dysfunction and death. Hence, much research on these diseases has concentrated on the outer retina. Over the past decade or so increasing attention has focused on concomitant changes in complex inner retinal neural circuits that process visual signals for transmission to the brain. One striking abnormality develops before the ultimately profound anatomic disruption of the inner retina...
2018: Frontiers in Cellular Neuroscience
Cheng-Biao Hu, Bing-Dong Sui, Bao-Ying Wang, Gao Li, Cheng-Hu Hu, Chen-Xi Zheng, Fang-Ying Du, Chun-Hui Zhu, Hong-Bo Li, Yan Feng, Yan Jin, Xiao-Rui Yu
Photoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages...
2018: Cell Death Discovery
Mohsen Farvardin, Mehrdad Afarid, Adel Attarzadeh, Mohammad K Johari, Morsal Mehryar, M Hossein Nowroozzadeh, Feisal Rahat, Hossein Peyvandi, Reza Farvardin, Mohammad Nami
Over the past few years, visual prostheses (namely, Argus II retinal implant) and gene therapy have obtained FDA approval in treating blindness resulting from retinitis pigmentosa. Compared to gene therapy; Argus II is less costly with a demonstrated favorable outcome, though the vision is yet artificial. To obtain better results, expectation counseling and preoperative retinal assessment are critical. The global experience with Argus II has enrolled no more than 300 cases so far. The first Argus II retinal prosthesis in Iran was successfully implanted in Shiraz (October 2017)...
2018: Frontiers in Neuroscience
Qingquan Wei, Xiuwei Liang, Ye Peng, Donghui Yu, Ruiling Zhang, Huizi Jin, Jiaqi Fan, Wenting Cai, Chengda Ren, Jing Yu
Purpose: This study aimed to assess the effects of 17β-estradiol (βE2 ) on blue light-emitting diode (LED)-induced retinal degeneration (RD) in rats and hydrogen peroxide (H2 O2 )-induced retinal pigment epithelium cell injury in humans and elucidate the protective mechanism of βE2 underlying these processes. Methods: Female ovariectomized (OVX) rats were intravitreally injected with βE2 before blue LED exposure (3,000 lux, 2 hours). Retinal function and morphology were assayed via electroretinogram (ERG) and H&E, respectively...
2018: Drug Design, Development and Therapy
Alison J Hardcastle, Paul A Sieving, José-Alain Sahel, Samuel G Jacobson, Artur V Cideciyan, John G Flannery, William A Beltran, Gustavo D Aguirre
The following review summarizes the state of the art in representative aspects of gene therapy/translational medicine and evolves from a symposium held at the School of Veterinary Medicine, University of Pennsylvania on November 16, 2017 honoring Dr. Gustavo Aguirre, recipient of ARVO's 2017 Proctor Medal. Focusing on the retina, speakers highlighted current work on moving therapies for inherited retinal degenerative diseases from the laboratory bench to the clinic.
September 2018: Translational Vision Science & Technology
Alejandra Bosco, Sarah R Anderson, Kevin T Breen, Cesar O Romero, Michael R Steele, Vince A Chiodo, Sanford L Boye, William W Hauswirth, Stephen Tomlinson, Monica L Vetter
Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina and to determine its contribution to degeneration onset and/or progression...
October 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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
Scott J Dooley, Devin S McDougald, Krishna J Fisher, Jeanette L Bennicelli, Lloyd G Mitchell, Jean Bennett
Ocular gene therapy with recombinant adeno-associated virus (AAV) has shown vector-mediated gene augmentation to be safe and efficacious in the retina in one set of diseases (retinitis pigmentosa and Leber congenital amaurosis (LCA) caused by RPE65 deficiency), with excellent safety profiles to date and potential for efficacy in several additional diseases. However, size constraints imposed by the packaging capacity of the AAV genome restrict application to diseases with coding sequence lengths that are less than 5,000 nt...
September 7, 2018: Molecular Therapy. Nucleic Acids
Janet L Davis
PURPOSE: Review barriers to effective transduction of cells in the subretinal plane during gene therapy surgery for inherited retinal dystrophies (IRD). DESIGN: Perspective METHODS: Case-based learning in clinical trials and commercial applications of gene therapy in a tertiary care, university-affiliated hospital. MEDLINE search for publications relevant to retinal surgical technique for gene therapy, clinical trials results for gene therapy of IRD, adenoviral-associated viral vector design, and immune response to viral vectors...
September 5, 2018: American Journal of Ophthalmology
Marianthi Karali, Sandro Banfi
Accumulating evidence on the role of non-protein-coding RNA sequences in the regulation of gene expression is greatly expanding our understanding of the flow of genetic information within biological systems. The interplay between protein-coding and non-coding RNAs (ncRNAs) is essential for tissue development, homeostasis, and function. NcRNAs can be divided in short ncRNAs, whose main subtype is represented by microRNAs, and long ncRNAs, which constitute a more heterogeneous class. The retina is a light-sensitive tissue consisting of highly interconnected cell types and is the primary target of many genetic diseases...
September 5, 2018: Human Genetics
Norimitsu Ban, Tae Jun Lee, Abdoulaye Sene, Mayur Choudhary, Michael Lekwuwa, Zhenyu Dong, Andrea Santeford, Jonathan B Lin, Goldis Malek, Daniel S Ory, Rajendra S Apte
Advanced age-related macular degeneration (AMD), the leading cause of blindness among people over 50 years of age, is characterized by atrophic neurodegeneration or pathologic angiogenesis. Early AMD is characterized by extracellular cholesterol-rich deposits underneath the retinal pigment epithelium (RPE) called drusen or in the subretinal space called subretinal drusenoid deposits (SDD) that drive disease progression. However, mechanisms of drusen and SDD biogenesis remain poorly understood. Although human AMD is characterized by abnormalities in cholesterol homeostasis and shares phenotypic features with atherosclerosis, it is unclear whether systemic immunity or local tissue metabolism regulates this homeostasis...
September 6, 2018: JCI Insight
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
Rehan M Hussain, Thomas A Ciulla, Audina M Berrocal, Ninel Z Gregori, Harry W Flynn, Byron L Lam
Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments. Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage...
September 10, 2018: Expert Opinion on Biological Therapy
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 individuals with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a frameshift mutation...
October 16, 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 M 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...
October 2, 2018: Human Gene Therapy
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