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Gene therapy retina

Ruslan Grishanin, Brian Vuillemenot, Pallavi Sharma, Annahita Keravala, Judith Greengard, Claire Gelfman, Mark Blumenkrantz, Matthew Lawrence, Wenzheng Hu, Szilárd Kiss, Mehdi Gasmi
Inhibition of vascular endothelial growth factor, a key contributor to the choroidal neovascularization associated with wet age-related macular degeneration, is the mode of action of several approved therapies, including aflibercept, which requires frequent intravitreal injections to provide clinical benefit. Lack of compliance with the dosing schedule may result in recurrence of active wet macular degeneration, leading to irreversible vision impairment. Gene therapy providing sustained anti-vascular endothelial growth factor levels in the retina following a single injection could drastically reduce the treatment burden and improve visual outcomes...
November 13, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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
Nathalie Jean-Charles, Diego F Buenaventura, Mark M Emerson
BACKGROUND: Cone and rod photoreceptors are two of the primary cell types affected in human retinal disease. Potential strategies to combat these diseases are the use of gene therapy to rescue compromised photoreceptors or to generate new functional photoreceptors to replace those lost in the diseased retina. Cis-regulatory elements specific to cones, rods, or both types of photoreceptors are critical components of successful implementation of these two strategies. The purpose of this study was to identify and characterize the cell type specificity and activity of cis-regulatory elements active in developing photoreceptors...
November 22, 2018: Neural Development
Sally L Elshaer, William Evans, Mickey Pentecost, Raji Lenin, Ramesh Periasamy, Kumar Abhiram Jha, Shanta Alli, Jordy Gentry, Samuel M Thomas, Nicolas Sohl, Rajashekhar Gangaraju
BACKGROUND: Early-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model. METHODS: Ins2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 μL) or 20× conditioned media from cytokine-primed ASCs (ASC-CM, 1 μL)...
November 21, 2018: Stem Cell Research & Therapy
Andrew Doppenberg, Michel Meunier, Christos Boutopoulos
Intracellular delivery of molecular cargo is the basis for a plethora of therapeutic applications, including gene therapy and cancer treatment. A very efficient method to perform intracellular delivery is the photo-activation of nanomaterials that have been previously directed to the cell vicinity and bear releasable molecular cargo. However, potential in vivo applications of this method are limited by our ability to deliver nanomaterials and light in tissue. Here, we demonstrate intracelullar delivery using a needle-like optofluidic probe capable of penetrating soft tissue...
November 29, 2018: Nanoscale
Marcela Garita-Hernandez, Laure Guibbal, Lyes Toualbi, Fiona Routet, Antoine Chaffiol, Celine Winckler, Marylin Harinquet, Camille Robert, Stephane Fouquet, Sebastien Bellow, José-Alain Sahel, Olivier Goureau, Jens Duebel, Deniz Dalkara
Optogenetic technologies paved the way to dissect complex neural circuits and monitor neural activity using light in animals. In retinal disease, optogenetics has been used as a therapeutic modality to reanimate the retina after the loss of photoreceptor outer segments. However, it is not clear today which ones of the great diversity of microbial opsins are best suited for therapeutic applications in human retinas as cell lines, primary cell cultures and animal models do not predict expression patterns of microbial opsins in human retinal cells...
2018: Frontiers in Neuroscience
Marija Zekušić, Ana Škaričić, Ksenija Fumić, Dunja Rogić, Tamara Žigman, Danijela Petković Ramadža, Nenad Vukojević, Véronique Rüfenacht, Valentina Uroić, Ivo Barić
Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive disorder that occurs due to deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT). Hyperornithinemia causes degeneration of the retina with symptoms like myopia, reduced night vision and progressive vision loss. Our patient is a 10-year-old girl with impaired vision and strabismus. As part of the metabolic work-up, plasma amino acid analysis revealed significantly increased concentration of ornithine (1039 μmol/L; reference interval 20 - 155 μmol/L)...
October 15, 2018: Biochemia Medica: časopis Hrvatskoga Društva Medicinskih Biokemičara
Madhu Sudhana Saddala, Anton Lennikov, Dennis J Grab, Guei-Sheung Liu, Shibo Tang, Hu Huang
Placental growth factor (PlGF or PGF), a member of the vascular endothelial growth factor (VEGF) sub-family, plays a crucial role in pathological angiogenesis and inflammation. However, the underlying molecular mechanisms that PlGF mediates regarding the complications of non-proliferative diabetic retinopathy (DR) remain elusive. Using an LC-MS/MS-based label-free quantification proteomic approach we characterized the alterations in protein expression caused by PlGF ablation in the retinas obtained from C57BL6, Akita, PlGF-/- and Akita...
November 13, 2018: Scientific Reports
Michael Whitehead, Sanjeewa Wickremasinghe, Andrew Osborne, Peter Van Wijngaarden, Keith R Martin
Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina. This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors...
November 8, 2018: Expert Opinion on Biological Therapy
Tatiana Danilova, Maria Lindahl
Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson's disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo . However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it's expression in cells and tissues...
2018: Frontiers in Physiology
Tomas S Aleman, Katherine E Uyhazi, Leona W Serrano, Vidyullatha Vasireddy, Scott J Bowman, Michael J Ammar, Denise J Pearson, Albert M Maguire, Jean Bennett
Purpose: To describe the retinal phenotype of pediatric patients with mutations in the retinol dehydrogenase 12 (RDH12) gene. Methods: Twenty-one patients from 14 families (ages 2-17 years) with RDH12-associated inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted chromatic full-field stimulus testing (FST) and transient pupillometry...
October 1, 2018: Investigative Ophthalmology & Visual Science
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
Mohamed A Hamid, Mohamed Tarek Moustafa, Javier Càceres-Del-Carpio, Baruch D Kuppermann, M Cristina Kenney
BACKGROUND AND OBJECTIVE: To investigate the effects of antiangiogenic drugs on the transcription profile of acetylation genes in immortalized human retinal pigment epithelium cells (ARPE-19) in vitro. MATERIALS AND METHODS: This in vitro study evaluated the effect of antiangiogenic drugs on the expression of histone acetylation genes on immortalized ARPE-19 cell cultures. ARPE-19 cells were cultured, plated, and treated for 24 hours with aflibercept (Eylea; Regeneron, Tarrytown, NY), ranibizumab (Lucentis; Genentech, South San Francisco, CA), or bevacizumab (Avastin; Genentech, South San Francisco, CA) at one (1×) or two times (2×) the concentrations of the clinical intravitreal dose...
October 15, 2018: Ophthalmic Surgery, Lasers & Imaging 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
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