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Gene therapy retina

Renata Lejkowska, Miłosz Piotr Kawa, Ewa Pius-Sadowska, Dorota Rogińska, Karolina Łuczkowska, Bogusław Machaliński, Anna Machalińska
This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation...
February 12, 2019: International Journal of Molecular Sciences
Hongman Song, Ronald A Bush, Yong Zeng, Haohua Qian, Zhijian Wu, Paul A Sieving
Adeno-associated virus (AAV) vector-mediated gene delivery is a promising approach for therapy, but implementation in the eye currently is hampered by the need for delivering the vector underneath the retina, using surgical application into the subretinal space. This limits the extent of the retina that is treated and may cause surgical injury. Vector delivery into the vitreous cavity would be preferable because it is surgically less invasive and would reach more of the retina. Unfortunately, most conventional, non-modified AAV vector serotypes penetrate the retina poorly from the vitreous; this limits efficient transduction and expression by target cells (retinal pigment epithelium and photoreceptors)...
June 14, 2019: Molecular Therapy. Methods & Clinical Development
Zohar Habot-Wilner, Glenn Noronha, Charles C Wykoff
Delivery of pharmaceuticals to the posterior segment presents challenges that arise from the anatomy and clearance pharmacokinetics of the eye. Systemic and several local administration options [topical, periocular, intravitreal (IVT) and subretinal] are in clinical use, each with a unique benefit to risk profile shaped by factors including the administered agent, frequency of dosing, achievable pharmaceutical concentrations within posterior segment structures versus elsewhere in the eye or the body, invasiveness of the procedure and the inherent challenges with some administration methods...
January 31, 2019: Acta Ophthalmologica
Sergio Claudio Saccà, Paolo Corazza, Stefano Gandolfi, Daniele Ferrari, Samir Sukkar, Eugenio Luigi Iorio, Carlo Enrico Traverso
Glaucoma is a multifactorial disease in which pro-apoptotic signals are directed to retinal ganglion cells. During this disease the conventional outflow pathway becomes malfunctioning. Aqueous humour builds up in the anterior chamber, leading to increased intraocular pressure. Both of these events are related to functional impairment. The knowledge of molecular mechanisms allows us to better understand the usefulness of substances that can support anti-glaucoma therapy. The goal of glaucoma therapy is not simply to lower intraocular pressure; it should also be to facilitate the survival of retinal ganglion cells, as these constitute the real target tissue in this disease, in which the visual pathway is progressively compromised...
January 22, 2019: Nutrients
Yusaku Katada, Kenta Kobayashi, Kazuo Tsubota, Toshihide Kurihara
Purpose: The most common virus vector used in gene therapy research for ophthalmologic diseases is the adeno-associated virus (AAV) vector, which has been used successfully in a number of preclinical and clinical studies. It is important to evaluate novel AAV vectors in animal models for application of clinical gene therapy. The AAV-DJ (type 2/type 8/type 9 chimera) was engineered from shuffling eight different wild-type native viruses. In this study, we investigated the efficiency of gene transfer by AAV-DJ injections into the retina...
2019: PeerJ
Ala Moshiri, Rui Chen, Soohyun Kim, R Alan Harris, Yumei Li, Muthuswamy Raveendran, Sarah Davis, Qingnan Liang, Ori Pomerantz, Jun Wang, Laura Garzel, Ashley Cameron, Glenn Yiu, J Timothy Stout, Yijun Huang, Christopher J Murphy, Jeffrey Roberts, Kota N Gopalakrishna, Kimberly Boyd, Nikolai O Artemyev, Jeffrey Rogers, Sara M Thomasy
Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina...
January 22, 2019: Journal of Clinical Investigation
Si Hyung Lee, Jin Young Yang, Sanjar Madrakhimov, Ha Yan Park, Keerang Park, Tae Kwann Park
Adeno-associated viruses (AAVs) are currently the most popular vector platform technology for ocular gene therapy. While transduction efficiency and tropism of intravitreally administered AAV has been fairly well established in various retinal conditions, its transduction pattern in diabetic retinas has not previously been characterized. Here, we describe the transduction efficiencies of four different AAV serotypes, AAV2, 5, 8, and 9, in streptozotocin (STZ)-induced diabetic mouse retinas after intravitreal injections, which differed according to the duration of diabetic induction...
June 14, 2019: Molecular Therapy. Methods & Clinical Development
Edward H Wood, Peter H Tang, Irina De la Huerta, Edward Korot, Stephanie Muscat, Daniel A Palanker, George A Williams
PURPOSE: To review and discuss current innovations and future implications of promising biotechnology and biomedical offerings in the field of retina. We focus on therapies that have already emerged as clinical offerings or are poised to do so. METHODS: Literature review and commentary focusing on stem cell therapies, gene-based therapies, optogenetic therapies, and retinal prosthetic devices. RESULTS: The technologies discussed herein are some of the more recent promising biotechnology and biomedical developments within the field of retina...
January 16, 2019: Retina
Andrew Lloyd, Natalia Piglowska, Thomas Ciulla, Sarah Pitluck, Scott Johnson, Marric Buessing, Thomas O'Connell
BACKGROUND/AIMS: In rare diseases, health-related quality of life (HRQL) data can be difficult to capture. Given the ultrarare nature of RPE65 -mediated inherited retinal disease (IRD), it was not feasible to recruit a patient sample and collect HRQL data prospectively. The objectives of this study were to develop health state descriptions of RPE65 -mediated IRD, and to estimate associated patient utilities. METHODS: Vignette descriptions of IRD states were developed and then assessed to elicit utilities...
January 18, 2019: British Journal of Ophthalmology
Peter H Tang, Gabriel Velez, Stephen H Tsang, Alexander G Bassuk, Vinit B Mahajan
Purpose: To gain insight into the pathophysiology of vitreoretinal degeneration, the clinical course of three family members with Versican Vitreoretinopathy (VVR) is described, and a canonical splice site mutation in the gene encoding for versican (VCAN) protein was biochemically analyzed. Methods: A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed. Results: The proband (II:1), mother (I:2), and younger sibling (II:2) suffered retinal degeneration with foveal sparing and retinal detachments with proliferative vitreoretinopathy, features that were confirmed on histopathologic analysis...
January 2, 2019: Investigative Ophthalmology & Visual Science
Tuyen Ong, Mark E Pennesi, David G Birch, Byron L Lam, Stephen H Tsang
Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration...
January 7, 2019: Pharmaceutical Research
Yan Shao, Li-Jie Dong, Yusuke Takahashi, Jianglei Chen, Xun Liu, Qian Chen, Jian-Xing Ma, Xiao-Rong Li
PURPOSE: The purpose of this study was to explore the role of microRNA-451a (miR-451a) in diabetic retinopathy through activating transcription factor 2 (ATF2). METHODS: The epiretinal membrane samples from patients with proliferative diabetic retinopathy (PDR) were immunolabeled with an antibody for ki-67 to identify the proliferative cells. The expression of miR-451a was measured by qRT-PCR in the retina of Akita mice and in RPE cells under diabetic conditions...
December 21, 2018: American Journal of Physiology. Endocrinology and Metabolism
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
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