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Brunet AA, James RE, Swanson P, Carvalho LS. A review of the 661W cell line as a tool to facilitate treatment development for retinal diseases. Cell Biosci 2025; 15:41. [PMID: 40170180 PMCID: PMC11959731 DOI: 10.1186/s13578-025-01381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/23/2025] [Indexed: 04/03/2025] Open
Abstract
Retinal diseases encompass a diverse group of disorders that affect the structure and function of the retina, leading to visual impairment and, in some cases, irreversible vision loss. The investigation of retinal diseases is crucial for understanding their underlying mechanisms, identifying potential therapeutic targets, and developing effective treatments. The use of in vitro cell models has become instrumental in advancing our knowledge of these disorders, but given that these conditions usually affect retinal neuronal cell types, access to appropriate cell models can be potentially challenging. Among the available in vitro cell models, the 661W cone-like cell line has emerged as a valuable tool for studying various retinal diseases, ranging from monogenic conditions, such as inherited retinal diseases, to complex conditions such as age-related macular degeneration (AMD), diabetic retinopathy, amongst others. Developed from immortalized murine photoreceptor cells, and freely available for academics from its creator, the 661W cell line has offered visual scientists and clinicians around the world a reliable and well-characterised platform for investigating disease pathogenesis, exploring disease-specific molecular signatures, and evaluating potential therapeutic interventions. This review aims to provide an overview of the 661W cell line and its applications in the study of both inherited and acquired retinal diseases. By examining the applications and limitations of this unique cell line, we may gain valuable insights into its contributions in unravelling the complexities of retinal diseases and its potential impact on the development of novel treatments for these diseases.
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Affiliation(s)
- Alicia A Brunet
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, 6009, Australia
- Lions Eye Institute, 2 Verdun St, Nedlands, WA, 6009, Australia
| | - Rebekah E James
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, 6009, Australia
- Lions Eye Institute, 2 Verdun St, Nedlands, WA, 6009, Australia
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Petria Swanson
- Lions Eye Institute, 2 Verdun St, Nedlands, WA, 6009, Australia
- School of Biomedical Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Livia S Carvalho
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, 6009, Australia.
- Lions Eye Institute, 2 Verdun St, Nedlands, WA, 6009, Australia.
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, 3052, Australia.
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Luís MA, Goes MAD, Santos FM, Mesquita J, Tavares-Ratado P, Tomaz CT. Plasmid Gene Therapy for Monogenic Disorders: Challenges and Perspectives. Pharmaceutics 2025; 17:104. [PMID: 39861752 PMCID: PMC11768343 DOI: 10.3390/pharmaceutics17010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
Monogenic disorders are a group of human diseases caused by mutations in single genes. While some disease-altering treatments offer relief and slow the progression of certain conditions, the majority of monogenic disorders still lack effective therapies. In recent years, gene therapy has appeared as a promising approach for addressing genetic disorders. However, despite advancements in gene manipulation tools and delivery systems, several challenges remain unresolved, including inefficient delivery, lack of sustained expression, immunogenicity, toxicity, capacity limitations, genomic integration risks, and limited tissue specificity. This review provides an overview of the plasmid-based gene therapy techniques and delivery methods currently employed for monogenic diseases, highlighting the challenges they face and exploring potential strategies to overcome these barriers.
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Affiliation(s)
- Marco A. Luís
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- RISE-Health, Faculty of Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
- Departament of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal
| | - Marcelo A. D. Goes
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- RISE-Health, Faculty of Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
- Departament of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal
| | - Fátima Milhano Santos
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- RISE-Health, Faculty of Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
- Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD), Av. Reyes Católicos, 28040 Madrid, Spain
| | - Joana Mesquita
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- RISE-Health, Faculty of Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Paulo Tavares-Ratado
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
- Laboratory of Clinical Pathology, Sousa Martins Hospital, Unidade Local de Saúde (ULS) da Guarda, Av. Rainha D. Amélia, 6300-749 Guarda, Portugal
| | - Cândida Teixeira Tomaz
- CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; (M.A.L.); (M.A.D.G.); (F.M.S.); (J.M.); (P.T.-R.)
- RISE-Health, Faculty of Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
- Departament of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal
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Sorrentino FS, Di Terlizzi P, De Rosa F, Salati C, Spadea L, Gagliano C, Musa M, Zeppieri M. New frontiers in retinal transplantation. World J Transplant 2024; 14:97690. [PMID: 39697450 PMCID: PMC11438945 DOI: 10.5500/wjt.v14.i4.97690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells. Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells. Thus, the disruption of photoreceptors takes place. However, even in advanced forms of retinal degeneration, a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact. This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region. The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities. The eyeball's immunological privilege, characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues, is responsible for the low rate of graft rejection in transplant patients. The main discoveries highlight the capacity of embryonic stem cells (ESCs) and induced pluripotent stem cells to regenerate damaged retinal regions. Recent progress has shown significant enhancements in transplant procedures and results. The research also explores the ethical ramifications linked to the utilization of stem cells, emphasizing the ongoing issue surrounding ESCs. The analysis centers on recent breakthroughs, including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation. Moreover, researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation. The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location. Currently, most therapy approaches are in the first phases of development and necessitate further research, including both pre-clinical and clinical trials, to attain favorable visual results for individuals suffering from retinal degenerative illnesses.
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Affiliation(s)
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor, Onitsha 434112, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Jang MA, Lee JK, Park JH, Hwang S, Kim YG, Kim JW, Hong YJ, Kim SJ, Jang JH. Identification of diagnostic challenges in RP1 Alu insertion and strategies for overcoming them. Sci Rep 2024; 14:25119. [PMID: 39448676 PMCID: PMC11502683 DOI: 10.1038/s41598-024-76509-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024] Open
Abstract
Recently, a founder Alu insertion in exon 4 of RP1 was detected in Japanese and Korean patients with inherited retinal diseases (IRDs). However, carrier frequency and diagnostic challenges for detecting AluY insertion are not established. We aim to investigate the frequency of AluY in individuals with or without IRDs and to overcome common diagnostic pitfalls associated with AluY insertion. A total of 1,072 subjects comprising 411 patients with IRD (IRD group) and 661 patients with other suspected Mendelian genetic disease (non-IRD group) was screened for AluY insertion. Targeted panel sequencing and whole-genome sequencing were used for detection of AluY insertion, and an optimized allele-specific PCR (AS-PCR) was used for validation. The AluY insertion was detected in 1.5% in IRD group (6/411). The AluY insertion was not observed in non-IRD group (0/661). All patients with AluY were confirmed to have RP1 pathogenic variants on the paired allele. We identified AluY allele dropout leading to false homozygosity for c.4196del pathogenic variant in Sanger sequencing. The allelic relationship between variants of RP1 was accurately determined by AluY AS-PCR. Delineating diagnostic challenges of AluY insertion and strategies to avoid potential pitfalls could aid clinicians in an accurate molecular diagnosis for patients with IRD.
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Affiliation(s)
- Mi-Ae Jang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Kwon Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Ho Park
- Clinical Genome Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sungsoon Hwang
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Gon Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Won Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Youn-Ji Hong
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Jin Kim
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Ja-Hyun Jang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Kong Q, Han X, Cheng H, Liu J, Zhang H, Dong T, Chen J, So KF, Mi X, Xu Y, Tang S. Lycium barbarum glycopeptide (wolfberry extract) slows N-methyl-N-nitrosourea-induced degradation of photoreceptors. Neural Regen Res 2024; 19:2290-2298. [PMID: 38488563 PMCID: PMC11034605 DOI: 10.4103/1673-5374.390958] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2023] [Accepted: 09/16/2023] [Indexed: 04/24/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202410000-00030/figure1/v/2024-02-06T055622Z/r/image-tiff Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum (L. barbarum) polysaccharide (LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide (LbGP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of LbGP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of LbGP as a protective pre-treatment on days 1-7; intraperitoneal administration of 40 mg/kg N-methyl-N-nitrosourea to induce photoreceptor injury on day 7; and continuation of orally administered LbGP on days 8-14. Treatment with LbGP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. LbGP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, LbGP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.
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Affiliation(s)
- Qihang Kong
- Department of Ophthalmology, Aier Eye Hospital, Jinan University, Guangzhou, Guangdong Province, China
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Xiu Han
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, Guangdong Province, China
| | - Haiyang Cheng
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, Guangdong Province, China
| | - Jiayu Liu
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Huijun Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
- Department of Ophthalmology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong Province, China
| | - Tangrong Dong
- School of Stomatology, Jinan University, Guangzhou, Guangdong Province, China
| | - Jiansu Chen
- Department of Ophthalmology, Aier Eye Hospital, Jinan University, Guangzhou, Guangdong Province, China
- Aier Academician Station, Changsha, Hunan Province, China
| | - Kwok-Fai So
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, Guangdong Province, China
- Aier Academician Station, Changsha, Hunan Province, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
- State Key Laboratory of Brain and Cognitive Sciences, Hong Kong Special Administrative Region, China
| | - Xuesong Mi
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
- Aier Academician Station, Changsha, Hunan Province, China
| | - Ying Xu
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, Guangdong Province, China
- Aier Academician Station, Changsha, Hunan Province, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Shibo Tang
- Department of Ophthalmology, Aier Eye Hospital, Jinan University, Guangzhou, Guangdong Province, China
- Aier Academician Station, Changsha, Hunan Province, China
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Gowda DAA, Birappa G, Rajkumar S, Ajaykumar CB, Srikanth B, Kim SL, Singh V, Jayachandran A, Lee J, Ramakrishna S. Recent progress in CRISPR/Cas9 system for eye disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 210:21-46. [PMID: 39824582 DOI: 10.1016/bs.pmbts.2024.07.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2025]
Abstract
Ocular disorders encompass a broad spectrum of phenotypic and clinical symptoms resulting from several genetic variants and environmental factors. The unique anatomy and physiology of the eye facilitate validation of cutting-edge gene editing treatments. Genome editing developments have allowed researchers to treat a variety of diseases, including ocular disorders. The clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system holds considerable promise for therapeutic applications in the field of ophthalmology, including repair of aberrant genes and treatment of retinal illnesses related to the genome or epigenome. Application of CRISPR/Cas9 systems to the study of ocular disease and visual sciences have yielded innovations including correction of harmful mutations in patient-derived cells and gene modifications in several mammalian models of eye development and disease. In this study, we discuss the generation of several ocular disease models in mammalian cell lines and in vivo systems using a CRISPR/Cas9 system. We also provide an overview of current uses of CRISPR/Cas9 technologies for the treatment of ocular pathologies, as well as future challenges.
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Affiliation(s)
- D A Ayush Gowda
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Girish Birappa
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Sripriya Rajkumar
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - C Bindu Ajaykumar
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | | | - Sammy L Kim
- Department of Biological Science, College of Sang-Huh Life Science, Department of Biological Science, Konkuk University, Seoul, South Korea
| | - Vijai Singh
- Department of Biosciences, School of Science, Indrashil University, Rajpur, Mehsana, Gujarat, India
| | - Aparna Jayachandran
- Fiona Elsey Cancer Research Institute, VIC, Australia; Federation University, VIC, Australia.
| | - Junwon Lee
- Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul, South Korea.
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Lima Barrientos J, Rojas Huerta A, Perez Mendoza A, Abreu Lopez BA, Salolin Vargas VP, Garcia Gonzalez OY, Saldaña Ruiz MA, Diarte E, Torijano Sarria AJ. The Relationship Between Gut Microbiome and Ophthalmologic Diseases: A Comprehensive Review. Cureus 2024; 16:e66808. [PMID: 39280427 PMCID: PMC11392598 DOI: 10.7759/cureus.66808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/18/2024] Open
Abstract
The gut microbiome has been studied in recent years due to its association with various pathological pathways involved in different diseases, caused by its structure, function, and diversity alteration. The knowledge of this mechanism has generated interest in the investigation of its relationship with ophthalmologic diseases. Recent studies infer the existence of a gut-eye microbiota axis, influenced by the intestinal barrier, the blood-retina barrier, and the immune privilege of the eye. A common denominator among ophthalmologic diseases that have been related to this axis is inflammation, which is perpetuated by dysbiosis, causing an alteration of the intestinal barrier leading to increased permeability and, in turn, the release of components such as lipopolysaccharides (LPS), trimethylamine oxide (TMAO), and bacterial translocation. Some theories explain that depending on how the microbiome is composed, a different type of T cells will be activated, while others say that some bacteria can pre-activate T cells that mimic ocular structures and intestinal permeability that allow leakage of metabolites into the circulation. In addition, therapies such as probiotics, diet, and fecal microbiota transplantation (FMT) have been shown to favor the presence of a balanced population of microorganisms that limit inflammation and, in turn, generate a beneficial effect in these eye pathologies. This review aims to analyze how the intestinal microbiome influences various ocular pathologies based on microbial composition and pathological mechanisms, which may provide a better understanding of the diseases and their therapeutic potential.
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Affiliation(s)
| | - Anahi Rojas Huerta
- General Practice, Benemérita Universidad Autónoma de Puebla, Puebla, MEX
| | | | | | | | | | | | - Edna Diarte
- Medicine, Universidad Autónoma de Sinaloa, Culiacan, MEX
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Wu Y, Li X, Fu X, Huang X, Zhang S, Zhao N, Ma X, Saiding Q, Yang M, Tao W, Zhou X, Huang J. Innovative Nanotechnology in Drug Delivery Systems for Advanced Treatment of Posterior Segment Ocular Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403399. [PMID: 39031809 PMCID: PMC11348104 DOI: 10.1002/advs.202403399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/29/2024] [Indexed: 07/22/2024]
Abstract
Funduscopic diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), significantly impact global visual health, leading to impaired vision and irreversible blindness. Delivering drugs to the posterior segment of the eye remains a challenge due to the presence of multiple physiological and anatomical barriers. Conventional drug delivery methods often prove ineffective and may cause side effects. Nanomaterials, characterized by their small size, large surface area, tunable properties, and biocompatibility, enhance the permeability, stability, and targeting of drugs. Ocular nanomaterials encompass a wide range, including lipid nanomaterials, polymer nanomaterials, metal nanomaterials, carbon nanomaterials, quantum dot nanomaterials, and so on. These innovative materials, often combined with hydrogels and exosomes, are engineered to address multiple mechanisms, including macrophage polarization, reactive oxygen species (ROS) scavenging, and anti-vascular endothelial growth factor (VEGF). Compared to conventional modalities, nanomedicines achieve regulated and sustained delivery, reduced administration frequency, prolonged drug action, and minimized side effects. This study delves into the obstacles encountered in drug delivery to the posterior segment and highlights the progress facilitated by nanomedicine. Prospectively, these findings pave the way for next-generation ocular drug delivery systems and deeper clinical research, aiming to refine treatments, alleviate the burden on patients, and ultimately improve visual health globally.
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Affiliation(s)
- Yue Wu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xin Li
- Wenzhou Medical UniversityWenzhouZhejiang325035China
| | - Xueyu Fu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xiaomin Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | | | - Nan Zhao
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xiaowei Ma
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Qimanguli Saiding
- Center for Nanomedicine and Department of AnesthesiologyBrigham and Women's Hospital, Harvard Medical SchoolBostonMA02115USA
| | - Mei Yang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Wei Tao
- Center for Nanomedicine and Department of AnesthesiologyBrigham and Women's Hospital, Harvard Medical SchoolBostonMA02115USA
| | - Xingtao Zhou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Jinhai Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
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Berneshawi AR, Seyedmadani K, Goel R, Anderson MR, Tyson TL, Akay YM, Akay M, Leung LSB, Stone LS. Oculometric biomarkers of visuomotor deficits in clinically asymptomatic patients with systemic lupus erythematosus undergoing long-term hydroxychloroquine treatment. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1354892. [PMID: 39104603 PMCID: PMC11298511 DOI: 10.3389/fopht.2024.1354892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 05/10/2024] [Indexed: 08/07/2024]
Abstract
Introduction This study examines a set of oculomotor measurements, or "oculometric" biomarkers, as potential early indicators of visual and visuomotor deficits due to retinal toxicity in asymptomatic Systemic Lupus Erythematosus (SLE) patients on long-term hydroxychloroquine (HCQ) treatment. The aim is to identify subclinical functional impairments that are otherwise undetectable by standard clinical tests and to link them to structural retinal changes. Methods We measured oculomotor responses in a cohort of SLE patients on chronic HCQ therapy using a previously established behavioral task and analysis technique. We also examined the relationship between oculometrics, OCT measures of retinal thickness, and standard clinical perimetry measures of visual function in our patient group using Bivariate Pearson Correlation and a Linear Mixed-Effects Model (LMM). Results Significant visual and visuomotor deficits were found in 12 asymptomatic SLE patients on long-term HCQ therapy compared to a cohort of 17 age-matched healthy controls. Notably, six oculometrics were significantly different. The median initial pursuit acceleration was 22%, steady-state pursuit gain 16%, proportion smooth 7%, and target speed responsiveness 31% lower, while catch-up saccade amplitude was 46% and fixation error 46% larger. Excluding the two patients with diagnosed mild toxicity, four oculometrics, all but fixation error and proportion smooth, remained significantly impaired compared to controls. Across our population of 12 patients (24 retinae), we found that pursuit latency, initial acceleration, steady-state gain, and fixation error were linearly related to retinal thickness even when age was accounted for, while standard measures of clinical function (Mean Deviation and Pattern Standard Deviation) were not. Discussion Our data show that specific oculometrics are sensitive early biomarkers of functional deficits in SLE patients on HCQ that could be harnessed to assist in the early detection of HCQ-induced retinal toxicity and other visual pathologies, potentially providing early diagnostic value beyond standard visual field and OCT evaluations.
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Affiliation(s)
- Andrew R. Berneshawi
- Ophthalmology Department, Stanford University School of Medicine, Stanford, CA, United States
| | - Kimia Seyedmadani
- Research Operations and Integration Laboratory, Johnson Space Center, National Aeronautics and Space Administration, Houston, TX, United States
- Biomedical Engineering Department, University of Houston, Houston, TX, United States
| | - Rahul Goel
- San Jose State University Foundation, San Jose, CA, United States
- Human Systems Integration Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field, CA, United States
| | - Mark R. Anderson
- Human Systems Integration Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field, CA, United States
- Arctic Slope Regional Corporation (ASRC) Federal Data Solutions, Moffett Field, CA, United States
| | - Terence L. Tyson
- Human Systems Integration Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field, CA, United States
| | - Yasmin M. Akay
- Biomedical Engineering Department, University of Houston, Houston, TX, United States
| | - Metin Akay
- Biomedical Engineering Department, University of Houston, Houston, TX, United States
| | - Loh-Shan B. Leung
- Ophthalmology Department, Stanford University School of Medicine, Stanford, CA, United States
| | - Leland S. Stone
- Human Systems Integration Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field, CA, United States
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10
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Paredes DI, Bello NR, Capasso JE, Procopio R, Levin AV. Mutations in AGBL5 associated with Retinitis pigmentosa. Ophthalmic Genet 2024; 45:275-280. [PMID: 38078364 DOI: 10.1080/13816810.2023.2291687] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 11/30/2023] [Accepted: 11/30/2023] [Indexed: 08/09/2024]
Abstract
BACKGROUND Retinitis pigmentosa (RP) is the leading cause of heritable retinal visual impairment. Clinically, it is characterized by a variable onset of progressive night blindness and visual field constriction. RP is characterized by wide genetic heterogeneity with a broad range of potential genes involved in the genesis of this disease. Very few cases have been reported of RP due to pathogenic variants in AGBL5. MATERIALS AND METHODS We report two patients with RP and bilallelic pathogenic variants in AGBL5. RESULTS Genetic sequencing showed one homozygous AGBL5 missense variant in one patient and a homozygous nonsense variant in the other. These patients presented with progressive peripheral vision loss and nyctalopia. Their RP phenotypes were similar to previous reports in literature. CONCLUSION These two cases provide further evidence regarding the relationship of pathogenic variants in AGBL5 as a cause of autosomal recessive RP.
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Affiliation(s)
- Diego I Paredes
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, Rochester, New York, USA
- Departamento de Oftalmologia, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago de Chile, Chile
| | - Nicholas R Bello
- Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
| | - Jenina E Capasso
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, Rochester, New York, USA
| | - Rebecca Procopio
- Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
| | - Alex V Levin
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, Rochester, New York, USA
- Clinical Genetics, Golisano Children's Hospital, University of Rochester, Rochester, New York, USA
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11
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Chen X, Zhang S, Yang L, Kong Q, Zhang W, Zhang J, Hao X, So KF, Xu Y. Zeaxanthin dipalmitate-enriched wolfberry extract improves vision in a mouse model of photoreceptor degeneration. PLoS One 2024; 19:e0302742. [PMID: 38768144 PMCID: PMC11104671 DOI: 10.1371/journal.pone.0302742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 04/11/2024] [Indexed: 05/22/2024] Open
Abstract
Zeaxanthin dipalmitate (ZD) is a chemical extracted from wolfberry that protects degenerated photoreceptors in mouse retina. However, the pure ZD is expensive and hard to produce. In this study, we developed a method to enrich ZD from wolfberry on a production line and examined whether it may also protect the degenerated mouse retina. The ZD-enriched wolfberry extract (ZDE) was extracted from wolfberry by organic solvent method, and the concentration of ZD was identified by HPLC. The adult C57BL/6 mice were treated with ZDE or solvent by daily gavage for 2 weeks, at the end of the first week the animals were intraperitoneally injected with N-methyl-N-nitrosourea to induce photoreceptor degeneration. Then optomotor, electroretinogram, and immunostaining were used to test the visual behavior, retinal light responses, and structure. The final ZDE product contained ~30mg/g ZD, which was over 9 times higher than that from the dry fruit of wolfberry. Feeding degenerated mice with ZDE significantly improved the survival of photoreceptors, enhanced the retinal light responses and the visual acuity. Therefore, our ZDE product successfully alleviated retinal morphological and functional degeneration in mouse retina, which may provide a basis for further animal studies for possible applying ZDE as a supplement to treat degenerated photoreceptor in the clinic.
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Affiliation(s)
- Xiongmin Chen
- Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Non-Human Primate Research, Jinan University, Guangzhou, Guangdong Province, China
| | - Sensen Zhang
- Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Non-Human Primate Research, Jinan University, Guangzhou, Guangdong Province, China
| | - Lili Yang
- Bairuiyuan Gouqi Corp., Yinchuan, Ningxia Province, China
| | - Qihang Kong
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Wenhua Zhang
- Bairuiyuan Gouqi Corp., Yinchuan, Ningxia Province, China
| | - Jinhong Zhang
- Bairuiyuan Gouqi Corp., Yinchuan, Ningxia Province, China
| | - Xiangfeng Hao
- Bairuiyuan Gouqi Corp., Yinchuan, Ningxia Province, China
| | - Kwok-Fai So
- Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Non-Human Primate Research, Jinan University, Guangzhou, Guangdong Province, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
- State Key Laboratory of Brain and Cognitive Sciences, Hong Kong Special Administrative Region, Hong Kong, China
| | - Ying Xu
- Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Non-Human Primate Research, Jinan University, Guangzhou, Guangdong Province, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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12
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Lozano B LL, Cervantes A LA. Development of experimental treatments for patients with retinitis pigmentosa. ARCHIVOS DE LA SOCIEDAD ESPANOLA DE OFTALMOLOGIA 2023; 98:646-655. [PMID: 37640142 DOI: 10.1016/j.oftale.2023.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023]
Abstract
Retinitis pigmentosa (RP) is a group of inherited diseases that lead to degeneration of the retina and decreased vision. The World Health Organization reports around 1,300 million people affected by some type of visual impairment worldwide. The prevalence is 1 in every 4000 inhabitants and it is the first cause of blindness of genetic origin, frequent in men with a percentage of 60% and 40% in women. There is a lack of information on this pathology in the world, mainly on the existing treatments for this disease, so this bibliographic review aims to update the existing or under-study treatments and inform the limitations of each of these therapies. This review of scientific literature was carried out by consulting databases such as PubMed and Web of science, the search will be limited to articles from the years 2018-2022. There are several types of therapy in studies: gene therapy, transcorneal electrical stimulation, use of neuroprotectors, optogenic therapy, stem cell transplants and oligonucleotide therapy, which will be discussed in this article, both their benefits and the existing barriers in each treatment experimental. In conclusion, each of these therapies promises a viable treatment in the future for selective groups of people with retinitis pigmentosa, however, some therapies have shown benefit at the beginning of the disease, losing their efficacy in the long term.
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Affiliation(s)
- L L Lozano B
- Universidad Católica de Cuenca, Cuenca, Ecuador.
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13
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Sundaresan Y, Yacoub S, Kodati B, Amankwa CE, Raola A, Zode G. Therapeutic applications of CRISPR/Cas9 gene editing technology for the treatment of ocular diseases. FEBS J 2023; 290:5248-5269. [PMID: 36877952 PMCID: PMC10480348 DOI: 10.1111/febs.16771] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 02/04/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023]
Abstract
Ocular diseases are a highly heterogeneous group of phenotypes, caused by a spectrum of genetic variants and environmental factors that exhibit diverse clinical symptoms. As a result of its anatomical location, structure and immune privilege, the eye is an ideal system to assess and validate novel genetic therapies. Advances in genome editing have revolutionized the field of biomedical science, enabling researchers to understand the biology behind disease mechanisms and allow the treatment of several health conditions, including ocular pathologies. The advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing facilitates efficient and specific genetic modifications in the nucleic acid sequence, resulting in permanent changes at the genomic level. This approach has advantages over other treatment strategies and is promising for the treatment of various genetic and non-genetic ocular conditions. This review provides an overview of the CRISPR/CRISPR-associated protein 9 (Cas9) system and summarizes recent advances in the therapeutic application of CRISPR/Cas9 for the treatment of various ocular pathologies, as well as future challenges.
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Affiliation(s)
| | | | - Bindu Kodati
- Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107
| | - Charles E. Amankwa
- Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107
| | - Akash Raola
- Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107
| | - Gulab Zode
- Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107
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14
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Gonzalez Calle A, Paknahad J, Pollalis D, Kosta P, Thomas B, Tew BY, Salhia B, Louie S, Lazzi G, Humayun M. An extraocular electrical stimulation approach to slow down the progression of retinal degeneration in an animal model. Sci Rep 2023; 13:15924. [PMID: 37741821 PMCID: PMC10517961 DOI: 10.1038/s41598-023-40547-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/12/2023] [Indexed: 09/25/2023] Open
Abstract
Retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are characterized by unrelenting neuronal death. However, electrical stimulation has been shown to induce neuroprotective changes in the retina capable of slowing down the progression of retinal blindness. In this work, a multi-scale computational model and modeling platform were used to design electrical stimulation strategies to better target the bipolar cells (BCs), that along with photoreceptors are affected at the early stage of retinal degenerative diseases. Our computational findings revealed that biphasic stimulus pulses of long pulse duration could decrease the activation threshold of BCs, and the differential stimulus threshold between ganglion cells (RGCs) and BCs, offering the potential of targeting the BCs during the early phase of degeneration. In vivo experiments were performed to evaluate the electrode placement and parameters found to target bipolar cells and evaluate the safety and efficacy of the treatment. Results indicate that the proposed transcorneal Electrical Stimulation (TES) strategy can attenuate retinal degeneration in a Royal College of Surgeon (RCS) rodent model, offering the potential to translate this work to clinical practice.
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Affiliation(s)
- Alejandra Gonzalez Calle
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
| | - Javad Paknahad
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Institute for Technology and Medical Systems Innovation, Los Angeles, CA, 90033, USA
| | - Dimitrios Pollalis
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
| | - Pragya Kosta
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Institute for Technology and Medical Systems Innovation, Los Angeles, CA, 90033, USA
| | - Biju Thomas
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
| | - Ben Yi Tew
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Bodour Salhia
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Stan Louie
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Gianluca Lazzi
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA
- USC Institute for Technology and Medical Systems Innovation, Los Angeles, CA, 90033, USA
| | - Mark Humayun
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
- USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, 90033, USA.
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15
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Díaz-Lezama N, Kajtna J, Wu J, Ayten M, Koch SF. Microglial and macroglial dynamics in a model of retinitis pigmentosa. Vision Res 2023; 210:108268. [PMID: 37295269 DOI: 10.1016/j.visres.2023.108268] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 05/12/2023] [Accepted: 05/12/2023] [Indexed: 06/12/2023]
Abstract
In retinal degenerative diseases, such as retinitis pigmentosa (RP), the characteristic photoreceptor cell death is associated with changes of microglia and macroglia cells. Gene therapy, a promising treatment option for RP, is based on the premise that glial cell remodeling does not impact vision rescue. However, the dynamics of glial cells after treatment at late disease stages are not well understood. Here, we tested the reversibility of specific RP glia phenotypes in a Pde6b-deficient RP gene therapy mouse model. We demonstrated an increased number of activated microglia, retraction of microglial processes, reactive gliosis of Müller cells, astrocyte remodelling and an upregulation of glial fibrillary acidic protein (GFAP) in response to photoreceptor degeneration. Importantly, these changes returned to normal following rod rescue at late disease stages. These results suggest that therapeutic approaches restore the homeostasis between photoreceptors and glial cells.
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Affiliation(s)
- Nundehui Díaz-Lezama
- Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Jacqueline Kajtna
- Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Jiou Wu
- Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Monika Ayten
- Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Susanne F Koch
- Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
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16
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Gao TT, Oh T, Mehta K, Huang YA, Camp T, Fan H, Han JW, Barnes CM, Zhang K. The clinical potential of optogenetic interrogation of pathogenesis. Clin Transl Med 2023; 13:e1243. [PMID: 37132114 PMCID: PMC10154842 DOI: 10.1002/ctm2.1243] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/05/2023] [Accepted: 04/13/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Opsin-based optogenetics has emerged as a powerful biomedical tool using light to control protein conformation. Such capacity has been initially demonstrated to control ion flow across the cell membrane, enabling precise control of action potential in excitable cells such as neurons or muscle cells. Further advancement in optogenetics incorporates a greater variety of photoactivatable proteins and results in flexible control of biological processes, such as gene expression and signal transduction, with commonly employed light sources such as LEDs or lasers in optical microscopy. Blessed by the precise genetic targeting specificity and superior spatiotemporal resolution, optogenetics offers new biological insights into physiological and pathological mechanisms underlying health and diseases. Recently, its clinical potential has started to be capitalized, particularly for blindness treatment, due to the convenient light delivery into the eye. AIMS AND METHODS This work summarizes the progress of current clinical trials and provides a brief overview of basic structures and photophysics of commonly used photoactivable proteins. We highlight recent achievements such as optogenetic control of the chimeric antigen receptor, CRISPR-Cas system, gene expression, and organelle dynamics. We discuss conceptual innovation and technical challenges faced by current optogenetic research. CONCLUSION In doing so, we provide a framework that showcases ever-growing applications of optogenetics in biomedical research and may inform novel precise medicine strategies based on this enabling technology.
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Affiliation(s)
- Tianyu Terry Gao
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Teak‐Jung Oh
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Kritika Mehta
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Yu‐En Andrew Huang
- University of Illinois at Urbana‐ChampaignCenter for Biophysics and Quantitative BiologyUrbanaIllinoisUSA
| | - Tyler Camp
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Huaxun Fan
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Jeong Won Han
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Collin Michael Barnes
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
| | - Kai Zhang
- University of Illinois at Urbana‐ChampaignDepartment of BiochemistryUrbanaIllinoisUSA
- University of Illinois at Urbana‐ChampaignCenter for Biophysics and Quantitative BiologyUrbanaIllinoisUSA
- Cancer Center at IllinoisUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
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17
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Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of monogenic intestinal epithelial disorders. Hum Genet 2023; 142:613-654. [PMID: 36422736 PMCID: PMC10182130 DOI: 10.1007/s00439-022-02501-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/23/2022] [Indexed: 11/27/2022]
Abstract
Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.
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Affiliation(s)
- Stephen J Babcock
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - David Flores-Marin
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Jay R Thiagarajah
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA.
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Yamoah A, Tripathi P, Guo H, Scheve L, Walter P, Johnen S, Müller F, Weis J, Goswami A. Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the rd10 Mouse Model of Retinitis Pigmentosa (RP). Cells 2023; 12:cells12071094. [PMID: 37048167 PMCID: PMC10092976 DOI: 10.3390/cells12071094] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 04/14/2023] Open
Abstract
The retinal degeneration 10 (rd10) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated Pde6b gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the Pde6b gene defect. We used a combination of immunohistochemistry (DAB, immunofluorescence), electron microscopy (EM), subcellular fractionation, and Western blot analysis on the retinal preparations obtained from both rd10 and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca2+) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca2+ buffering proteins in both photoreceptors and non-photoreceptor neuronal cells before any noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of the autophagy proteins p62 and LC3, together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs including pTDP-43 and FET family RBPs and stress granule formation. We conclude that progressive neurodegeneration in the rd10 mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation.
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Affiliation(s)
- Alfred Yamoah
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
- EURON-European Graduate School of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Priyanka Tripathi
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
- EURON-European Graduate School of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Haihong Guo
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Leonie Scheve
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Peter Walter
- Department of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Sandra Johnen
- Department of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Frank Müller
- Institute of Biological Information Processing, Molecular and Cellular Physiology, IBI-1, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
| | - Joachim Weis
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Anand Goswami
- Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
- Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
- Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY 10032, USA
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19
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Wu KY, Kulbay M, Toameh D, Xu AQ, Kalevar A, Tran SD. Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development. Pharmaceutics 2023; 15:685. [PMID: 36840007 PMCID: PMC9963330 DOI: 10.3390/pharmaceutics15020685] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/19/2023] Open
Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.
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Affiliation(s)
- Kevin Y. Wu
- Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Merve Kulbay
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Dana Toameh
- Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
| | - An Qi Xu
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Ananda Kalevar
- Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges. Cells 2023; 12:cells12040617. [PMID: 36831285 PMCID: PMC9954064 DOI: 10.3390/cells12040617] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additionally, we discuss challenges in overcoming the reported eye toxicity of some MAPK inhibitors.
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21
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Murenu E, Gerhardt MJ, Biel M, Michalakis S. More than meets the eye: The role of microglia in healthy and diseased retina. Front Immunol 2022; 13:1006897. [PMID: 36524119 PMCID: PMC9745050 DOI: 10.3389/fimmu.2022.1006897] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/11/2022] [Indexed: 11/30/2022] Open
Abstract
Microglia are the main resident immune cells of the nervous system and as such they are involved in multiple roles ranging from tissue homeostasis to response to insults and circuit refinement. While most knowledge about microglia comes from brain studies, some mechanisms have been confirmed for microglia cells in the retina, the light-sensing compartment of the eye responsible for initial processing of visual information. However, several key pieces of this puzzle are still unaccounted for, as the characterization of retinal microglia has long been hindered by the reduced population size within the retina as well as the previous lack of technologies enabling single-cell analyses. Accumulating evidence indicates that the same cell type may harbor a high degree of transcriptional, morphological and functional differences depending on its location within the central nervous system. Thus, studying the roles and signatures adopted specifically by microglia in the retina has become increasingly important. Here, we review the current understanding of retinal microglia cells in physiology and in disease, with particular emphasis on newly discovered mechanisms and future research directions.
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Affiliation(s)
- Elisa Murenu
- Department of Ophthalmology, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany,*Correspondence: Elisa Murenu, ; ; Stylianos Michalakis,
| | | | - Martin Biel
- Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Stylianos Michalakis
- Department of Ophthalmology, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany,*Correspondence: Elisa Murenu, ; ; Stylianos Michalakis,
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22
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Liu F, Zhang M, Xiong G, Han X, Lee VWH, So KF, Chiu K, Xu Y. Trans-Sclera Electrical Stimulation Improves Retinal Function in a Mouse Model of Retinitis Pigmentosa. Life (Basel) 2022; 12:1917. [PMID: 36431052 PMCID: PMC9693292 DOI: 10.3390/life12111917] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/12/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Retinitis pigmentosa (RP) is a photoreceptor-degenerating disease with no effective treatment. Trans-corneal electrical stimulation has neuroprotective effects in degenerating retinas, but repeated applications cause corneal injury. To avoid the risk of corneal damage, here we tested whether repetitive trans-sclera electrical stimulation (TsES) protects degenerating retinas in rd10 mice, a model of RP. At postnatal day 20 (P20), the right eyes of rd10 mice were exposed to 30 min of TsES daily or every other day till P25, at the amplitude of 50 or 100 μA, with zero current as the sham. Immunostaining, multi-electrode-array (MEA) recording, and a black-and-white transition box were applied to examine the morphological and functional changes of the treated retina. Functionally, TsES modified the retinal light responses. It also reduced the high spontaneous firing of retinal ganglion cells. TsES at 100 μA but not 50 μA increased the light sensitivities of ganglion cells as well as their signal-to-noise ratios. TsES at 100 μA increased the survival of photoreceptors without improving the visual behavior of rd10 mice. Our data suggest that repetitive TsES improves the retinal function of rd10 mice at the early degenerating stage, therefore, it might be an effective long-term strategy to delay retinal degeneration in RP patients.
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Affiliation(s)
- Feng Liu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, 601 West Huangpu Ave., Guangzhou 510632, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Mengrong Zhang
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, 601 West Huangpu Ave., Guangzhou 510632, China
| | - Guoyin Xiong
- Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, China
| | - Xiu Han
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, 601 West Huangpu Ave., Guangzhou 510632, China
| | | | - Kwok-Fai So
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, 601 West Huangpu Ave., Guangzhou 510632, China
- Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China
- The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China
- Department of Psychology, The University of Hong Kong, Hong Kong SAR, China
| | - Kin Chiu
- Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, China
- The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China
- Department of Psychology, The University of Hong Kong, Hong Kong SAR, China
| | - Ying Xu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, 601 West Huangpu Ave., Guangzhou 510632, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China
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Xiao X, Ling F, Chen CB, Liang J, Cao Y, Xu Y, Chen H. PRPF31 interacts with PRPH2 confirmed by co-immunoprecipitation and co-localization. Biochem Biophys Res Commun 2022; 629:12-16. [PMID: 36088804 DOI: 10.1016/j.bbrc.2022.08.090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/22/2022] [Accepted: 08/30/2022] [Indexed: 11/02/2022]
Abstract
Both PRPF31 and PRPH2 are the causative genes for retinitis pigmentosa. And both of them are associated with the balance of rhodopsin. In this study, we aim to investigate the co-expression and interaction of PRPF31 and PRPH2. We used PRPF31-eGFP, PRPF31-3xFlag and PRPH2-mCherry vectors were transfected into HEK293T and APRE-19 cells. Immunoblotting and co-immunoprecipitation (Co-IP) were used for gene expression validation and protein interaction. Immunofluorescence staining assay was used to test the co-localization analysis of PRPF31 and PRPH2. Co-IP experiments showed that PRPF31 could be pulled down with an anti-PRPH2 antibody. There was co-localization between PRPF31 and PRPH2 in HEK293T, APRE-19 and mouse retina. The Co-IP and co-localization experiments suggest that PRPF31 interacted with PRPH2.
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Affiliation(s)
- Xiaoqiang Xiao
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Fangyi Ling
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Chong-Bo Chen
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Jiajian Liang
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Yingjie Cao
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Yanxuan Xu
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
| | - Haoyu Chen
- Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
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24
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Leong YC, Di Foggia V, Pramod H, Bitner-Glindzicz M, Patel A, Sowden JC. Molecular pathology of Usher 1B patient-derived retinal organoids at single cell resolution. Stem Cell Reports 2022; 17:2421-2437. [DOI: 10.1016/j.stemcr.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/08/2022] Open
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Retinitis Pigmentosa'nın Genetik ve Klinik Değerlendirilmesi. JOURNAL OF CONTEMPORARY MEDICINE 2022. [DOI: 10.16899/jcm.1131536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: The aim of this study was to evaluate the most common underlying genetic and clinical etiologies of retinitis pigmentosa (RP) disease in our geographical area.
Material and Method: In our archive, there are about 3000 patients who applied to our clinic between the years 2015-2021. The files of approximately 700 patients with a definitive genetic diagnosis were retrospectively scanned. A definitive genetic diagnosis was made in 22 of these patients. During our research, we collected some clinical parameters including the prenatal, natal, and postnatal history of the patients, history of surgery and seizures, and family history. In family history, we did a detailed pedigree with at least 3 generational analyses, questioned parental kinship, looked for similar members in families, and identified inheritance patterns of their disorder. We draw 3 generations pedigree and we collected peripheral venous blood samples from patients and sent them to a commercial lab for gene panels or WES. After obtaining the definitive genetic diagnosis of all patients, we compiled a table with the other parameters we questioned.
Results: As a result of our WES analysis in patients 1 and 2, homozygous c.1331_1332 dupAG/p. Thr445ArgfsTer10 Class 2 variant was detected in the POC1B gene of patient #2.In the RP panel 1 reports of patients 3 and 4, the genomic alteration of c.2254dupA (p.Ser752Lysfs*14) was detected in exon 15 of the ABCA4 (NM_000350) gene. Patient 5, EYS c.4964T>C heterozygous. Patient 6. SEMA4A C.1168A>G (heterozygous). Patient 7, SEMA4A C.1168A>G (heterozygous), RP1 c.5402C>T (heterozygous), CGNB1 c.1382C>T (heterozygous).Patient #8, . Heterozygous variation of p.Thr390Ala (c.1168A>G) in the SEMA4A gene is present.As a result of our WES analysis, a homozygous c.2021C>A/p.Pro674His Class 2 variant was detected in the RPGRIP1 gene of patient #9. Heterozygous c.119-2A>C Class 1 mutation was detected in the NR2E3 gene of patient 10. Homozygous c.271C>T/p.Gln91* Class 1 mutation was detected in the MFRP gene in patient 11. Patient #12 was diagnosed at the age of 7-8 years. When we look at the exome sequencing results, a homozygous mutation in the CNGB1 gene c.413-1G> of patient 13 was detected. Heterozygous p.Ser361Tyr (c.1082C>A) change detected in the ABCA4 gene of patient #14 was detected. The heterozygous p.Glu150Lys (c.448G>A) change detected in the RHO gene of patient #15 was pathogenic according to ClinVar database and in silico analysis. rated as. Prediagnosis was Bardet-Biedle Syndrome in patient 16. P.Gly244Asp change was detected in RPE65 gene of patients 17 and 18. Automated DNA sequencing of patient #19 and patient #20 results in a homozygous sequence variation in the coding sequence of the NR2E3 genes, a homozygous CGG>CAG nucleotide substitution, and an amino acid replacement of Arg311Gln. Heterozygous mutation was detected in the same gene region in patient 21 (fathers). Variation in NR2E3 is the most likely cause of these patients' eye condition, as it is a complete genotype and is strongly associated with RP in many published families. Genetic results on an allele of the BBS1 gene of patient 22 (chr11:66.278.121-66.291.364 (13.2kb)/ISCN: seq [GRCH37]11q13.2(66.278).121-66.291.364)x1). The other allele has a heterozygous point mutation (c.1424dupT p.Ser476fs-rs886039798).
Conclusıons: As determined in our study, the disease can be encountered with many different genetic etiologies. In this regard, patients undergoing genetic testing should be carefully examined for both SNP (single nucleotide polymorphism) and CNV (copy number variation).In addition, before genetic tests are performed, it should be well determined whether there is an isolated RP or an accompanying RP. In this respect, patients should be evaluated by making a detailed anamnesis and physical examination and drawing a pedigree containing at least 3 generations. Therefore, it was concluded that accompanying abnormalities should also be examined in the evaluation of retinitis pigmentosa anomalies.
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Wang H, Ouyang W, Liu Y, Zhang M, Zhao H, Wang J, Yin Z. Visual task-related functional and structural magnetic resonance imaging for the objective quantitation of visual function in patients with advanced retinitis pigmentosa. Front Aging Neurosci 2022; 14:825204. [PMID: 36034150 PMCID: PMC9416479 DOI: 10.3389/fnagi.2022.825204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 06/28/2022] [Indexed: 11/22/2022] Open
Abstract
Purpose The objective quantitation of visual function in patients with advanced retinitis pigmentosa (RP) presents a difficult challenge due to the weak visual function of these patients. This study utilized magnetic resonance imaging (MRI) to assess the function and structure of the visual cortex (VC) in patients with RP and quantitatively categorize them. Materials and Methods Twenty-three patients with RP and ten healthy controls (HCs) were enrolled for MRI examinations. The patients were divided into form perception (FP) and no form perception (NFP) groups. Participants underwent structural MRI scans, and two visual task functional MRI scans were performed using stimuli, including white flash and black and white checkerboard patterns. Eight regions of interest (ROIs) were studied. In structural MRI, the gray matter volume (GMV) was compared in the ROIs. In the two visual tasks, the response intensity and functional connectivity (FC) of ROIs were also compared separately. Correlation analysis was performed to explore the correlations between the structural and functional parameters. Results In the structural analysis, the GMV in Brodmann areas 17, 18, and 19 of the FP and NFP groups was significantly lower than that of HCs. Regarding the functional data, the response intensity in the VC of both the FP and NFP groups was significantly lower than that in HCs. The response in Brodmann areas 17, 18, and 19 obtained using the pattern stimulus was significantly lower in the NFP group than in the FP group. For the FC comparison, the FP and NFP groups exhibited significantly lower values in several pathways than the HCs, and FC in the ipsilateral V1–contralateral V1 pathway in the flash task was significantly lower in the NFP group than in the FP group. A positive correlation between response intensity and GMV was observed in Brodmann areas 17, 18, and 19 in both flash and pattern visual tasks. Conclusion Magnetic resonance imaging was an effective tool to objectively and quantitatively evaluate the visual function of patients with advanced RP. Response intensity and FC were effective parameters to distinguish FP and NFP patients. A positive correlation between response intensity and GMV was observed in the VC.
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Affiliation(s)
- Hao Wang
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
| | - Wangbin Ouyang
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
| | - Yong Liu
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
| | - Minfang Zhang
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
| | - He Zhao
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
| | - Jian Wang
- Department of Radiology, Southwest Hospital, Army Medical University, Chongqing, China
- *Correspondence: Jian Wang,
| | - Zhengqin Yin
- Southwest Hospital/Southwest Eye Hospital, Army Medical University, Chongqing, China
- Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, China
- Zhengqin Yin,
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Wang DH, Gu C, Yuan YZ. Case Report: A Case of Cystoid Macular Edema in Retinitis Pigmentosa With Central Retinal Vein Occlusion. Front Med (Lausanne) 2022; 9:877429. [PMID: 35755060 PMCID: PMC9218176 DOI: 10.3389/fmed.2022.877429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/09/2022] [Indexed: 11/24/2022] Open
Abstract
Significance Cystoid macular edema (CME) is a common complication of retinitis pigmentosa (RP). However, CME in RP with central retinal vein occlusion (CRVO) is rare. Prompt administration of anti-vascular endothelial growth factor (anti-VEGF) medication can achieve a satisfactory prognosis. Purpose This report describes a case of using anti-VEGF medication to treat CME secondary to RP with impending or mild CRVO. Case Report A 26-year-old female presented for blurred vision in both eyes. Best-corrected visual acuity (BCVA) was 20/50 in the right eye and finger-counting in the left eye. According to ophthalmic examinations, CME secondary to RP in the right eye and CME secondary to RP with impending or mild CRVO in her left eye can be diagnosed. Central macular thickness (CMT) was 554 μ m in the right eye and 831 μm in the left eye. Only the left eye was treated with a single intravitreal injection of anti-VEGF medication. One month later, BCVA increased to 20/200 and CMT decreased to 162 μm in the left eye. Interestingly, BCVA in the right eye also had an improvement (20/40) and intraretinal fluid decreased significantly. However, 3 months after injection, these improvements of both eyes were not maintained. Conclusion This is the second case of RP with CRVO. Intravitreal injection of anti-VEGF medication for addressing CME secondary to RP with CRVO is an effective treatment, but it needs to be reinjected.
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Affiliation(s)
- Da-Hu Wang
- Department of Ophthalmology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cao Gu
- Department of Ophthalmology, Shanghai Xinshijie Zhongxing Eye Hospital, Shanghai, China
| | - Yuan-Zhi Yuan
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.,Centre for Evidence-Based Medicine, Fudan University, Shanghai, China
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28
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Brunet AA, Harvey AR, Carvalho LS. Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options. Int J Mol Sci 2022; 23:ijms23020726. [PMID: 35054919 PMCID: PMC8775779 DOI: 10.3390/ijms23020726] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Inherited retinal diseases (IRDs) are a leading cause of blindness. To date, 260 disease-causing genes have been identified, but there is currently a lack of available and effective treatment options. Cone photoreceptors are responsible for daylight vision but are highly susceptible to disease progression, the loss of cone-mediated vision having the highest impact on the quality of life of IRD patients. Cone degeneration can occur either directly via mutations in cone-specific genes (primary cone death), or indirectly via the primary degeneration of rods followed by subsequent degeneration of cones (secondary cone death). How cones degenerate as a result of pathological mutations remains unclear, hindering the development of effective therapies for IRDs. This review aims to highlight similarities and differences between primary and secondary cone cell death in inherited retinal diseases in order to better define cone death mechanisms and further identify potential treatment options.
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Affiliation(s)
- Alicia A. Brunet
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Lions Eye Institute Ltd., 2 Verdun St, Nedlands, WA 6009, Australia
- Correspondence: ; Tel.: +61-423-359-714
| | - Alan R. Harvey
- School of Human Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Perron Institute for Neurological and Translational Science, 8 Verdun St, Nedlands, WA 6009, Australia
| | - Livia S. Carvalho
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Lions Eye Institute Ltd., 2 Verdun St, Nedlands, WA 6009, Australia
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29
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Ryu J, Gulamhusein H, Oh JK, Chang JH, Chen J, Tsang SH. Nutrigenetic reprogramming of oxidative stress. Taiwan J Ophthalmol 2021; 11:207-215. [PMID: 34703735 PMCID: PMC8493979 DOI: 10.4103/tjo.tjo_4_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/17/2021] [Indexed: 12/30/2022] Open
Abstract
Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders.
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Affiliation(s)
- Joseph Ryu
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA
| | - Huzeifa Gulamhusein
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA.,Department of Ophthalmology, The University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA
| | - Jin Kyun Oh
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, State University of New York at Downstate Medical Center, Brooklyn, USA
| | - Joseph H Chang
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA
| | - Jocelyn Chen
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Columbia University, New York, USA
| | - Stephen H Tsang
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA.,Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute of Human Nutrition, Columbia University, NY, USA
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Shughoury A, Ciulla TA, Bakall B, Pennesi ME, Kiss S, Cunningham ET. Genes and Gene Therapy in Inherited Retinal Disease. Int Ophthalmol Clin 2021; 61:3-45. [PMID: 34584043 DOI: 10.1097/iio.0000000000000377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
Visual retinal prostheses aim to restore vision for blind individuals who suffer from outer retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration. Perception through retinal prostheses is very limited, but it can be improved by applying object isolation. We used an object isolation algorithm based on integral imaging to isolate objects of interest according to their depth from the camera and applied image processing manipulation to the isolated-object images. Subsequently, we applied a spatial prosthetic vision simulation that converted the isolated-object images to phosphene images. We compared the phosphene images for two types of input images, the original image (before applying object isolation), and the isolated-object image to illustrate the effects of object isolation on simulated prosthetic vision without and with multiple spatial variations of phosphenes, such as size and shape variations, spatial shifts, and dropout rate. The results show an improvement in the perceived shape, contrast, and dynamic range (number of gray levels) of objects in the phosphene image.
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Ahmed I, Johnston RJ, Singh MS. Pluripotent stem cell therapy for retinal diseases. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1279. [PMID: 34532416 PMCID: PMC8421932 DOI: 10.21037/atm-20-4747] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022]
Abstract
Pluripotent stem cells (PSCs), which include human embryonic stem cells (hESCs) and induced pluripotent stem cell (iPSC), have been used to study development of disease processes, and as potential therapies in multiple organ systems. In recent years, there has been increasing interest in the use of PSC-based transplantation to treat disorders of the retina in which retinal cells have been functionally damaged or lost through degeneration. The retina, which consists of neuronal tissue, provides an excellent system to test the therapeutic utility of PSC-based transplantation due to its accessibility and the availability of high-resolution imaging technology to evaluate effects. Preclinical trials in animal models of retinal diseases have shown improvement in visual outcomes following subretinal transplantation of PSC-derived photoreceptors or retinal pigment epithelium (RPE) cells. This review focuses on preclinical studies and clinical trials exploring the use of PSCs for retinal diseases. To date, several phase I/II clinical trials in patients with age-related macular degeneration (AMD) and Stargardt disease (STGD1) have demonstrated the safety and feasibility of PSC-derived RPE transplantation. Additional phase I/II clinical trials using PSC-derived RPE or photoreceptor cells for the treatment of AMD, STGD1, and also retinitis pigmentosa (RP) are currently in the pipeline. As this field continues to evolve, additional technologies may enhance PSC-derived cell transplantation through gene-editing of autologous cells, transplantation of more complex cellular structures such as organoids, and monitoring of transplanted cells through novel imaging technologies.
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Affiliation(s)
- Ishrat Ahmed
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Mandeep S Singh
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Avraham D, Jung JH, Yitzhaky Y, Peli E. Retinal prosthetic vision simulation: temporal aspects. J Neural Eng 2021; 18. [PMID: 34359062 DOI: 10.1088/1741-2552/ac1b6c] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 08/06/2021] [Indexed: 11/11/2022]
Abstract
Objective. The perception of individuals fitted with retinal prostheses is not fully understood, although several retinal implants have been tested and commercialized. Realistic simulations of perception with retinal implants would be useful for future development and evaluation of such systems.Approach.We implemented a retinal prosthetic vision simulation, including temporal features, which have not been previously simulated. In particular, the simulation included temporal aspects such as persistence and perceptual fading of phosphenes and the electrode activation rate.Main results.The simulated phosphene persistence showed an effective reduction in flickering at low electrode activation rates. Although persistence has a positive effect on static scenes, it smears dynamic scenes. Perceptual fading following continuous stimulation affects prosthetic vision of both static and dynamic scenes by making them disappear completely or partially. However, we showed that perceptual fading of a static stimulus might be countered by head-scanning motions, which together with the persistence revealed the contours of the faded object. We also showed that changing the image polarity may improve simulated prosthetic vision in the presence of persistence and perceptual fading.Significance.Temporal aspects have important roles in prosthetic vision, as illustrated by the simulations. Considering these aspects may improve the future design, the training with, and evaluation of retinal prostheses.
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Affiliation(s)
- David Avraham
- Department of Electro-Optical Engineering, School of Electrical and Computer Engineering, Ben-Gurion University of the Negev, Beer Sheva, Israel.,Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - Jae-Hyun Jung
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - Yitzhak Yitzhaky
- Department of Electro-Optical Engineering, School of Electrical and Computer Engineering, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Eli Peli
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
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Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa. Cells 2021; 10:cells10082153. [PMID: 34440922 PMCID: PMC8393369 DOI: 10.3390/cells10082153] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/13/2022] Open
Abstract
Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.
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Karapanos L, Abbott CJ, Ayton LN, Kolic M, McGuinness MB, Baglin EK, Titchener SA, Kvansakul J, Johnson D, Kentler WG, Barnes N, Nayagam DAX, Allen PJ, Petoe MA. Functional Vision in the Real-World Environment With a Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis. Transl Vis Sci Technol 2021; 10:7. [PMID: 34383875 PMCID: PMC8362639 DOI: 10.1167/tvst.10.10.7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 06/09/2021] [Indexed: 11/24/2022] Open
Abstract
Purpose In a clinical trial (NCT03406416) of a second-generation (44-channel) suprachoroidal retinal prosthesis implanted in subjects with late-stage retinitis pigmentosa (RP), we assessed performance in real-world functional visual tasks and emotional well-being. Methods The Functional Low-Vision Observer Rated Assessment (FLORA) and Impact of Vision Impairment-Very Low Vision (IVI-VLV) instruments were administered to four subjects before implantation and after device fitting. The FLORA contains 13 self-reported and 35 observer-reported items ranked for ease of conducting task (impossible-easy, central tendency given as mode). The IVI-VLV instrument quantified the impact of low vision on daily activities and emotional well-being. Results Three subjects completed the FLORA for two years after device fitting; the fourth subject ceased participation in the FLORA after fitting for reasons unrelated to the device. For all subjects at each post-fitting visit, the mode ease of task with device ON was better or equal to device OFF. Ease of task improved over the first six months with device ON, then remained stable. Subjects reported improvements in mobility, functional vision, and quality of life with device ON. The IVI-VLV suggested self-assessed vision-related quality of life was not impacted by device implantation or usage. Conclusions Subjects demonstrated sustained improved ease of task scores with device ON compared to OFF, indicating the device has a positive impact in the real-world setting. Translational Relevance Our suprachoroidal retinal prosthesis shows potential utility in everyday life, by enabling an increased environmental awareness and improving access to sensory information for people with end-stage RP.
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Affiliation(s)
- Lewis Karapanos
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
| | - Carla J. Abbott
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
| | - Lauren N. Ayton
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
- Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Maria Kolic
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
| | - Myra B. McGuinness
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
- Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia
| | - Elizabeth K. Baglin
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
| | - Samuel A. Titchener
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Jessica Kvansakul
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Dean Johnson
- Specialised Orientation and Mobility, Melbourne, VIC, Australia
| | - William G. Kentler
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC, Australia
| | - Nick Barnes
- Research School of Engineering, Australian National University, Canberra, ACT, Australia
| | - David A. X. Nayagam
- Bionics Institute, East Melbourne, VIC, Australia
- Department of Pathology, University of Melbourne, St. Vincent's Hospital, Fitzroy, VIC, Australia
| | - Penelope J. Allen
- Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
| | - Matthew A. Petoe
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
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Yang JY, Lu B, Feng Q, Alfaro JS, Chen PH, Loscalzo J, Wei WB, Zhang YY, Lu SJ, Wang S. Retinal Protection by Sustained Nanoparticle Delivery of Oncostatin M and Ciliary Neurotrophic Factor Into Rodent Models of Retinal Degeneration. Transl Vis Sci Technol 2021; 10:6. [PMID: 34347033 PMCID: PMC8340648 DOI: 10.1167/tvst.10.9.6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Retinitis pigmentosa (RP) is caused by mutations in more than 60 genes. Mutation-independent approaches to its treatment by exogeneous administration of neurotrophic factors that will preserve existing retinal anatomy and visual function are a rational strategy. Ciliary neurotrophic factor (CNTF) and oncostatin M (OSM) are two potent survival factors for neurons. However, growth factors degrade rapidly if administered directly. A sustained delivery of growth factors is required for translating their potential therapeutic benefit into patients. Methods Stable and biocompatible nanoparticles (NP) that incorporated with CNTF and OSM (CNTF- and OSM-NP) were formulated. Both NP-trophic factors were tested in vitro using photoreceptor progenitor cells (PPC) and retinal ganglion progenitor cells (RGPC) derived from induced pluripotent stem cells and in vivo using an optic nerve crush model for glaucoma and the Royal College of Surgeons rat, model of RP (n = 8/treatment) by intravitreal delivery. Efficacy was evaluated by electroretinography and optokinetic response. Retinal histology and a whole mount analysis were performed at the end of experiments. Results Significant prosurvival and pro-proliferation effects of both complexes were observed in both photoreceptor progenitor cells and RGPC in vitro. Importantly, significant RGC survival and preservation of vision and photoreceptors in both complex-treated animals were observed compared with control groups. Conclusions These results demonstrate that NP-trophic factors are neuroprotective both in vitro and in vivo. A single intravitreal delivery of both NP-trophic factors offered neuroprotection in animal models of retinal degeneration. Translational Relevance Sustained nanoparticle delivery of neurotrophic factors may offer beneficial effects in slowing down progressive retinal degenerative conditions, including retinitis pigmentosa, age-related macular degeneration, and glaucoma.
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Affiliation(s)
- Jing-Yan Yang
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Beijing Tongren Hospital, Capital Medical University, Beijing, P.R. China
| | - Bin Lu
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Qiang Feng
- NanoNeuron Therapeutics and HebeCell Corp., Natick, MA, USA
| | - Jorge S Alfaro
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Po-Hsuen Chen
- NanoNeuron Therapeutics and HebeCell Corp., Natick, MA, USA
| | - Joseph Loscalzo
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wen-Bin Wei
- Beijing Tongren Hospital, Capital Medical University, Beijing, P.R. China
| | - Ying-Yi Zhang
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shi-Jiang Lu
- NanoNeuron Therapeutics and HebeCell Corp., Natick, MA, USA
| | - Shaomei Wang
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Yang C, Georgiou M, Atkinson R, Collin J, Al-Aama J, Nagaraja-Grellscheid S, Johnson C, Ali R, Armstrong L, Mozaffari-Jovin S, Lako M. Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond. Front Cell Dev Biol 2021; 9:700276. [PMID: 34395430 PMCID: PMC8355544 DOI: 10.3389/fcell.2021.700276] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/09/2021] [Indexed: 12/20/2022] Open
Abstract
Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium that eventually results in blindness. Mutations in pre-mRNA processing factors (PRPF3, 4, 6, 8, 31, SNRNP200, and RP9) have been linked to 15–20% of autosomal dominant RP (adRP) cases. Current evidence indicates that PRPF mutations cause retinal specific global spliceosome dysregulation, leading to mis-splicing of numerous genes that are involved in a variety of retina-specific functions and/or general biological processes, including phototransduction, retinol metabolism, photoreceptor disk morphogenesis, retinal cell polarity, ciliogenesis, cytoskeleton and tight junction organization, waste disposal, inflammation, and apoptosis. Importantly, additional PRPF functions beyond RNA splicing have been documented recently, suggesting a more complex mechanism underlying PRPF-RPs driven disease pathogenesis. The current review focuses on the key RP-PRPF genes, depicting the current understanding of their roles in RNA splicing, impact of their mutations on retinal cell’s transcriptome and phenome, discussed in the context of model species including yeast, zebrafish, and mice. Importantly, information on PRPF functions beyond RNA splicing are discussed, aiming at a holistic investigation of PRPF-RP pathogenesis. Finally, work performed in human patient-specific lab models and developing gene and cell-based replacement therapies for the treatment of PRPF-RPs are thoroughly discussed to allow the reader to get a deeper understanding of the disease mechanisms, which we believe will facilitate the establishment of novel and better therapeutic strategies for PRPF-RP patients.
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Affiliation(s)
- Chunbo Yang
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Maria Georgiou
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Robert Atkinson
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Joseph Collin
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jumana Al-Aama
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Colin Johnson
- Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
| | - Robin Ali
- King's College London, London, United Kingdom
| | - Lyle Armstrong
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Sina Mozaffari-Jovin
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Majlinda Lako
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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Liu F, Liu X, Zhou Y, Yu Y, Wang K, Zhou Z, Gao H, So KF, Vardi N, Xu Y. Wolfberry-derived zeaxanthin dipalmitate delays retinal degeneration in a mouse model of retinitis pigmentosa through modulating STAT3, CCL2 and MAPK pathways. J Neurochem 2021; 158:1131-1150. [PMID: 34265077 DOI: 10.1111/jnc.15472] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/20/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022]
Abstract
Retinitis pigmentosa (RP) is a group of inherited photoreceptor degeneration diseases that causes blindness without effective treatment. The pathogenesis of retinal degeneration involves mainly oxidative stress and inflammatory responses. Zeaxanthin dipalmitate (ZD), a wolfberry-derived carotenoid, has anti-inflammatory and anti-oxidative stress effects. Here we investigated whether these properties of ZD can delay the retinal degeneration in rd10 mice, a model of RP, and explored its underlying mechanism. One shot of ZD or control vehicle was intravitreally injected into rd10 mice on postnatal day 16 (P16). Retinal function and structure of rd10 mice were assessed at P25, when rods degenerate substantially, using a visual behavior test, multi-electrode-array recordings and immunostaining. Retinal pathogenic gene expression and regulation of signaling pathways by ZD were explored using transcriptome sequencing and western blotting. Our results showed that ZD treatment improved the visual behavior of rd10 mice and delayed the degeneration of retinal photoreceptors. It also improved the light responses of photoreceptors, bipolar cells and retinal ganglion cells. The expression of genes that are involved in inflammation, apoptosis and oxidative stress were up-regulated in rd10 mice, and were reduced by ZD. ZD further reduced the activation of two key factors, signal transducer and activator of transcription 3 and chemokine (C-C motif) ligand 2, down-regulated the expression of the inflammatory factor GFAP, and inhibited extracellular signal regulated protein kinases and P38, but not the JNK pathways. In conclusion, ZD delays the degeneration of the rd10 retina both morphologically and functionally. Its anti-inflammatory function is mediated primarily through the signal transducer and activator of transcription 3, chemokine (C-C motif) ligand 2 and MAPK pathways. Thus, ZD may serve as a potential clinical candidate to treat RP.
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Affiliation(s)
- Feng Liu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaobin Liu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yamin Zhou
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yankun Yu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Ke Wang
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Zhengqun Zhou
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Hao Gao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Kwok-Fai So
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Jiangsu, China
| | - Noga Vardi
- Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA
| | - Ying Xu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Jiangsu, China
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39
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Atkinson SP. A Preview of Selected Articles. Stem Cells 2021. [DOI: 10.1002/stem.3419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Wiącek MP, Gosławski W, Grabowicz A, Sobuś A, Kawa MP, Baumert B, Paczkowska E, Milczarek S, Osękowska B, Safranow K, Zawiślak A, Lubiński W, Machaliński B, Machalińska A. Long-Term Effects of Adjuvant Intravitreal Treatment with Autologous Bone Marrow-Derived Lineage-Negative Cells in Retinitis Pigmentosa. Stem Cells Int 2021; 2021:6631921. [PMID: 34122558 PMCID: PMC8192192 DOI: 10.1155/2021/6631921] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 04/24/2021] [Accepted: 05/24/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Autologous bone marrow-derived lineage-negative (Lin-) cells present antiapoptotic and neuroprotective activity. The aim of the study was to evaluate the safety and efficacy of novel autologous Lin- cell therapy during a 12-month follow-up period. METHODS Intravitreal injection of Lin- cells in 30 eyes with retinitis pigmentosa (RP) was performed. The fellow eyes (FEs) were considered control eyes. Functional and morphological eye examinations were performed before and 1, 3, 6, 9, and 12 months after the injection. RESULTS Patients whose symptoms started less than 10 years ago gained 14 ± 10 letters, while those with a longer disease duration gained 2.86 ± 8.54 letters compared to baseline at the 12-month follow-up (p = 0.021). There were significantly higher differences in response densities of P1-wave amplitudes in the first ring of multifocal ERGs in treated eyes than FE recordings in all follow-up points were detected. Accordingly, the mean deviation in 10-2 static perimetry improved significantly in the treated eyes compared with fellow eyes 12 months after the procedure. The QoL scores improved significantly and lasted until the 9-month visit. CONCLUSION Lin- cell-based therapy is safe and effective, especially for a well-selected group of RP patients who still maintained good function of the foveal cones.
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Affiliation(s)
- Marta P. Wiącek
- First Department of Ophthalmology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Wojciech Gosławski
- Second Department of Ophthalmology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Aleksandra Grabowicz
- First Department of Ophthalmology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Anna Sobuś
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Miłosz P. Kawa
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Bartłomiej Baumert
- Department of Bone Marrow Transplantation, Department of Hematology and Bone Marrow Transplantation, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | - Edyta Paczkowska
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
- Department of Bone Marrow Transplantation, Department of Hematology and Bone Marrow Transplantation, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | - Sławomir Milczarek
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
- Department of Bone Marrow Transplantation, Department of Hematology and Bone Marrow Transplantation, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | - Bogumiła Osękowska
- Department of Bone Marrow Transplantation, Department of Hematology and Bone Marrow Transplantation, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Alicja Zawiślak
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Wojciech Lubiński
- Second Department of Ophthalmology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
- Department of Bone Marrow Transplantation, Department of Hematology and Bone Marrow Transplantation, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | - Anna Machalińska
- First Department of Ophthalmology, Pomeranian Medical University, Powst. Wlkp. 72, 70-111 Szczecin, Poland
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Tezel T, Ruff A. Retinal cell transplantation in retinitis pigmentosa. Taiwan J Ophthalmol 2021; 11:336-347. [PMID: 35070661 PMCID: PMC8757529 DOI: 10.4103/tjo.tjo_48_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 11/25/2022] Open
Abstract
Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.
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Rincón Montes V, Gehlen J, Ingebrandt S, Mokwa W, Walter P, Müller F, Offenhäusser A. Development and in vitro validation of flexible intraretinal probes. Sci Rep 2020; 10:19836. [PMID: 33199768 PMCID: PMC7669900 DOI: 10.1038/s41598-020-76582-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/28/2020] [Indexed: 12/01/2022] Open
Abstract
The efforts to improve the treatment efficacy in blind patients with retinal degenerative diseases would greatly benefit from retinal activity feedback, which is lacking in current retinal implants. While the door for a bidirectional communication device that stimulates and records intraretinally has been opened by the recent use of silicon-based penetrating probes, the biological impact induced by the insertion of such rigid devices is still unknown. Here, we developed for the first time, flexible intraretinal probes and validated in vitro the acute biological insertion impact in mouse retinae compared to standard silicon-based probes. Our results show that probes based on flexible materials, such as polyimide and parylene-C, in combination with a narrow shank design 50 µm wide and 7 µm thick, and the use of insertion speeds as high as 187.5 µm/s will successfully penetrate the retina, reduce the footprint of the insertion to roughly 2 times the cross-section of the probe, and induce low dead cell counts, while keeping the vitality of the tissue and recording the neural activity at different depths.
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Affiliation(s)
- V Rincón Montes
- Bioelectronics, Institute of Biological Information Processing-3, Forschungszentrum Jülich, Jülich, Germany
- RWTH Aachen University, Aachen, Germany
| | - J Gehlen
- Molecular and Cellular Physiology, Institute of Biological Information Processing-1, Forschungszentrum Jülich, Jülich, Germany
| | - S Ingebrandt
- Institute of Materials in Electrical Engineering 1, RWTH Aachen University, Aachen, Germany
| | - W Mokwa
- Institute of Materials in Electrical Engineering 1, RWTH Aachen University, Aachen, Germany
| | - P Walter
- Department of Ophthalmology, RWTH Aachen University, Aachen, Germany
| | - F Müller
- Molecular and Cellular Physiology, Institute of Biological Information Processing-1, Forschungszentrum Jülich, Jülich, Germany
| | - A Offenhäusser
- Bioelectronics, Institute of Biological Information Processing-3, Forschungszentrum Jülich, Jülich, Germany.
- RWTH Aachen University, Aachen, Germany.
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Ryals RC, Huang SJ, Wafai D, Bernert C, Steele W, Six M, Bonthala S, Titus H, Yang P, Gillingham M, Pennesi ME. A Ketogenic & Low-Protein Diet Slows Retinal Degeneration in rd10 Mice. Transl Vis Sci Technol 2020; 9:18. [PMID: 33117609 PMCID: PMC7571290 DOI: 10.1167/tvst.9.11.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/23/2020] [Indexed: 01/01/2023] Open
Abstract
Purpose Treatments that delay retinal cell death regardless of genetic causation are needed for inherited retinal degeneration (IRD) patients. The ketogenic diet is a high-fat, low-carbohydrate diet, used to treat epilepsy, and has beneficial effects for neurodegenerative diseases. This study aimed to determine whether the ketogenic diet could slow retinal degeneration. Methods Early weaned, rd10 and wild-type (WT) mice were placed on either standard chow, a ketogenic diet, or a ketogenic & low-protein diet. From postnatal day (PD) 23 to PD50, weight and blood β-hydroxybutyrate levels were recorded. Retinal thickness, retinal function, and visual performance were measured via optical coherence tomography, electroretinography (ERG), and optokinetic tracking (OKT). At PD40, serum albumin, rhodopsin protein, and phototransduction gene expression were measured. Results Both ketogenic diets elicited a systemic induction of ketosis. However, rd10 mice on the ketogenic & low-protein diet had significant increases in photoreceptor thickness, ERG amplitudes, and OKT thresholds, whereas rd10 mice on the ketogenic diet showed no photoreceptor preservation. In both rd10 and WT mice, the ketogenic & low-protein diet was associated with abnormal weight gain and decreases in serum albumin levels, 27% and 56%, respectively. In WT mice, the ketogenic & low-protein diet was also associated with an ∼20% to 30% reduction in ERG amplitudes. Conclusions The ketogenic & low-protein diet slowed retinal degeneration in a clinically relevant IRD model. In WT mice, the ketogenic & low-protein diet was associated with a decrease in phototransduction and serum albumin, which could serve as a protective mechanism in the rd10 model. Although ketosis was associated with protection, its role remains unclear. Translational Relevance Neuroprotective mechanisms associated with the ketogenic & low-protein diet have potential to slow retinal degeneration.
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Affiliation(s)
- Renee C Ryals
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Samuel J Huang
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Dahlia Wafai
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Claire Bernert
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - William Steele
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Makayla Six
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Shasank Bonthala
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Hope Titus
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Paul Yang
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
| | - Melanie Gillingham
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Mark E Pennesi
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
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Iuliano L, Fogliato G, Corbelli E, Bandello F, Codenotti M. Blind patients in end-stage inherited retinal degeneration: multimodal imaging of candidates for artificial retinal prosthesis. Eye (Lond) 2020; 35:289-298. [PMID: 33037412 DOI: 10.1038/s41433-020-01188-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 11/09/2022] Open
Abstract
PURPOSE To characterize the imaging features of blind patients with end-stage inherited retinal degeneration (IRD) and to assess possible morpho-functional correlations. METHODS In this observational cross-sectional study, we reviewed the clinical data and multimodal imaging of 40 eyes of 21 blind (light perception or less) institutional patients affected by end-stage IRD screened for Alpha AMS (Retina Implant AG, Reutlingen, Germany) retinal prosthesis eligibility. Analysis was carried out using spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography and fundus autofluorescence. RESULTS Among patients with IRD-related low vision, the extrapolated prevalence of the blind was roughly 10%, median age 60.4 years with a disease duration of 40.4 years, showing epiretinal membranes (80%), hyperreflective intraretinal nodules (90%) and the absence of the ellipsoid zone (77.5%) on SD-OCT examination. Cystoid macular oedema was present in 52.5% of eyes, the majority of which being of the microcystoid subtype (42.5%), while 37.5% of eyes also lacked outer and inner retinal layer segmentation. Disease duration was found to be predictive of disrupted retinal layers (P = 0.029) and microcystoid macular oedema (P = 0.035), which was also more frequent in eyes without light perception (P = 0.013). CONCLUSIONS Eyes without vision due to end-stage IRD have a typical imaging pattern, predominantly characterized by epiretinal membranes, hyperreflective intraretinal nodules and the absence of the ellipsoid zone. Furthermore, microcystoid macular oedema and retinal layer disruption may be considered as signs of longstanding disease.
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Affiliation(s)
- Lorenzo Iuliano
- Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
| | - Giovanni Fogliato
- Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - Eleonora Corbelli
- Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Bandello
- Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - Marco Codenotti
- Department of Ophthalmology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
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Meng D, Ragi SD, Tsang SH. Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa. Mol Ther 2020; 28:2139-2149. [PMID: 32882181 PMCID: PMC7545001 DOI: 10.1016/j.ymthe.2020.08.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/22/2020] [Accepted: 08/19/2020] [Indexed: 12/20/2022] Open
Abstract
Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a hereditary degenerative disorder in which mutations in the gene encoding RHO, the light-sensitive G protein-coupled receptor involved in phototransduction in rods, lead to progressive loss of rods and subsequently cones in the retina. Clinical phenotypes are diverse, ranging from mild night blindness to severe visual impairments. There is currently no cure for RHO-adRP. Although there have been significant advances in gene therapy for inherited retinal diseases, treating RHO-adRP presents a unique challenge since it is an autosomal dominant disease caused by more than 150 gain-of-function mutations in the RHO gene, rendering the established gene supplementation strategy inadequate. This review provides an update on RNA therapeutics and therapeutic editing genome surgery strategies and ongoing clinical trials for RHO-adRP, discussing mechanisms of action, preclinical data, current state of development, as well as risk and benefit considerations. Potential outcome measures useful for future clinical trials are also addressed.
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Affiliation(s)
- Da Meng
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Sara D Ragi
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY 10032, USA
| | - Stephen H Tsang
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY 10032, USA; Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA.
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Özmert E, Arslan U. Management of retinitis pigmentosa by Wharton's jelly-derived mesenchymal stem cells: prospective analysis of 1-year results. Stem Cell Res Ther 2020; 11:353. [PMID: 32787913 PMCID: PMC7425139 DOI: 10.1186/s13287-020-01870-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/31/2022] Open
Abstract
PURPOSE The aim of the study was to investigate annual structural and functional results, and their correlation with inheritance pattern of retinitis pigmentosa (RP) patients who were treated with Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). MATERIAL AND METHODS This prospective, sequential, open-label phase-3 clinical study was conducted at Ankara University Faculty of Medicine, Department of Ophthalmology, between April 2019 and May 2020. The study included 34 eyes from 32 retinitis pigmentosa patients of various genotypes who were enrolled in the stem cells clinical trial. The patients were followed for 12 months after the WJ-MSCs transplantation into subtenon space and evaluated with consecutive examinations. Genetic mutations were investigated using a retinitis pigmentosa panel sequencing method consisting of 90 genes. All patients underwent a complete routine ophthalmic examination with best corrected visual acuity, optical coherence tomography angiography, visual field, and full-field electroretinography. Quantitative data obtained from baseline (T0), 6th month (T1), and 12th month (T2) examinations were compared. RESULTS According to timepoints at T0, T1, and T2: The mean outer retinal thickness was 100.3 μm, 119.1 μm, and 118.0 μm, respectively (p = 0.01; T0 < T1, T2). The mean horizontal ellipsoid zone width were 2.65 mm, 2.70 mm, and 2.69 mm respectively (p = 0.01; T0 < T1, T2). The mean best corrected visual acuity (BCVA) were 70.5 letters, 80.6 letters, and 79.9 letters, respectively (p = 0.01; T0 < T1, T2). The mean fundus perimetry deviation index (FPDI) was 8.0%, 11.4%, and 11.6%, respectively (p = 0.01; T0 < T1, T2). The mean full-field flicker ERG parameters at T0, T1, and T2: amplitudes were 2.4 mV, 5.0 mV, and 4.6 mV, respectively (p = 0.01; T0 < T1, T2). Implicit time were 43.3 ms, 37.9 ms, and 38.6 ms, respectively (p = 0.01; T0 > T1, T2). According to inheritance pattern, BCVA, FPDI, ERG amplitude, and implicit time data improved significantly in autosomal dominant (AD) and in autosomal recessive (AR) RP at 1 year follow-up (pAD = 0.01, pAR = 0.01; pAD = pAR > pX-linked). No ocular or systemic adverse events related to the surgical methods and/or WJ-MSCs were observed during the 1 year follow-up period. CONCLUSION Subtenon transplantation of WJ-MSCs was found to be effective and safe in the treatment of RP during the first year, similar to the sixth month's results. In autosomal dominant and autosomal recessive inheritance of RP, regardless of the genetic mutations, subtenon administration of WJ-MSCs can be considered an effective and safe option without any adverse effect for slowing or stopping the disease progression. TRIAL REGISTRATION ClinicalTrials.gov, NCT04224207 . Registered 8 January 2020.
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Affiliation(s)
- Emin Özmert
- Faculty of Medicine Department of Ophthalmology, Ankara University, Ankara, Turkey
| | - Umut Arslan
- Bioretina Eye Clinic, Ankara University Technopolis, Neorama Ofis 55-56 Yaşam Cad. No 13/A Beştepe, Yenimahalle, Ankara, Turkey
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Kim YK, Chae SC, Yang HJ, An DE, Lee S, Yeo MG, Lee KJ. Cereblon Deletion Ameliorates Lipopolysaccharide-induced Proinflammatory Cytokines through 5'-Adenosine Monophosphate-Activated Protein Kinase/Heme Oxygenase-1 Activation in ARPE-19 Cells. Immune Netw 2020; 20:e26. [PMID: 32655974 PMCID: PMC7327155 DOI: 10.4110/in.2020.20.e26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/14/2022] Open
Abstract
Cereblon (CRBN), a negative modulator of AMP-activated protein kinase (AMPK), is highly expressed in the retina. We confirmed the expression of CRBN in ARPE-19 human retinal cells by Western blotting. We also demonstrated that CRBN knock-down (KD) could effectively downregulate IL-6 and MCP-1 protein and gene expression in LPS-stimulated ARPE-19 cells. Additionally, CRBN KD increased the phosphorylation of AMPK/acetyl-coenzyme A carboxylase (ACC) and the expression of heme oxygenase-1 (HO-1) in ARPE-19 cells. Furthermore, CRBN KD significantly reduced LPS-induced nuclear translocation of NF-κB p65 and activation of NF-κB promoter activity. However, these processes could be inactivated by compound C (inhibitor of AMPK) and zinc protoporphyrin-1 (ZnPP-1; inhibitor of HO-1). In conclusion, compound C and ZnPP-1 can rescue LPS-induced levels of proinflammatory cytokines (IL-6 and MCP-1) in CRBN KD ARPE-19 cells. Our data demonstrate that CRBN deficiency negatively regulates proinflammatory cytokines via the activation of AMPK/HO-1 in the retina.
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Affiliation(s)
- Yun Kyu Kim
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea
| | - Soo Chul Chae
- Department of Integrative Medical Sciences, Nambu University, Gwangju 62271, Korea.,Department of Life Science, Hanyang University, Seoul 04763, Korea
| | - Hun Ji Yang
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea
| | - Da Eun An
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea
| | - Sion Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea
| | - Myeong Gu Yeo
- Department of Integrative Medical Sciences, Nambu University, Gwangju 62271, Korea
| | - Kyung Jin Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea.,Department of Life Science, Hanyang University, Seoul 04763, Korea
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Abstract
PURPOSE OF REVIEW The goal is providing an update to the latest research surrounding optoelectronic devices, highlighting key studies and benefits and limitations of each device. RECENT FINDINGS The Argus II demonstrated long-term safety after five-year follow-up. Due to lack of tack fixation, subretinal implants appear to displace over time. PRIMA's completed primate trial showed initial safety and potential for improved vision, resulting in ongoing clinical trials Bionic Vision Australia developed a new 44-electrode suprachoroidal device currently in a clinical trial. Orion (cortical stimulation) is currently undergoing a clinical trial to demonstrate safety. SUMMARY Devices using external camera for images are unaffected by corneal or lens opacities but disconnect eye movements from image perception, while the opposite is true for implants directly detecting light. Visual acuity provided by devices is more complicated than implant electrode density and new devices aim to target this with innovative approaches.
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Affiliation(s)
- Victor Wang
- University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Ajay E. Kuriyan
- Retina Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA
- Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY, USA
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Management of Retinitis Pigmentosa via Platelet-Rich Plasma or Combination with Electromagnetic Stimulation: Retrospective Analysis of 1-Year Results. Adv Ther 2020; 37:2390-2412. [PMID: 32303913 DOI: 10.1007/s12325-020-01308-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate whether the natural progression rate of retinitis pigmentosa can be decreased by subtenon autologous platelet-rich plasma application alone or combination with retinal electromagnetic stimulation. METHODS The study includes retrospective analysis of 60 patients with retinitis pigmentosa. Patients constitute three groups with similar demographic characteristics: the combined management group (group 1) consists of 20 patients with retinitis pigmentosa (40 eyes) who received combined retinal electromagnetic stimulation and subtenon platelet-rich plasma; the subtenon platelet-rich plasma-only group (group 2) consisted of 20 patients with retinitis pigmentosa (40 eyes); the natural course (control) group (group 3) consists of 20 patients with retinitis pigmentosa (40 eyes) who did not receive any treatment. Horizontal and vertical ellipsoid zone width, fundus perimetry deviation index, and best corrected visual acuity changes were compared within and between groups after a 1-year follow-up period. RESULTS Detected horizontal ellipsoid zone percentage changes were + 1% in group 1, - 2.85% in group 2, and - 9.36% in group 3 (Δp 1 > 2 > 3). Detected vertical ellipsoid zone percentage changes were + 0.34% in group 1, - 3.05% in group 2, and - 9.09% in group 3 (Δp 1 > 2 > 3). Detected fundus perimetry deviation index percentage changes were + 0.05% in group 1, - 2.68% in group 2, and - 8.78% in group 3 (Δp 1 > 2 > 3). CONCLUSION Platelet-rich plasma is a good source of growth factors, but its half-life is 4-6 months. Subtenon autologous platelet-rich plasma might more effectively slow down photoreceptor loss when repeated as booster injections and combined with retinal electromagnetic stimulation. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04252534.
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The uPAR System as a Potential Therapeutic Target in the Diseased Eye. Cells 2019; 8:cells8080925. [PMID: 31426601 PMCID: PMC6721659 DOI: 10.3390/cells8080925] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/07/2019] [Accepted: 08/17/2019] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.
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