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Towards an Understanding of Retinal Diseases and Novel Treatment 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 41066

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Special Issue Editor

Prof. Dr. Stephanie C. Joachim

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Guest Editor

Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, 44892 Bochum, Germany
Interests: glaucoma; age-related macular degeneration; retinal diseases; retinal organ culture models; autoimmunity; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Retinal diseases like glaucoma or age-related macular degeneration (AMD) are the leading causes of blindness worldwide and represent a major socioeconomic burden. Due to an aging society, more and more people will be affected with these diseases. Nevertheless, their precise pathogenesis is still unknown. In regard to glaucoma, elevated intraocular pressure and increased age are risk factors, but multiple other factors seem to contribute. Among these factors are vascular deficiencies, toxic components, and immunological reactions are considered relevant for glaucoma pathogenesis. AMD is characterized by drusen and RPE hypo- and hyper-pigmentation and/or horoidal neovascularization, resulting in edema and photoreceptor degeneration. AMD is a multifactorial disease, with aging being the highest risk factor. Genetic disposition also supports AMD development. Oxidative stress, inflammation or complement dysregulation seem to be among the other factors contributing to AMD. Hence complex disease models, based on cell or organ cultures as well as animal models, are needed to understand these pathologies. In addition, there is a strong need for novel or modified treatment options.

Topics of this Special Issue include but are not limited to:

Pathogenesis of retinal diseases
Approaches for neuroprotection
Novel treatment options for retinal diseases

Prof. Dr. Stephanie C. Joachim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

retina
glaucoma
age-related macular degeneration (AMD)
animal model
cell culture
organ culture
molecular pathways
biomarker
neuroprotection

Published Papers (10 papers)

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Research

Jump to: Review

24 pages, 5138 KiB

Open AccessArticle

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats

by Dimitris Spyridakos, Niki Mastrodimou, Kiran Vemuri, Thanh C. Ho, Spyros P. Nikas, Alexandros Makriyannis and Kyriaki Thermos

Int. J. Mol. Sci. 2023, 24(1), 240; https://doi.org/10.3390/ijms24010240 - 23 Dec 2022

Cited by 6 | Viewed by 2694

Abstract

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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Graphical abstract

21 pages, 11426 KiB

Open AccessArticle

Decreased Expression of Soluble Epoxide Hydrolase Suppresses Murine Choroidal Neovascularization

by Bomina Park, Sheik Pran Babu Sardar Pasha, Kamakshi L. Sishtla, Gabriella D. Hartman, Xiaoping Qi, Michael E. Boulton and Timothy W. Corson

Int. J. Mol. Sci. 2022, 23(24), 15595; https://doi.org/10.3390/ijms232415595 - 9 Dec 2022

Cited by 1 | Viewed by 2112

Abstract

Neovascular or “wet” age-related macular degeneration (nAMD) is a leading cause of blindness among older adults. Choroidal neovascularization (CNV) is a major pathological feature of nAMD, in which abnormal new blood vessel growth from the choroid leads to irreversible vision loss. There is a critical need to develop novel therapeutic strategies to address limitations of the current anti-vascular endothelial growth factor biologics. Previously, we identified soluble epoxide hydrolase (sEH) as a possible therapeutic target for CNV through a forward chemical genetic approach. The purpose of this study was to validate sEH as a target by examining retinal expression of sEH protein and mRNA by immunohistochemistry and RNAscope in situ hybridization, respectively, and to assess the efficacy of an adeno-associated virus (AAV) vector designed to knock down the sEH gene, Ephx2, in the murine laser-induced (L-) CNV model. nAMD patient postmortem eye tissue and murine L-CNV showed overexpression of sEH in photoreceptors and retinal pigment epithelial cells. Ephx2 knockdown significantly reduced CNV and normalized mRNA expression levels of CNV-related inflammatory markers. Thus, this study further establishes sEH as a promising therapeutic target against CNV associated with nAMD. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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16 pages, 4628 KiB

Open AccessArticle

Transient Retention of Photoreceptor Outer Segments in Matrigel-Embedded Retinal Organoids

by Patricia Berber, Sofiia Bondarenko, Lisa Michaelis and Bernhard Heinrich Friedrich Weber

Int. J. Mol. Sci. 2022, 23(23), 14893; https://doi.org/10.3390/ijms232314893 - 28 Nov 2022

Cited by 2 | Viewed by 1897

Abstract

Retinal organoids (ROs) are three-dimensional retinal tissues, which are differentiated in vitro from induced pluripotent stem cells (iPSC), ultimately forming all main retinal cell types under defined culture conditions. ROs show several highly specialized retinal features, including the outgrowth of photoreceptor outer segments (OSs). In vivo, the photoreceptor OSs are enveloped and maintained by protrusions of retinal pigment epithelium (RPE) cells, the so-called apical microvilli, while ROs fail to recapitulate this critical interaction in culture development. Here, we define specific co-culture conditions aiming to compensate for the missing physical proximity of RPE and OSs in RO development. Accordingly, functional RPE cells and ROs were differentiated simultaneously from the same iPSC clone, the former resulting in byproduct RPE or bRPE cells. While some co-culture approaches indicated a temporary functional interaction between bRPE and RO photoreceptors, they did not improve the photoreceptor histoarchitecture. In contrast, embedding ROs in a basement membrane extract without bRPE cells showed a robust improvement in the rate of photoreceptor OS retention. RO embedding is a quick and easy method that greatly enhances the preservation of photoreceptor OSs, an important structure for modelling retinal diseases with the involvement of photoreceptors. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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20 pages, 3294 KiB

Open AccessArticle

Out of the Shadow: Blue Light Exposure Induces Apoptosis in Müller Cells

by Agnes Fietz, José Hurst and Sven Schnichels

Int. J. Mol. Sci. 2022, 23(23), 14540; https://doi.org/10.3390/ijms232314540 - 22 Nov 2022

Cited by 7 | Viewed by 1743

Abstract

Awareness toward the risks of blue light (BL) exposure is rising due to increased use of BL-enriched LEDs in displays. Short-wave BL (400–500 nm) has a high photochemical energy, leading to the enhanced production of reactive oxygen species (ROS). BL potentially plays a role in causing dry eye, cataracts, and age-related macular degeneration (AMD). The effect of BL on retinal pigment epithelium cells (RPEs) or photoreceptors has been extensively investigated. In contrast, only a few studies have investigated the effects of BL exposure on Müller cells (MCs). This is mainly due to their lack of photosensitive elements and the common assumption that their reaction to stress is only secondary in disease development. However, MCs perform important supportive, secretory, and immune functions in the retina, making them essential for retinal survival. Increased oxidative stress is a key player in many retinal diseases such as AMD or glaucoma. We hypothesize that increased oxidative stress can also affect MCs. Thus, we simulated oxidative stress levels by exposing primary porcine MCs and human MIO-M1 cells to BL. To confirm the wavelength-specificity, the cells were further exposed to red (RL), purple (PL), and white light (WL). BL and WL exposure increased ROS levels, but only BL exposure led to apoptosis in primary MCs. Thus, BL accounted for the harmful part of WL exposure. When cells were simultaneously exposed to BL and RL (i.e., PL), cell damage due to BL could be partly prevented, as could the inhibition of p53, demonstrating the protective effect of RL and p53 dependency. In contrast, BL hardly induced apoptosis in MIO-M1 cells, which is likely due to the immortalization of the cells. Therefore, enhanced oxidative stress levels can significantly harm MC function, probably leading to decreased retinal survival and, thus, further enhancing the progression of retinal diseases. Preventing the cell death of these essential retinal cells represents a promising therapy option to enhance retinal survival. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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14 pages, 1379 KiB

Open AccessArticle

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue

by Sarah Schlick, Marianna Lucio, Gerd Wallukat, Alexander Bartsch, Adam Skornia, Jakob Hoffmanns, Charlotte Szewczykowski, Thora Schröder, Franziska Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Robert Lämmer, Christian Mardin and Bettina Hohberger Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(22), 13683; https://doi.org/10.3390/ijms232213683 - 8 Nov 2022

Cited by 11 | Viewed by 7669

Abstract

Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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17 pages, 3378 KiB

Open AccessArticle

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

by Charlotte Szewczykowski, Christian Mardin, Marianna Lucio, Gerd Wallukat, Jakob Hoffmanns, Thora Schröder, Franziska Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Martin Kräter, Jochen Guck, Robert Lämmer, Matthias Zenkel, Andreas Gießl and Bettina Hohberger Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(13), 7209; https://doi.org/10.3390/ijms23137209 - 29 Jun 2022

Cited by 36 | Viewed by 14227

Abstract

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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10 pages, 1307 KiB

Open AccessArticle

Effect of Photobiomodulation in Suppression of Oxidative Stress on Retinal Pigment Epithelium

by Jongmin Kim and Jae Yon Won

Int. J. Mol. Sci. 2022, 23(12), 6413; https://doi.org/10.3390/ijms23126413 - 8 Jun 2022

Cited by 7 | Viewed by 2228

Abstract

As the world undergoes aging, the number of age-related diseases has increased. One of them is disease related to retinal pigment epithelium (RPE) degeneration, such as age-related macular degeneration, causing vision loss without physical damage in the ocular system. It is the leading cause of blindness, with no cure. Although the exact pathogenesis is still unknown, the research shows that oxidative stress is one of the risk factors. Various molecules have been reported as anti-oxidative materials; however, the disease has not yet been conquered. Here, we would like to introduce photobiomodulation (PBM). PBM is a non-invasive treatment based on red and near-infrared light and has been used to cure various diseases by regulating cellular functions. Furthermore, recent studies showed its antioxidant effect, and due to this reason, PBM is arising as a new treatment for ocular disease. In this study, we confirm the antioxidant effect of PBM in retinal pigment epithelium via an RPE model with hypoxia. The function of RPE is protected by PBM against damage from hypoxia. Furthermore, we observed the protective mechanism of PBM by its suppression effect on reactive oxygen species generation. These results indicate that PBM shows great potential to cure RPE degeneration to help patients with blindness. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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15 pages, 3635 KiB

Open AccessArticle

Statins Inhibit the Gliosis of MIO-M1, a Müller Glial Cell Line Induced by TRPV4 Activation

by Youn Hye Jo, Go Woon Choi, Mi-Lyang Kim and Kyung Rim Sung

Int. J. Mol. Sci. 2022, 23(9), 5190; https://doi.org/10.3390/ijms23095190 - 6 May 2022

Cited by 3 | Viewed by 2292

Abstract

We characterized Müller cell gliosis induced by the activation of transient receptor potential vanilloid-type 4 (TRPV4) and assessed whether statins could modulate the gliosis. The human Müller cell line, MIO-M1, was used to analyze the gliosis caused by glaucomatous stimulation. To induce Müller gliosis in MIO-M1 cells, GSK101 was used to activate TRPV4, and Müller gliosis was evaluated by analyzing vimentin, nestin, and glial fibrillary acidic protein (GFAP) expression. The expression level of TNF-α was determined by ELISA. To evaluate the GSK101 activation of the NF-κB pathway, p65 phosphorylation was measured by Western blotting, and the nuclear translocation of p65 and IκBα phosphorylation were assessed by immunostaining. To assess the effect of statins on MIO-M1 gliosis, cells were pretreated for 24 h with statins before GSK101 treatment. Vimentin, nestin, and GFAP expression were upregulated by GSK101, while statins effectively inhibited them. The expression of TNF-α was increased by GSK101. The phosphorylation and nuclear translocation of p65 and IκBα phosphorylation, which occurs prior to p65 activation, were induced. Statins suppressed the GSK101-mediated phosphorylation of IκBα and p65 translocation. Statins can mitigate gliosis in the human Müller cell line. Because TRPV4 activation in Müller cells reflects glaucoma pathophysiology, statins may have the potential to prevent RGC death. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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Review

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11 pages, 1017 KiB

Open AccessReview

Minicircle Delivery to the Neural Retina as a Gene Therapy Approach

by Federica Staurenghi, Michelle E. McClements, Ahmed Salman and Robert E. MacLaren

Int. J. Mol. Sci. 2022, 23(19), 11673; https://doi.org/10.3390/ijms231911673 - 2 Oct 2022

Cited by 2 | Viewed by 2539

Abstract

Non-viral gene therapy has the potential to overcome several shortcomings in viral vector-based therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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13 pages, 2149 KiB

Open AccessReview

New CRISPR Tools to Correct Pathogenic Mutations in Usher Syndrome

by Lauren Major, Michelle E. McClements and Robert E. MacLaren

Int. J. Mol. Sci. 2022, 23(19), 11669; https://doi.org/10.3390/ijms231911669 - 1 Oct 2022

Cited by 2 | Viewed by 2743

Abstract

Inherited retinal degenerations are a leading cause of blindness in the UK. Significant advances have been made to tackle this issue in recent years, with a pioneering FDA approved gene therapy treatment (Luxturna^®), which targets a loss of function mutation in the RPE65 gene. However, there remain notable shortcomings to this form of gene replacement therapy. In particular, the lack of viability for gene sequences exceeding the 4.7 kb adeno-associated virus (AAV) packaging limit or for toxic gain of function mutations. The USH2A gene at ~15.7 kb for instance is too large for AAV delivery: a safe and effective vehicle capable of transducing photoreceptor cells for gene replacement therapy. Usher Syndrome is a clinically and genetically heterogenous deaf-blindness syndrome with autosomal recessive inheritance. The USH2A gene encodes the protein usherin, which localises to the photoreceptor cilium and cochlear hair cells. Mutations in the USH2A gene cause Usher Syndrome type II (USH2), which is the most common subtype of Usher Syndrome and the focus of this review. To date, researchers have been unable to create an efficient, safe editing tool that is small enough to fit inside a single AAV vector for delivery into human cells. This article reviews the potential of CRISPR technology, derived from bacterial defence mechanisms, to overcome these challenges; delivering tools to precisely edit and correct small insertions, deletions and base transitions in USH2A without the need to deliver the full-length gene. Such an ultra-compact therapy could make strides in combating a significant cause of blindness in young people. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment 2.0)

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