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Retinal Diseases: From Molecular Pathology to Therapies

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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 (31 May 2024) | Viewed by 15699

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Prof. Dr. Peter Koulen

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Departments of Ophthalmology and Basic Medical Science, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
Interests: drug target discovery and drug development for disorders of the CNS and retina; calcium signaling; neuroprotection; neurodegeneration; synaptic signaling; neurophysiology
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Dear Colleagues,

The identification of mechanisms underlying the pathophysiology and therapies of retinal diseases continues to be an area of significant research activity, attracting scientists from a diverse range of fields, including neuroscience, pharmacology, and medicinal chemistry, among several others. With the ultimate goal to generate intervention strategies that slow or even reverse the structural and functional degeneration of the retina and that attenuate or eliminate subsequent vision loss input from numerous fields, such as neurology, ophthalmology, genetics, and neuroscience, effective therapies for many retinal diseases are lacking and critically needed.

Research efforts towards preventing, treating, or curing retinal diseases are characteristic for how clinical practice as well as basic and translational research inform each other and how such interactions can result in novel therapeutic strategies of high clinical relevance. Recent methodological advances in synthetic and medicinal chemistry, mass spectrometry, proteomics, drug target discovery, and drug development have generated significant developments in this field. Therefore, this Special Issue invites manuscript submissions, namely research and review papers, targeting the gamut of methodological and scientific innovation in this field. This Special Issue specifically calls for papers focused on the discovery and mechanistic characterization of novel drug targets, signaling pathways, and mechanisms of action as they are relevant for retinal diseases. These contributions can be general and broad in their basic science, and translational research can focus more on specific research models related to the structural and functional degeneration of the retina and related complications.

Prof. Dr. Peter Koulen
Guest Editor

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Keywords

diabetic retinopathy
age-related macular degeneration
neuroprotection
retina
diabetic macular edema
therapy development
pathophysiology
retinitis pigmentosa
aging
eye trauma
vitreous
macula
choroideremia
Stargardt disease
cone-rod dystrophy
Leber congenital amaurosis
best vitelliform macular dystrophy

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Retinal Diseases: From Molecular Pathology to Therapies—2nd Edition in International Journal of Molecular Sciences (1 article)

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Research

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17 pages, 546 KiB

Open AccessArticle

Exudative Age-Related Macular Degeneration: Association between Treatment Efficacy and Single-Nucleotide Variants in RAD51B, TRIB1, COL8A1, COL10A1, IL-9, IL-10, and VEGFA Genes

by Alvita Vilkeviciute, Dzastina Cebatoriene, Loresa Kriauciuniene, Dalia Zaliuniene and Rasa Liutkeviciene

Int. J. Mol. Sci. 2024, 25(13), 6859; https://doi.org/10.3390/ijms25136859 - 22 Jun 2024

Viewed by 829

Abstract

Age-related macular degeneration (AMD) is a progressive neurodegenerative condition leading to vision loss and eventual blindness, with exudative AMD posing a heightened risk due to choroidal neovascularization and localized edema. Therapies targeting the VEGF pathway aim to address this mechanism for treatment effectiveness. Our study aimed to evaluate associations between specific genetic variants (RAD51B rs8017304, rs2588809; TRIB1 rs6987702, rs4351379; COL8A1 rs13095226; COL10A1 rs1064583; IL-9 rs1859430, rs2069870, rs11741137, rs2069885, rs2069884; IL-10 rs1800871, rs1800872, rs1800896; VEGFA rs1570360, rs699947, rs3025033, rs2146323) and the response to anti-VEGF treatment for exudative AMD. We enrolled 119 patients with exudative AMD categorized as responders or non-responders based on their response to anti-VEGF treatment. Statistical analysis revealed that RAD51B rs8017304 heterozygous and homozygous minor allele carriers had increased CMT before treatment compared to wild-type genotype carriers (p = 0.004). Additionally, TRIB1 rs4351379 heterozygous and homozygous minor allele carriers exhibited a greater decrease in central macular thickness (CMT) after 6 months of treatment than wild-type genotype carriers (p = 0.030). IL-9 rs1859430, rs2069870, and rs2069884 heterozygous and homozygous minor allele carriers had worse BCVA before treatment than wild-type genotype carriers (p = 0.018, p = 0.012, p = 0.041, respectively). Conversely, IL-9 rs2069885 heterozygous and homozygous minor allele carriers showed greater improvement in BCVA after 6 months compared to wild-type genotype carriers (p = 0.032). Furthermore, VEGFA rs699947 heterozygous and homozygous minor allele carriers had better BCVA before treatment and after 3 and 6 months of treatment than wild-type genotype carriers (p = 0.003, p = 0.022, respectively), with these carriers also exhibiting higher CMT after 6 months of anti-VEGF treatment (p = 0.032). Not all results remained statistically significant under this stringent correction for multiple comparisons. The comparisons of the serum concentrations of IL-10, VEGF-A, and VEGF-R2/KDR between non-responders and responders did not yield statistically significant differences. Our study identified significant associations between genetic variants, including RAD51B rs8017304, TRIB1 rs4351379, IL-9 rs1859430, rs2069870, rs2069884, rs2069885, and VEGFA rs699947, and parameters related to the efficacy of exudative AMD treatment, such as BCVA and CMT. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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24 pages, 3915 KiB

Open AccessArticle

Integrative Kinase Activity Profiling and Phosphoproteomics of rd10 Mouse Retina during cGMP-Dependent Retinal Degeneration

by Akanksha Roy, Jiaming Zhou, Merijn Nolet, Charlotte Welinder, Yu Zhu, François Paquet-Durand, John Groten, Tushar Tomar and Per Ekström

Int. J. Mol. Sci. 2024, 25(6), 3446; https://doi.org/10.3390/ijms25063446 - 19 Mar 2024

Viewed by 1389

Abstract

Inherited retinal degenerative diseases (IRDs) are a group of rare diseases that lead to a progressive loss of photoreceptor cells and, ultimately, blindness. The overactivation of cGMP-dependent protein kinase G (PKG), one of the key effectors of cGMP-signaling, was previously found to be involved in photoreceptor cell death and was studied in murine IRD models to elucidate the pathophysiology of retinal degeneration. However, PKG is a serine/threonine kinase (STK) with several hundred potential phosphorylation targets and, so far, little is known about the specificity of the target interaction and downstream effects of PKG activation. Here, we carried out both the kinome activity and phosphoproteomic profiling of organotypic retinal explant cultures derived from the rd10 mouse model for IRD. After treating the explants with the PKG inhibitor CN03, an overall decrease in peptide phosphorylation was observed, with the most significant decrease occurring in seven peptides, including those from the known PKG substrate cyclic-AMP-response-element-binding CREB, but also Ca²⁺/calmodulin-dependent kinase (CaMK) peptides and TOP2A. The phosphoproteomic data, in turn, revealed proteins with decreased phosphorylation, as well as proteins with increased phosphorylation. The integration of both datasets identified common biological networks altered by PKG inhibition, which included kinases predominantly from the so-called AGC and CaMK families of kinases (e.g., PKG1, PKG2, PKA, CaMKs, RSKs, and AKTs). A pathway analysis confirmed the role of CREB, Calmodulin, mitogen-activated protein kinase (MAPK) and CREB modulation. Among the peptides and pathways that showed reduced phosphorylation activity, the substrates CREB, CaMK2, and CaMK4 were validated for their retinal localization and activity, using immunostaining and immunoblotting in the rd10 retina. In summary, the integrative analysis of the kinome activity and phosphoproteomic data revealed both known and novel PKG substrates in a murine IRD model. This data establishes a basis for an improved understanding of the biological pathways involved in cGMP-mediated photoreceptor degeneration. Moreover, validated PKG targets like CREB and CaMKs merit exploration as novel (surrogate) biomarkers to determine the effects of a clinical PKG-targeted treatment for IRDs. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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19 pages, 3401 KiB

Open AccessArticle

A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

by Janya Grainok, Ianthe L. Pitout, Fred K. Chen, Samuel McLenachan, Rachael C. Heath Jeffery, Chalermchai Mitrpant and Sue Fletcher

Int. J. Mol. Sci. 2024, 25(6), 3391; https://doi.org/10.3390/ijms25063391 - 16 Mar 2024

Viewed by 1856

Abstract

Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 PRPF31. The expression level of PRPF31 is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within PRPF31 exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a PRPF31 1205C>A nonsense mutation were investigated; PRPF31 transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in PRPF31 mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold PRPF31 mRNA upregulation in the RP11 patient fibroblasts. The level of PRPF31 upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased PRPF31 expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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15 pages, 18290 KiB

Open AccessArticle

Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber’s Hereditary Optic Neuropathy

by Tsung-Han Chou, Zixuan Hao, Diego Alba, Angelina Lazo, Gabriele Gallo Afflitto, Jeremy D. Eastwood, Vittorio Porciatti, John Guy and Hong Yu

Int. J. Mol. Sci. 2023, 24(23), 17068; https://doi.org/10.3390/ijms242317068 - 2 Dec 2023

Cited by 1 | Viewed by 1682

Abstract

Leber’s hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups (p < 0.001), with significant differences among groups (p = 0.023; Control vs. LHON, p = 0.008; Control vs. Rescue, p = 0.228). Inner retinal thickness and intraocular pressure did not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype hND4 exhibited improved retinal visual acuity (0.29 ± 0.1 cy/deg vs. 0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, p < 0.001, effect of Group, p = 0.004; Interaction Flicker × Group, p < 0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, p < 0.001, Control vs. LHON, p < 0.001, Control vs. Rescue, p = 0.106). These results suggest that MTSAAV-delivered wildtype hND4 gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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13 pages, 1439 KiB

Open AccessArticle

Foveal Hypoplasia in CRB1-Related Retinopathies

by Ana Catalina Rodriguez-Martinez, Bethany Elora Higgins, Vijay Tailor-Hamblin, Samantha Malka, Riccardo Cheloni, Alexander Mark Collins, John Bladen, Robert Henderson and Mariya Moosajee

Int. J. Mol. Sci. 2023, 24(18), 13932; https://doi.org/10.3390/ijms241813932 - 11 Sep 2023

Cited by 1 | Viewed by 1811

Abstract

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47–0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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24 pages, 13965 KiB

Open AccessArticle

Macrophage-Myofibroblast Transition Contributes to Myofibroblast Formation in Proliferative Vitreoretinal Disorders

by Ahmed M. Abu El-Asrar, Gert De Hertogh, Eef Allegaert, Mohd I. Nawaz, Sara Abouelasrar Salama, Priscilla W. Gikandi, Ghislain Opdenakker and Sofie Struyf

Int. J. Mol. Sci. 2023, 24(17), 13510; https://doi.org/10.3390/ijms241713510 - 31 Aug 2023

Cited by 4 | Viewed by 2742

Abstract

Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of macrophage-myofibroblast transition (MMT) in the contribution to myofibroblast populations present in epiretinal membranes. Vitreous samples from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and nondiabetic control patients, epiretinal fibrovascular membranes from PDR patients and fibrocellular membranes from PVR patients, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by ELISA, immunohistochemistry and flow cytometry analysis. Myofibroblasts expressing α-SMA, fibroblast activation protein-α (FAP-α) and fibroblast-specific protein-1 (FSP-1) were present in all membranes. The majority of CD68⁺ monocytes/macrophages co-expressed the M2 macrophage marker CD206. In epiretinal membranes, cells undergoing MMT were identified by co-expression of the macrophage marker CD68 and myofibroblast markers α-SMA and FSP-1. Further analysis revealed that CD206⁺ M2 macrophages co-expressed α-SMA, FSP-1, FAP-α and ß-catenin. Soluble (s) CD206 and sFAP-α levels were significantly higher in vitreous samples from PDR and PVR patients than in nondiabetic control patients. The proinflammatory cytokine TNF-α and the hypoxia mimetic agent cobalt chloride induced upregulation of sFAP-α in culture media of Müller cells but not of HRMECs. The NF-ĸß inhibitor BAY11-7085 significantly attenuated TNF-α-induced upregulation of sFAP-α in Müller cells. Our findings suggest that the process of MMT might contribute to myofibroblast formation in epiretinal membranes, and this transition involved macrophages with a predominant M2 phenotype. In addition, sFAP-α as a vitreous biomarker may be derived from M2 macrophages transitioned to myofibroblasts and from Müller cells. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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Review

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14 pages, 673 KiB

Open AccessReview

Benefits and Caveats in the Use of Retinal Pigment Epithelium-Specific Cre Mice

by Sai Kocherlakota and Myriam Baes

Int. J. Mol. Sci. 2024, 25(2), 1293; https://doi.org/10.3390/ijms25021293 - 20 Jan 2024

Cited by 1 | Viewed by 1677

Abstract

The retinal pigment epithelium (RPE) is an important monolayer of cells present in the outer retina, forming a major part of the blood–retina barrier (BRB). It performs many tasks essential for the maintenance of retinal integrity and function. With increasing knowledge of the retina, it is becoming clear that both common retinal disorders, like age-related macular degeneration, and rare genetic disorders originate in the RPE. This calls for a better understanding of the functions of various proteins within the RPE. In this regard, mice enabling an RPE-specific gene deletion are a powerful tool to study the role of a particular protein within the RPE cells in their native environment, simultaneously negating any potential influences of systemic changes. Moreover, since RPE cells interact closely with adjacent photoreceptors, these mice also provide an excellent avenue to study the importance of a particular gene function within the RPE to the retina as a whole. In this review, we outline and compare the features of various Cre mice created for this purpose, which allow for inducible or non-inducible RPE-specific knockout of a gene of interest. We summarize the various benefits and caveats involved in the use of such mouse lines, allowing researchers to make a well-informed decision on the choice of Cre mouse to use in relation to their research needs. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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29 pages, 2070 KiB

Open AccessReview

Role of Lnc-RNAs in the Pathogenesis and Development of Diabetic Retinopathy

by Sofia Perisset, M. Constanza Potilinski and Juan E. Gallo

Int. J. Mol. Sci. 2023, 24(18), 13947; https://doi.org/10.3390/ijms241813947 - 11 Sep 2023

Cited by 1 | Viewed by 2744

Abstract

Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular alterations have been well established. So, new strategies are required for earlier and more effective treatment of DR, which still is the first cause of blindness in working age. We describe herein gene regulation through Lnc-RNAs as an interesting subject related to DR. Long non-coding RNAs (Lnc-RNAs) are non-protein-coding transcripts larger than 200 nucleotides. Lnc-RNAs regulate gene expression and protein formation at the epigenetic, transcriptional, and translational levels and can impact cell proliferation, apoptosis, immune response, and oxidative stress. These changes are known to take part in the mechanism of DR. Recent investigations pointed out that Lnc-RNAs might play a role in retinopathy development as Metastasis-Associated Lung Adenocarcinoma Transcript (Lnc-MALAT1), Maternally expressed gene 3 (Lnc-MEG3), myocardial-infarction-associated transcript (Lnc-MIAT), Lnc-RNA H19, Lnc-RNA HOTAIR, Lnc-RNA ANRIL B-Raf proto-oncogene (Lnc-RNA BANCR), small nucleolar RNA host gene 16 (Lnc-RNA SNHG16) and others. Several molecular pathways are impacted. Some of them play a role in DR pathophysiology, including the PI3K-Akt signaling axis, NAD-dependent deacetylase sirtuin-1 (Sirti1), p38 mitogen-activated protein kinase (P38/mapk), transforming growth factor beta signaling (TGF-β) and nuclear factor erythroid 2-related factor 2 (Nrf2). The way Lnc-RNAs affect diabetic retinopathy is a question of great relevance. Performing a more in-depth analysis seems to be crucial for researchers if they want to target Lnc-RNAs. New knowledge on gene regulation and biomarkers will enable investigators to develop more specialized therapies for diabetic retinopathy, particularly in the current growing context of precision medicine. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies)

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