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Retinal Degeneration—From Genetics to Therapy 2.0
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Retinal Degeneration—From Genetics to Therapy 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 3945

Special Issue Editors

Dr. Nan-Kai Wang

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Guest Editor
Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
Interests: genetics; mitochondrial function; inherited retinal dystrophies; optic neuropathy; electrophysiology; mouse models; myopic maculopathy; diabetes
Special Issues, Collections and Topics in MDPI journals
Dr. Peter M.J. Quinn

E-Mail Website
Guest Editor
Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
Interests: organoids; organ chips; induced pluripotent stem cells; neurodegeneration; neuroinflammation; retina, RPE, mitochondria; microglia; Crumbs homologue-1; CRB1; metabolome reprogramming, gene augmentation; gene editing; cell therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce a new Special Issue of the International Journal of Molecular Sciences entitled “Retinal Degeneration—from Genetics to Therapy 2.0”, in which we invite you to submit your latest research findings in the fields of genetic and translational ophthalmology.

Loss of vision is one of the most feared health conditions in society and severely impacts patients’ quality of life. The burden and prevalence of monogenic and multifactorial ophthalmic diseases in the human population highlight the need to better understand the phenotypic, histopathological, and molecular changes underlying these diseases. As such, there is an urgent need for the development, testing, and refinement of potential treatments to halt, slow, or hopefully cure progressive and disabling retinal degenerative diseases.

In this Special Issue, we aim to gather a broad scope of contributions that cover but are not limited to animal models and induced pluripotent stem cell (iPSC)-derived retina or retinal pigment epithelium (RPE) models associated with retinal degeneration, prospective and retrospective natural history studies, hereditary disease, retinal imaging and therapeutics toward the amelioration of retinal degeneration, including gene editing, gene augmentation, metabolic reprogramming, and splice modulation therapy.

The published papers in this Special Issue of IJMS will describe new developments in these areas. We will accept high-quality articles including original research results, case reports, and reviews.

We look forward to your contributions.

Dr. Nan-Kai Wang
Dr. Peter M.J. Quinn
Guest Editors

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

  • ophthalmology
  • inherited retinal dystrophies
  • retinal degeneration
  • genetics
  • natural history studies
  • gene augmentation
  • gene editing
  • reprogramming
  • optogenetics and splice modulation therapy
  • animal models
  • human iPSC-derived retina and retinal pigment epithelium

Related Special Issue

Published Papers (4 papers)

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Research

18 pages, 1618 KiB  
Article
PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort
by Lidia Fernández-Caballero, Inmaculada Martín-Merida, Fiona Blanco-Kelly, Almudena Avila-Fernandez, Ester Carreño, Patricia Fernandez-San Jose, Cristina Irigoyen, Belen Jimenez-Rolando, Fermina Lopez-Grondona, Ignacio Mahillo, María Pilar Martin-Gutierrez, Pablo Minguez, Irene Perea-Romero, Marta Del Pozo-Valero, Rosa Riveiro-Alvarez, Cristina Rodilla, Lidya Rodriguez-Peña, Ana Isabel Sánchez-Barbero, Saoud T. Swafiri, María José Trujillo-Tiebas, Olga Zurita, Blanca García-Sandoval, Marta Corton and Carmen Ayusoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(5), 2913; https://doi.org/10.3390/ijms25052913 - 02 Mar 2024
Viewed by 602
Abstract
PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype–phenotype correlations. A [...] Read more.
PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype–phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype–phenotype correlations. Full article
(This article belongs to the Special Issue Retinal Degeneration—From Genetics to Therapy 2.0)
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15 pages, 1855 KiB  
Article
Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation–Effect of an ALG6 Modifier Variant
by Elisha Monson, Artur V. Cideciyan, Alejandro J. Roman, Alexander Sumaroka, Malgorzata Swider, Vivian Wu, Iryna Viarbitskaya, Samuel G. Jacobson, Steven J. Fliesler and Steven J. Pittler
Int. J. Mol. Sci. 2024, 25(2), 1004; https://doi.org/10.3390/ijms25021004 - 13 Jan 2024
Viewed by 1101
Abstract
Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in [...] Read more.
Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina. Full article
(This article belongs to the Special Issue Retinal Degeneration—From Genetics to Therapy 2.0)
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15 pages, 3301 KiB  
Article
MicroRNA-152-3p and MicroRNA-196a-5p Are Downregulated When Müller Cells Are Promoted by Components of the Internal Limiting Membrane: Implications for Macular Hole Healing
by Hung-Da Chou, Shine-Gwo Shiah, Lan-Hsin Chuang, Wei-Chi Wu, Yih-Shiou Hwang, Kuan-Jen Chen, Eugene Yu-Chuan Kang, Ling Yeung, Chung-Yi Nien and Chi-Chun Lai
Int. J. Mol. Sci. 2023, 24(24), 17188; https://doi.org/10.3390/ijms242417188 - 06 Dec 2023
Viewed by 735
Abstract
Müller cells play a critical role in the closure of macular holes, and their proliferation and migration are facilitated by the internal limiting membrane (ILM). Despite the importance of this process, the underlying molecular mechanism remains underexplored. This study investigated the effects of [...] Read more.
Müller cells play a critical role in the closure of macular holes, and their proliferation and migration are facilitated by the internal limiting membrane (ILM). Despite the importance of this process, the underlying molecular mechanism remains underexplored. This study investigated the effects of ILM components on the microRNA (miRNA) profile of Müller cells. Rat Müller cells (rMC-1) were cultured with a culture insert and varying concentrations of ILM component coatings, namely, collagen IV, laminin, and fibronectin, and cell migration was assessed by measuring cell-free areas in successive photographs following insert removal. MiRNAs were then extracted from these cells and analyzed. Mimics and inhibitors of miRNA candidates were transfected into Müller cells, and a cell migration assay and additional cell viability assays were performed. The results revealed that the ILM components promoted Müller cell migration (p < 0.01). Among the miRNA candidates, miR-194-3p was upregulated, whereas miR-125b-1-3p, miR-132-3p, miR-146b-5p, miR-152-3p, miR-196a-5p, miR-542-5p, miR-871-3p, miR-1839-5p, and miR-3573-3p were significantly downregulated (p < 0.05; fold change > 1.5). Moreover, miR-152-3p and miR-196a-5p reduced cell migration (p < 0.05) and proliferation (p < 0.001), and their suppressive effects were reversed by their respective inhibitors. In conclusion, miRNAs were regulated in ILM component-activated Müller cells, with miR-152-3p and miR-196a-5p regulating Müller cell migration and proliferation. These results serve as a basis for understanding the molecular healing process of macular holes and identifying potential new target genes in future research. Full article
(This article belongs to the Special Issue Retinal Degeneration—From Genetics to Therapy 2.0)
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15 pages, 5686 KiB  
Article
Novel Function of Nogo-A as Negative Regulator of Endothelial Progenitor Cell Angiogenic Activity: Impact in Oxygen-Induced Retinopathy
by Pakiza Ruknudin, Ali Riza Nazari, Maelle Wirth, Isabelle Lahaie, Emmanuel Bajon, Alain Rivard, Sylvain Chemtob and Michel Desjarlais
Int. J. Mol. Sci. 2023, 24(17), 13185; https://doi.org/10.3390/ijms241713185 - 24 Aug 2023
Cited by 1 | Viewed by 825
Abstract
Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in oxygen-induced retinopathy (OIR). Yet the mechanisms responsible for their dysfunction is unclear. Nogo-A, whose function is traditionally related to the inhibition of neurite function in the central nervous system, has recently been documented [...] Read more.
Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in oxygen-induced retinopathy (OIR). Yet the mechanisms responsible for their dysfunction is unclear. Nogo-A, whose function is traditionally related to the inhibition of neurite function in the central nervous system, has recently been documented to display anti-angiogenic pro-repellent properties. Based on the significant impact of EPCs in retinal vascularization, we surmised that Nogo-A affects EPC function, and proceeded to investigate the role of Nogo-A on EPC function in OIR. The expression of Nogo-A and its specific receptor NgR1 was significantly increased in isolated EPCs exposed to hyperoxia, as well as in EPCs isolated from rats subjected to OIR compared with respective controls (EPCs exposed to normoxia). EPCs exposed to hyperoxia displayed reduced migratory and tubulogenic activity, associated with the suppressed expression of prominent EPC-recruitment factors SDF-1/CXCR4. The inhibition of Nogo-A (using a Nogo-66 neutralizing antagonist peptide) or siRNA-NGR1 in hyperoxia-exposed EPCs restored SDF-1/CXCR4 expression and, in turn, rescued the curtailed neovascular functions of EPCs in hyperoxia. The in vivo intraperitoneal injection of engineered EPCs (Nogo-A-inhibited or NgR1-suppressed) in OIR rats at P5 (prior to exposure to hyperoxia) prevented retinal and choroidal vaso-obliteration upon localization adjacent to vasculature; coherently, the inhibition of Nogo-A/NgR1 in EPCs enhanced the expression of key angiogenic factors VEGF, SDF-1, PDGF, and EPO in retina; CXCR4 knock-down abrogated suppressed NgR1 pro-angiogenic effects. The findings revealed that hyperoxia-induced EPC malfunction is mediated to a significant extent by Nogo-A/NgR1 signaling via CXCR4 suppression; the inhibition of Nogo-A in EPCs restores specific angiogenic growth factors in retina and the ensuing vascularization of the retina in an OIR model. Full article
(This article belongs to the Special Issue Retinal Degeneration—From Genetics to Therapy 2.0)
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