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Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0
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Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0

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 December 2020) | Viewed by 83329

Special Issue Editor

Dr. Jan Wijnholds

E-Mail Website
Guest Editor
Department of Ophthalmology, LUMC, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
Interests: retinal degeneration; AAV gene therapy; Crumbs homologue-1; CRB1
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Loss of vision due to retinal degeneration can have monogenic or multifactorial causes. There is an urgent search for cures, treatments and prevention for children as well as adults affected by retinitis pigmentosa, age-related macular degeneration, Usher syndrome and other retinal degenerative diseases. A first retinal gene therapy medicine has recently been approved by regulatory agencies and other studies are ongoing in the clinic, but there are many more retinal disease genes without an available medicine. The retina is well accessible through image-guided surgical intervention including gene therapy and the transplantation of retinal cells. Neural retina and retinal pigment epithelium (RPE) can be generated from induced pluripotent stem cells (hiPSC) and used for pre-clinical studies.

This issue of the International Journal of Molecular Sciences will focus on recent insights in “Retinal Degeneration: From Pathophysiology to Therapeutic Approaches”, including new insights into hereditary disease, human and animal retinal pathology due to gene mutations, retinal inflammation, retinal gene therapy, hiPSC-derived neural retina and RPE, natural history studies on patients, pre-and clinical gene therapy, animal models for hereditary retinal dystrophy, retinal imaging, and submissions dealing with these topics are welcome. According to the Aims and Scope of IJMS, each manuscript needs to include basic studies in biochemistry, molecular biology, or molecular medicine.

Assoc. Prof. Dr. Jan Wijnholds
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

  • hereditary retinal disease
  • retinal inflammation
  • retinal gene augmentation, editing, optogenetics and splice modulation therapy
  • natural history studies of the retina
  • human iPSC-derived retina and retinal pigment epithelium
  • retinal iPSC-derived cell therapy
  • retinal pathology
  • pre- and clinical gene therapy
  • animal models for retinal dystrophy
  • retinal imaging

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Published Papers (20 papers)

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17 pages, 2826 KiB  
Article
The Major Ciliary Isoforms of RPGR Build Different Interaction Complexes with INPP5E and RPGRIP1L
by Christine Vössing, Paul Atigbire, Jannis Eilers, Fenja Markus, Knut Stieger, Fei Song and John Neidhardt
Int. J. Mol. Sci. 2021, 22(7), 3583; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073583 - 30 Mar 2021
Cited by 9 | Viewed by 2656
Abstract
X-linked retinitis pigmentosa (XLRP) is frequently caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. A complex splicing process acts on the RPGR gene resulting in three major isoforms: RPGRex1-19, RPGRORF15 and RPGRskip14/15. We [...] Read more.
X-linked retinitis pigmentosa (XLRP) is frequently caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. A complex splicing process acts on the RPGR gene resulting in three major isoforms: RPGRex1-19, RPGRORF15 and RPGRskip14/15. We characterized the widely expressed, alternatively spliced transcript RPGRskip14/15 lacking exons 14 and 15. Using the CRISPR/eSpCas9 system, we generated HEK293T cell lines exclusively expressing the RPGRskip14/15 transcript from the endogenous RPGR gene. RPGRex1-19 and RPGRORF15 were knocked out. Immunocytochemistry demonstrated that the RPGRskip14/15 protein localizes along primary cilia, resembling the expression pattern of RPGRex1-19. The number of cilia-carrying cells was not affected by the absence of the RPGRex1-19 and RPGRORF15 isoforms. Co-immunoprecipitation assays demonstrated that both RPGRex1-19 and RPGRskip14/15 interact with PDE6D, further supporting that RPGRskip14/15 is associated with the protein networks along the primary cilium. Interestingly, interaction complexes with INPP5E or RPGRIP1L were only detectable with isoform RPGRex1-19, but not with RPGRskip14/15, demonstrating distinct functional properties of the major RPGR isoforms in spite of their similar subcellular localization. Our findings lead to the conclusion that protein binding sites within RPGR are mediated through alternative splicing. A tissue-specific expression ratio between RPGRskip14/15 and RPGRex1-19 seems required to regulate the ciliary concentration of RPGR interaction partners. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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23 pages, 5563 KiB  
Article
Defining Phenotype, Tropism, and Retinal Gene Therapy Using Adeno-Associated Viral Vectors (AAVs) in New-Born Brown Norway Rats with a Spontaneous Mutation in Crb1
by Nanda Boon, C. Henrique Alves, Aat A. Mulder, Charlotte A. Andriessen, Thilo M. Buck, Peter M. J. Quinn, Rogier M. Vos, Abraham J. Koster, Carolina R. Jost and Jan Wijnholds
Int. J. Mol. Sci. 2021, 22(7), 3563; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073563 - 30 Mar 2021
Cited by 9 | Viewed by 2918
Abstract
Mutations in the Crumbs homologue 1 (CRB1) gene cause inherited retinal dystrophies, such as early-onset retinitis pigmentosa and Leber congenital amaurosis. A Brown Norway rat strain was reported with a spontaneous insertion-deletion (indel) mutation in exon 6 of Crb1. It [...] Read more.
Mutations in the Crumbs homologue 1 (CRB1) gene cause inherited retinal dystrophies, such as early-onset retinitis pigmentosa and Leber congenital amaurosis. A Brown Norway rat strain was reported with a spontaneous insertion-deletion (indel) mutation in exon 6 of Crb1. It has been reported that these Crb1 mutant rats show vascular abnormalities associated with retinal telangiectasia and possess an early-onset retinal degenerative phenotype with outer limiting membrane breaks and focal loss of retinal lamination at 2 months of age. Here, we further characterized the morphological phenotype of new-born and adult Crb1 mutant rats in comparison with age-matched Brown Norway rats without a mutation in Crb1. A significantly decreased retinal function and visual acuity was observed in Crb1 mutant rats at 1 and 3 months of age, respectively. Moreover, in control rats, the subcellular localization of canonical CRB1 was observed at the subapical region in Müller glial cells while CRB2 was observed at the subapical region in both photoreceptors and Müller glial cells by immuno-electron microscopy. CRB1 localization was lost in the Crb1 mutant rats, whereas CRB2 was still observed. In addition, we determined the tropism of subretinal or intravitreally administered AAV5-, AAV9- or AAV6-variant ShH10Y445F vectors in new-born control and Crb1 mutant rat retinas. We showed that subretinal injection of AAV5 and AAV9 at postnatal days 5 (P5) or 8 (P8) predominantly infected the retinal pigment epithelium (RPE) and photoreceptor cells; while intravitreal injection of ShH10Y445F at P5 or P8 resulted in efficient infection of mainly Müller glial cells. Using knowledge of the subcellular localization of CRB1 and the ability of ShH10Y445F to infect Müller glial cells, canonical hCRB1 and hCRB2 AAV-mediated gene therapy were explored in new-born Crb1 mutant rats. Enhanced retinal function after gene therapy delivery in the Crb1 rat was not observed. No timely rescue of the retinal phenotype was observed using retinal function and visual acuity, suggesting the need for earlier onset of expression of recombinant hCRB proteins in Müller glial cells to rescue the severe retinal phenotype in Crb1 mutant rats. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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21 pages, 2771 KiB  
Article
Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3
by Michalitsa Diakatou, Gregor Dubois, Nejla Erkilic, Carla Sanjurjo-Soriano, Isabelle Meunier and Vasiliki Kalatzis
Int. J. Mol. Sci. 2021, 22(5), 2607; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052607 - 05 Mar 2021
Cited by 19 | Viewed by 4180
Abstract
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant [...] Read more.
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant is exclusively responsible for all cases of NR2E3-associated adRP. Currently, there is no treatment for NR2E3-related or, other, adRP, but genome editing holds promise. A pertinent approach would be to specifically knockout the dominant mutant allele, so that the wild type allele can perform unhindered. In this study, we developed a CRISPR/Cas strategy to specifically knockout the mutant G56R allele of NR2E3 and performed a proof-of-concept study in induced pluripotent stem cells (iPSCs) of an adRP patient. We demonstrate allele-specific knockout of the mutant G56R allele in the absence of off-target events. Furthermore, we validated this knockout strategy in an exogenous overexpression system. Accordingly, the mutant G56R-CRISPR protein was truncated and mis-localized to the cytosol in contrast to the (peri)nuclear localizations of wild type or G56R NR2E3 proteins. Finally, we show, for the first time, that G56R iPSCs, as well as G56R-CRISPR iPSCs, can differentiate into NR2E3-expressing retinal organoids. Overall, we demonstrate that G56R allele-specific knockout by CRISPR/Cas could be a clinically relevant approach to treat NR2E3-associated adRP. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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21 pages, 6851 KiB  
Article
Metabolic Analysis of Vitreous/Lens and Retina in Wild Type and Retinal Degeneration Mice
by Elisa Murenu, Sarantos Kostidis, Shibojyoti Lahiri, Anna S. Geserich, Axel Imhof, Martin Giera and Stylianos Michalakis
Int. J. Mol. Sci. 2021, 22(5), 2345; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052345 - 26 Feb 2021
Cited by 5 | Viewed by 3009
Abstract
Photoreceptors are the light-sensing cells of the retina and the major cell type affected in most inherited retinal degenerations. Different metabolic pathways sustain their high energetic demand in physiological conditions, particularly aerobic glycolysis. The principal metabolome of the mature retina has been studied, [...] Read more.
Photoreceptors are the light-sensing cells of the retina and the major cell type affected in most inherited retinal degenerations. Different metabolic pathways sustain their high energetic demand in physiological conditions, particularly aerobic glycolysis. The principal metabolome of the mature retina has been studied, but only limited information is available on metabolic adaptations in response to key developmental events, such as eye opening. Moreover, dynamic metabolic changes due to retinal degeneration are not well understood. Here, we aimed to explore and map the ocular metabolic dynamics induced by eye opening in healthy (wild type) or Pde6b-mutant (retinal degeneration 1, Rd1) mice, in which photoreceptors degenerate shortly after eye opening. To unravel metabolic differences emerging before and after eye opening under physiological and pathophysiological conditions, we performed nuclear magnetic resonance (NMR) spectrosco-py-based metabolome analysis of wild type and Rd1 retina and vitreous/lens. We show that eye opening is accompanied by changes in the concentration of selected metabolites in the retina and by alterations in the vitreous/lens composition only in the retinal degeneration context. As such, we identify N-Acetylaspartate as a potential novel vitreous/lens marker reflecting progressive retinal degeneration. Thus, our data can help elucidating mechanisms underlying key events in retinal physiology and reveal changes occurring in pathology, while highlighting the importance of the vitreous/lens in the characterization of retinal diseases. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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49 pages, 6758 KiB  
Article
Transcriptomic Changes Associated with Loss of Cell Viability Induced by Oxysterol Treatment of a Retinal Photoreceptor-Derived Cell Line: An In Vitro Model of Smith–Lemli–Opitz Syndrome
by Bruce A. Pfeffer, Libin Xu and Steven J. Fliesler
Int. J. Mol. Sci. 2021, 22(5), 2339; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052339 - 26 Feb 2021
Cited by 2 | Viewed by 2662
Abstract
Smith–Lemli–Opitz Syndrome (SLOS) results from mutations in the gene encoding the enzyme DHCR7, which catalyzes conversion of 7-dehydrocholesterol (7DHC) to cholesterol (CHOL). Rats treated with a DHCR7 inhibitor serve as a SLOS animal model, and exhibit progressive photoreceptor-specific cell death, with accumulation of [...] Read more.
Smith–Lemli–Opitz Syndrome (SLOS) results from mutations in the gene encoding the enzyme DHCR7, which catalyzes conversion of 7-dehydrocholesterol (7DHC) to cholesterol (CHOL). Rats treated with a DHCR7 inhibitor serve as a SLOS animal model, and exhibit progressive photoreceptor-specific cell death, with accumulation of 7DHC and oxidized sterols. To understand the basis of this cell type specificity, we performed transcriptomic analyses on a photoreceptor-derived cell line (661W), treating cells with two 7DHC-derived oxysterols, which accumulate in tissues and bodily fluids of SLOS patients and in the rat SLOS model, as well as with CHOL (negative control), and evaluated differentially expressed genes (DEGs) for each treatment. Gene enrichment analysis and compilation of DEG sets indicated that endoplasmic reticulum stress, oxidative stress, DNA damage and repair, and autophagy were all highly up-regulated pathways in oxysterol-treated cells. Detailed analysis indicated that the two oxysterols exert their effects via different molecular mechanisms. Changes in expression of key genes in highlighted pathways (Hmox1, Ddit3, Trib3, and Herpud1) were validated by immunofluorescence confocal microscopy. The results extend our understanding of the pathobiology of retinal degeneration and SLOS, identifying potential new druggable targets for therapeutic intervention into these and other related orphan diseases. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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13 pages, 4954 KiB  
Article
Gene Correction Recovers Phagocytosis in Retinal Pigment Epithelium Derived from Retinitis Pigmentosa-Human-Induced Pluripotent Stem Cells
by Ana Artero-Castro, Kathleen Long, Andrew Bassett, Almudena Ávila-Fernandez, Marta Cortón, Antonio Vidal-Puig, Pavla Jendelova, Francisco Javier Rodriguez-Jimenez, Eleonora Clemente, Carmen Ayuso and Slaven Erceg
Int. J. Mol. Sci. 2021, 22(4), 2092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042092 - 20 Feb 2021
Cited by 10 | Viewed by 3202
Abstract
Hereditary retinal dystrophies (HRD) represent a significant cause of blindness, affecting mostly retinal pigment epithelium (RPE) and photoreceptors (PRs), and currently suffer from a lack of effective treatments. Highly specialized RPE and PR cells interact mutually in the functional retina, therefore primary HRD [...] Read more.
Hereditary retinal dystrophies (HRD) represent a significant cause of blindness, affecting mostly retinal pigment epithelium (RPE) and photoreceptors (PRs), and currently suffer from a lack of effective treatments. Highly specialized RPE and PR cells interact mutually in the functional retina, therefore primary HRD affecting one cell type leading to a secondary HRD in the other cells. Phagocytosis is one of the primary functions of the RPE and studies have discovered that mutations in the phagocytosis-associated gene Mer tyrosine kinase receptor (MERTK) lead to primary RPE dystrophy. Treatment strategies for this rare disease include the replacement of diseased RPE with healthy autologous RPE to prevent PR degeneration. The generation and directed differentiation of patient-derived human-induced pluripotent stem cells (hiPSCs) may provide a means to generate autologous therapeutically-relevant adult cells, including RPE and PR. However, the continued presence of the MERTK gene mutation in patient-derived hiPSCs represents a significant drawback. Recently, we reported the generation of a hiPSC model of MERTK-associated Retinitis Pigmentosa (RP) that recapitulates disease phenotype and the subsequent creation of gene-corrected RP-hiPSCs using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9. In this study, we differentiated gene-corrected RP-hiPSCs into RPE and found that these cells had recovered both wild-type MERTK protein expression and the lost phagocytosis of fluorescently-labeled photoreceptor outer segments observed in uncorrected RP-hiPSC-RPE. These findings provide proof-of-principle for the utility of gene-corrected hiPSCs as an unlimited cell source for personalized cell therapy of rare vision disorders. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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23 pages, 24073 KiB  
Article
PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions
by Nundehui Díaz-Lezama, Anne Wolf, Susanne Koch, Anna M. Pfaller, Josef Biber, Xavier Guillonneau, Thomas Langmann and Antje Grosche
Int. J. Mol. Sci. 2021, 22(3), 1174; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031174 - 25 Jan 2021
Cited by 4 | Viewed by 3573
Abstract
Müller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Müller glia has been reported earlier, their actual role for Müller cell function and [...] Read more.
Müller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Müller glia has been reported earlier, their actual role for Müller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Müller cell-specific PDGF receptor alpha (PDGFRα) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFRα-deficient Müller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFRα ligand PDGF-BB prevented Müller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFRα KO Müller cells. Additionally, PDGFRα KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Müller glial PDGFRα is central for retinal functions under physiological conditions. In contrast, Müller cell-specific PDGFRα KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy—a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Müller cell homeostatic functions potentially interfering with a long-term positive outcome. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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18 pages, 2240 KiB  
Article
Disruption of 24-Hour Rhythm in Intraocular Pressure Correlates with Retinal Ganglion Cell Loss in Glaucoma
by Vladimir Neroev, Tatyana Malishevskaya, Dietmar Weinert, Sergei Astakhov, Sergey Kolomeichuk, Germaine Cornelissen, Yana Kabitskaya, Elena Boiko, Irina Nemtsova and Denis Gubin
Int. J. Mol. Sci. 2021, 22(1), 359; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010359 - 31 Dec 2020
Cited by 8 | Viewed by 3348
Abstract
Parameters of 24-h rhythm in intraocular pressure (IOP) were assessed in patients with stable or advanced primary open-angle glaucoma (S-POAG/A-POAG) and referenced to the phase of “marker” circadian temperature rhythm of each patient. Body temperature and IOP were measured over a 72-h span [...] Read more.
Parameters of 24-h rhythm in intraocular pressure (IOP) were assessed in patients with stable or advanced primary open-angle glaucoma (S-POAG/A-POAG) and referenced to the phase of “marker” circadian temperature rhythm of each patient. Body temperature and IOP were measured over a 72-h span in 115 participants (65 S-POAG and 50 A-POAG). Retinal Ganglion Cell (RGC) damage was assessed by high-definition optical coherence tomography. The 24-h IOP rhythm in A-POAG patients peaked during the night, opposite to the daytime phase position in S-POAG patients (p < 0.0001). The 24-h IOP phase correlated with RGC loss (p < 0.0001). The internal phase shift between IOP and body temperature gradually increased with POAG progression (p < 0.001). Angiotensin converting enzyme Alu-repeat deletion/insertion (ACE I/D) emerged as a candidate gene polymorphism, which may play a role in the alteration of the circadian IOP variability in advanced glaucoma. To conclude, a reliable estimation of the 24-h rhythm in IOP requires the degree of RGC damage to be assessed. In advanced POAG, the 24-h phase of IOP tended to occur during the night and correlated with RGC loss, being progressively delayed relative to the phase of temperature. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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22 pages, 4448 KiB  
Article
Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
by Fabian A. Garces, Jessica F. Scortecci and Robert S. Molday
Int. J. Mol. Sci. 2021, 22(1), 185; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010185 - 27 Dec 2020
Cited by 14 | Viewed by 4049
Abstract
ABCA4 is an ATP-binding cassette (ABC) transporter expressed in photoreceptors, where it transports its substrate, N-retinylidene-phosphatidylethanolamine (N-Ret-PE), across outer segment membranes to facilitate the clearance of retinal from photoreceptors. Mutations in ABCA4 cause Stargardt macular degeneration (STGD1), an autosomal recessive [...] Read more.
ABCA4 is an ATP-binding cassette (ABC) transporter expressed in photoreceptors, where it transports its substrate, N-retinylidene-phosphatidylethanolamine (N-Ret-PE), across outer segment membranes to facilitate the clearance of retinal from photoreceptors. Mutations in ABCA4 cause Stargardt macular degeneration (STGD1), an autosomal recessive disorder characterized by a loss of central vision and the accumulation of bisretinoid compounds. The purpose of this study was to determine the molecular properties of ABCA4 variants harboring disease-causing missense mutations in the transmembrane domains. Thirty-eight variants expressed in culture cells were analyzed for expression, ATPase activities, and substrate binding. On the basis of these properties, the variants were divided into three classes: Class 1 (severe variants) exhibited significantly reduced ABCA4 expression and basal ATPase activity that was not stimulated by its substrate N-Ret-PE; Class 2 (moderate variants) showed a partial reduction in expression and basal ATPase activity that was modestly stimulated by N-Ret-PE; and Class 3 (mild variants) displayed expression and functional properties comparable to normal ABCA4. The p.R653C variant displayed normal expression and basal ATPase activity, but lacked substrate binding and ATPase activation, suggesting that arginine 653 contributes to N-Ret-PE binding. Our classification provides a basis for better understanding genotype–phenotype correlations and evaluating therapeutic treatments for STGD1. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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16 pages, 4530 KiB  
Article
Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease
by Yassin Jabri, Josef Biber, Nundehui Diaz-Lezama, Antje Grosche and Diana Pauly
Int. J. Mol. Sci. 2020, 21(22), 8468; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228468 - 11 Nov 2020
Cited by 6 | Viewed by 3005
Abstract
Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4−/− retinae and aligned these findings with morphological markers of retinal degeneration. We [...] Read more.
Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4−/− retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4−/− mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4−/− mice expressed more c3 in the RPE and fewer cfi transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4−/−, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4−/− mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4−/− retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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20 pages, 4959 KiB  
Article
Bone Marrow-Derived Mononuclear Cell Transplants Decrease Retinal Gliosis in Two Animal Models of Inherited Photoreceptor Degeneration
by Johnny Di Pierdomenico, Diego García-Ayuso, María Elena Rodríguez González-Herrero, David García-Bernal, Miguel Blanquer, José Manuel Bernal-Garro, Ana M. García-Hernández, Manuel Vidal-Sanz and María P. Villegas-Pérez
Int. J. Mol. Sci. 2020, 21(19), 7252; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197252 - 30 Sep 2020
Cited by 14 | Viewed by 3013
Abstract
Inherited photoreceptor degenerations are not treatable diseases and a frequent cause of blindness in working ages. In this study we investigate the safety, integration and possible rescue effects of intravitreal and subretinal transplantation of adult human bone-marrow-derived mononuclear stem cells (hBM-MSCs) in two [...] Read more.
Inherited photoreceptor degenerations are not treatable diseases and a frequent cause of blindness in working ages. In this study we investigate the safety, integration and possible rescue effects of intravitreal and subretinal transplantation of adult human bone-marrow-derived mononuclear stem cells (hBM-MSCs) in two animal models of inherited photoreceptor degeneration, the P23H-1 and the Royal College of Surgeons (RCS) rat. Immunosuppression was started one day before the injection and continued through the study. The hBM-MSCs were injected in the left eyes and the animals were processed 7, 15, 30 or 60 days later. The retinas were cross-sectioned, and L- and S- cones, microglia, astrocytes and Müller cells were immunodetected. Transplantations had no local adverse effects and the CD45+ cells remained for up to 15 days forming clusters in the vitreous and/or a 2–3-cells-thick layer in the subretinal space after intravitreal or subretinal injections, respectively. We did not observe increased photoreceptor survival nor decreased microglial cell numbers in the injected left eyes. However, the injected eyes showed decreased GFAP immunoreactivity. We conclude that intravitreal or subretinal injection of hBM-MSCs in dystrophic P23H-1 and RCS rats causes a decrease in retinal gliosis but does not have photoreceptor neuroprotective effects, at least in the short term. However, this treatment may have a potential therapeutic effect that merits further investigation. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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11 pages, 1547 KiB  
Article
Pigment Epithelium-Derived Factor (PEDF) Fragments Prevent Mouse Cone Photoreceptor Cell Loss Induced by Focal Phototoxicity In Vivo
by Francisco J. Valiente-Soriano, Johnny Di Pierdomenico, Diego García-Ayuso, Arturo Ortín-Martínez, Juan A. Miralles de Imperial-Ollero, Alejandro Gallego-Ortega, Manuel Jiménez-López, M. Paz Villegas-Pérez, S. Patricia Becerra and Manuel Vidal-Sanz
Int. J. Mol. Sci. 2020, 21(19), 7242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197242 - 30 Sep 2020
Cited by 13 | Viewed by 2042
Abstract
Here, we evaluated the effects of PEDF (pigment epithelium-derived factor) and PEDF peptides on cone-photoreceptor cell damage in a mouse model of focal LED-induced phototoxicity (LIP) in vivo. Swiss mice were dark-adapted overnight, anesthetized, and their left eyes were exposed to a blue [...] Read more.
Here, we evaluated the effects of PEDF (pigment epithelium-derived factor) and PEDF peptides on cone-photoreceptor cell damage in a mouse model of focal LED-induced phototoxicity (LIP) in vivo. Swiss mice were dark-adapted overnight, anesthetized, and their left eyes were exposed to a blue LED placed over the cornea. Immediately after, intravitreal injection of PEDF, PEDF-peptide fragments 17-mer, 17-mer[H105A] or 17-mer[R99A] (all at 10 pmol) were administered into the left eye of each animal. BDNF (92 pmol) and bFGF (27 pmol) injections were positive controls, and vehicle negative control. After 7 days, LIP resulted in a consistent circular lesion located in the supratemporal quadrant and the number of S-cones were counted within an area centered on the lesion. Retinas treated with effectors had significantly greater S-cone numbers (PEDF (60%), 17-mer (56%), 17-mer [H105A] (57%), BDNF (64%) or bFGF (60%)) relative to their corresponding vehicle groups (≈42%). The 17-mer[R99A] with no PEDF receptor binding and no neurotrophic activity, PEDF combined with a molar excess of the PEDF receptor blocker P1 peptide, or with a PEDF-R enzymatic inhibitor had undetectable effects in S-cone survival. The findings demonstrated that the cone survival effects were mediated via interactions between the 17-mer region of the PEDF molecule and its PEDF-R receptor. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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20 pages, 3813 KiB  
Article
Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling
by Adam C. Mirando, Raquel Lima e Silva, Zenny Chu, Peter A. Campochiaro, Niranjan B. Pandey and Aleksander S. Popel
Int. J. Mol. Sci. 2020, 21(14), 5142; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145142 - 21 Jul 2020
Cited by 10 | Viewed by 4219
Abstract
Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for [...] Read more.
Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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Review

Jump to: Research

13 pages, 1436 KiB  
Review
The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases
by Lyes Toualbi, Maria Toms and Mariya Moosajee
Int. J. Mol. Sci. 2021, 22(5), 2318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052318 - 26 Feb 2021
Cited by 6 | Viewed by 3074
Abstract
Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown [...] Read more.
Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. However, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Here, we review the advances in non-viral gene augmentation strategies, such as the use of plasmids with minimal bacterial backbones and scaffold/matrix attachment region (S/MAR) sequences, that have the capability to overcome these weaknesses by accommodating genes of any size and maintaining episomal transgene expression with a lower risk of eliciting an immune response. Low retinal transfection rates remain a limitation, but various strategies, including coupling the DNA with different types of chemical vehicles (nanoparticles) and the use of electrical methods such as iontophoresis and electrotransfection to aid cell entry, have shown promise in preclinical studies. Non-viral gene therapy may offer a safer and effective option for future treatment of IRDs. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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22 pages, 1770 KiB  
Review
Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels
by Yue Ruan, Subao Jiang and Adrian Gericke
Int. J. Mol. Sci. 2021, 22(3), 1296; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031296 - 28 Jan 2021
Cited by 66 | Viewed by 10359
Abstract
Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be [...] Read more.
Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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28 pages, 2856 KiB  
Review
Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration
by Emilie Grarup Jensen, Thomas Stax Jakobsen, Steffen Thiel, Anne Louise Askou and Thomas J. Corydon
Int. J. Mol. Sci. 2020, 21(24), 9752; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249752 - 21 Dec 2020
Cited by 11 | Viewed by 4475
Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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12 pages, 1104 KiB  
Review
The Molecular Network of YAP/Yorkie at the Cell Cortex and their Role in Ocular Morphogenesis
by Kassiani Skouloudaki, Dimitrios K. Papadopoulos and Toby W. Hurd
Int. J. Mol. Sci. 2020, 21(22), 8804; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228804 - 20 Nov 2020
Cited by 1 | Viewed by 2430
Abstract
During development, the precise control of tissue morphogenesis requires changes in the cell number, size, shape, position, and gene expression, which are driven by both chemical and mechanical cues from the surrounding microenvironment. Such physical and architectural features inform cells about their proliferative [...] Read more.
During development, the precise control of tissue morphogenesis requires changes in the cell number, size, shape, position, and gene expression, which are driven by both chemical and mechanical cues from the surrounding microenvironment. Such physical and architectural features inform cells about their proliferative and migratory capacity, enabling the formation and maintenance of complex tissue architecture. In polarised epithelia, the apical cell cortex, a thin actomyosin network that lies directly underneath the apical plasma membrane, functions as a platform to facilitate signal transmission between the external environment and downstream signalling pathways. One such signalling pathway culminates in the regulation of YES-associated protein (YAP) and TAZ transcriptional co-activators and their sole Drosophila homolog, Yorkie, to drive proliferation and differentiation. Recent studies have demonstrated that YAP/Yorkie exhibit a distinct function at the apical cell cortex. Here, we review recent efforts to understand the mechanisms that regulate YAP/Yki at the apical cell cortex of epithelial cells and how normal and disturbed YAP–actomyosin networks are involved in eye development and disease. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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13 pages, 881 KiB  
Review
The Rise of Retinal Organoids for Vision Research
by Kritika Sharma, Tim U. Krohne and Volker Busskamp
Int. J. Mol. Sci. 2020, 21(22), 8484; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228484 - 11 Nov 2020
Cited by 16 | Viewed by 4291
Abstract
Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have [...] Read more.
Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have been developed. These self-organizing 3D organ systems have shown to recapitulate the in vivo human retinogenesis resulting in morphological and functionally similar retinal cell types in vitro. In less than a decade, retinal organoids have assisted in modeling several retinal diseases that were rather difficult to mimic in rodent models. Retinal organoids are also considered as a photoreceptor source for cell transplantation therapies to counteract blindness. Here, we highlight the development and field’s improvements of retinal organoids and discuss their application aspects as human disease models, pharmaceutical testbeds, and cell sources for transplantations. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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19 pages, 2094 KiB  
Review
Retinal Degeneration and Alzheimer’s Disease: An Evolving Link
by Ajay Ashok, Neena Singh, Suman Chaudhary, Vindhya Bellamkonda, Alexander E Kritikos, Aaron S Wise, Neil Rana, Dallas McDonald and Rithvik Ayyagari
Int. J. Mol. Sci. 2020, 21(19), 7290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197290 - 02 Oct 2020
Cited by 69 | Viewed by 6998
Abstract
Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of [...] Read more.
Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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22 pages, 2474 KiB  
Review
Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy
by Laurel C. Chandler, Imran H. Yusuf, Michelle E. McClements, Alun R. Barnard, Robert E. MacLaren and Kanmin Xue
Int. J. Mol. Sci. 2020, 21(14), 4972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144972 - 14 Jul 2020
Cited by 26 | Viewed by 8790
Abstract
Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine [...] Read more.
Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)
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