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Molecular Advances in Retinal Diseases
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Molecular Advances in Retinal Diseases

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 (30 July 2024) | Viewed by 6702

Special Issue Editor

Dr. Jan Wijnholds

E-Mail Website
Guest Editor
Department of Ophthalmology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Interests: retinal degeneration; AAV gene therapy; crumbs homologue 1; CRB1; scRNAseq
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. There are many 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. The retina and retinal pigment epithelium (RPE) can be generated from induced pluripotent stem cells (hiPSC) and used for pre-clinical studies and single-cell RNAseq and biochemical studies.

This Special Issue of the International Journal of Molecular Sciences will focus on recent insights into “Molecular Advances in Retinal Diseases”, including hereditary disease, human and animal retinal pathology due to gene mutations, retinal inflammation, retinal gene therapy, hiPSC-derived neural retinal organoids and RPE, natural history studies on patients, pre-clinical and clinical gene therapy, animal models for hereditary retinal dystrophy, retinal imaging and scRNAseq. All submissions dealing with these topics are welcome. According to the Aims and Scope of IJMS, each manuscript must include basic studies in biochemistry, molecular biology or molecular medicine.

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

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Published Papers (3 papers)

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Research

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20 pages, 6680 KiB  
Article
A Proximity Complementation Assay to Identify Small Molecules That Enhance the Traffic of ABCA4 Misfolding Variants
by Davide Piccolo, Christina Zarouchlioti, James Bellingham, Rosellina Guarascio, Kalliopi Ziaka, Robert S. Molday and Michael E. Cheetham
Int. J. Mol. Sci. 2024, 25(8), 4521; https://doi.org/10.3390/ijms25084521 - 20 Apr 2024
Viewed by 1183
Abstract
ABCA4-related retinopathy is the most common inherited Mendelian eye disorder worldwide, caused by biallelic variants in the ATP-binding cassette transporter ABCA4. To date, over 2200 ABCA4 variants have been identified, including missense, nonsense, indels, splice site and deep intronic defects. Notably, more than [...] Read more.
ABCA4-related retinopathy is the most common inherited Mendelian eye disorder worldwide, caused by biallelic variants in the ATP-binding cassette transporter ABCA4. To date, over 2200 ABCA4 variants have been identified, including missense, nonsense, indels, splice site and deep intronic defects. Notably, more than 60% are missense variants that can lead to protein misfolding, mistrafficking and degradation. Currently no approved therapies target ABCA4. In this study, we demonstrate that ABCA4 misfolding variants are temperature-sensitive and reduced temperature growth (30 °C) improves their traffic to the plasma membrane, suggesting the folding of these variants could be rescuable. Consequently, an in vitro platform was developed for the rapid and robust detection of ABCA4 traffic to the plasma membrane in transiently transfected cells. The system was used to assess selected candidate small molecules that were reported to improve the folding or traffic of other ABC transporters. Two candidates, 4-PBA and AICAR, were identified and validated for their ability to enhance both wild-type ABCA4 and variant trafficking to the cell surface in cell culture. We envision that this platform could serve as a primary screen for more sophisticated in vitro testing, enabling the discovery of breakthrough agents to rescue ABCA4 protein defects and mitigate ABCA4-related retinopathy. Full article
(This article belongs to the Special Issue Molecular Advances in Retinal Diseases)
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20 pages, 3839 KiB  
Article
Therapeutic Delivery of Soluble Fractalkine Ameliorates Vascular Dysfunction in the Diabetic Retina
by Derek Rodriguez, Kaira A. Church, Chelsea T. Smith, Difernando Vanegas, Sandra M. Cardona, Isabel A. Muzzio, Kevin R. Nash and Astrid E. Cardona
Int. J. Mol. Sci. 2024, 25(3), 1727; https://doi.org/10.3390/ijms25031727 - 31 Jan 2024
Cited by 3 | Viewed by 2185
Abstract
Diabetic retinopathy (DR)-associated vision loss is a devastating disease affecting the working-age population. Retinal pathology is due to leakage of serum components into retinal tissues, activation of resident phagocytes (microglia), and vascular and neuronal damage. While short-term interventions are available, they do not [...] Read more.
Diabetic retinopathy (DR)-associated vision loss is a devastating disease affecting the working-age population. Retinal pathology is due to leakage of serum components into retinal tissues, activation of resident phagocytes (microglia), and vascular and neuronal damage. While short-term interventions are available, they do not revert visual function or halt disease progression. The impact of microglial inflammatory responses on the neurovascular unit remains unknown. In this study, we characterized microglia–vascular interactions in an experimental model of DR. Early diabetes presents activated retinal microglia, vascular permeability, and vascular abnormalities coupled with vascular tortuosity and diminished astrocyte and endothelial cell-associated tight-junction (TJ) and gap-junction (GJ) proteins. Microglia exclusively bind to the neuronal-derived chemokine fractalkine (FKN) via the CX3CR1 receptor to ameliorate microglial activation. Using neuron-specific recombinant adeno-associated viruses (rAAVs), we therapeutically overexpressed soluble (sFKN) or membrane-bound (mFKN) FKN using intra-vitreal delivery at the onset of diabetes. This study highlights the neuroprotective role of rAAV-sFKN, reducing microglial activation, vascular tortuosity, fibrin(ogen) deposition, and astrogliosis and supporting the maintenance of the GJ connexin-43 (Cx43) and TJ zonula occludens-1 (ZO-1) molecules. The results also show that microglia–vascular interactions influence the vascular width upon administration of rAAV-sFKN and rAAV-mFKN. Administration of rAAV-sFKN improved visual function without affecting peripheral immune responses. These findings suggest that overexpression of rAAV-sFKN can mitigate vascular abnormalities by promoting glia–neural signaling. sFKN gene therapy is a promising translational approach to reverse vision loss driven by vascular dysfunction. Full article
(This article belongs to the Special Issue Molecular Advances in Retinal Diseases)
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Review

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23 pages, 1300 KiB  
Review
Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models
by Andrew McDonald and Jan Wijnholds
Int. J. Mol. Sci. 2024, 25(5), 2887; https://doi.org/10.3390/ijms25052887 - 1 Mar 2024
Cited by 2 | Viewed by 2421
Abstract
The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor [...] Read more.
The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including RPGR, CEP290, MYO7A, and USH2A. Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques. Full article
(This article belongs to the Special Issue Molecular Advances in Retinal Diseases)
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