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Molecular Therapies for Inherited Retinal Diseases
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Molecular Therapies for Inherited Retinal Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (1 March 2019) | Viewed by 78057

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Rob W.J. Collin

E-Mail Website
Guest Editor
Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Interests: gene augmentation therapy; inherited retinal diseases; optogenetics; Retinitis Pigmentosa; Stargardt disease; splicing modulation; vertebrate model systems
Dr. Alejandro Garanto

E-Mail Website
Guest Editor
1. Department of Pediatrics, Amalia Children's Hospital, Nijmegen, The Netherlands
2. Department of Human Genetics and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
Interests: RNA editing; RNA delivery; genome editing; induced pluripotent stem cell technology; inherited retinal diseases; splicing modulation; molecular therapies; neurometabolic diseases; congenital disorders of glycosylation

Special Issue Information

Dear Colleagues,

Following the implementation of next-generation sequencing technologies (e.g., exome and genome sequencing) in molecular diagnostics, the majority of genetic defects underlying inherited retinal disease (IRD) can readily be identified. In parallel, the possibilities to counteract the molecular consequences of these defects are rapidly emerging, providing hope for personalized medicine. ‘Classical’ gene augmentation therapy has been under study for several genetic subtypes of IRD, and can be considered a safe and sometimes effective therapeutic strategy. The recent market approval of the first retinal gene augmentation therapy product (LuxturnaTM, for individuals with bi-allelic RPE65 mutations) by the FDA has not only demonstrated the potential of this specific approach, but also opens avenues for the development of other strategies. Yet, every gene—or even every mutation—may need a tailor-made therapeutic approach, in order to obtain the most efficacious strategy with minimal risks associated. Besides gene augmentation therapy, other subtypes of molecular therapy are currently being designed and/or implemented, including splice modulation, DNA or RNA editing, optogenetics and pharmacological modulation. In addition, the development of proper delivery vectors has gained strong attention, and should not be overlooked when designing and testing a novel therapeutic approach. In this Special Issue, we aim to describe the current state-of-the-art of molecular therapeutics for IRD, and discuss existing and novel therapeutic strategies, from idea to implementation, and from bench to bedside. This issue is not meant to include papers on therapeutic strategies for multifactorial eye diseases, such as age-related macular degeneration, glaucoma or myopia, nor on non-molecular therapeutics of IRDs such as cell replacement therapy or retinal implants.

Dr. Rob W.J. Collin
Dr. Alejandro Garanto
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. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • Inherited retinal disease
  • Molecular therapy
  • Gene augmentation
  • Splicing modulation
  • Genome editing
  • RNA editing
  • Optogenetics
  • Delivery vectors
  • Retina

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

1 pages, 129 KiB  
Editorial
Preface of Special Issue "Molecular Therapies for Inherited Retinal Diseases"
by Rob W.J. Collin and Alejandro Garanto
Genes 2020, 11(2), 169; https://doi.org/10.3390/genes11020169 - 05 Feb 2020
Cited by 3 | Viewed by 1743
Abstract
Inherited retinal diseases (IRDs) are a group of progressive disorders that lead to severe visual impairment or even complete blindness [...] Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)

Research

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14 pages, 1475 KiB  
Article
Antisense Oligonucleotide Screening to Optimize the Rescue of the Splicing Defect Caused by the Recurrent Deep-Intronic ABCA4 Variant c.4539+2001G>A in Stargardt Disease
by Alejandro Garanto, Lonneke Duijkers, Tomasz Z. Tomkiewicz and Rob W. J. Collin
Genes 2019, 10(6), 452; https://doi.org/10.3390/genes10060452 - 14 Jun 2019
Cited by 49 | Viewed by 4769
Abstract
Deep-sequencing of the ABCA4 locus has revealed that ~10% of autosomal recessive Stargardt disease (STGD1) cases are caused by deep-intronic mutations. One of the most recurrent deep-intronic variants in the Belgian and Dutch STGD1 population is the c.4539+2001G>A mutation. This variant introduces a [...] Read more.
Deep-sequencing of the ABCA4 locus has revealed that ~10% of autosomal recessive Stargardt disease (STGD1) cases are caused by deep-intronic mutations. One of the most recurrent deep-intronic variants in the Belgian and Dutch STGD1 population is the c.4539+2001G>A mutation. This variant introduces a 345-nt pseudoexon to the ABCA4 mRNA transcript in a retina-specific manner. Antisense oligonucleotides (AONs) are short sequences of RNA that can modulate splicing. In this work, we designed 26 different AONs to perform a thorough screening to identify the most effective AONs to correct splicing defects associated with c.4539+2001G>A. All AONs were tested in patient-derived induced pluripotent stem cells (iPSCs) that were differentiated to photoreceptor precursor cells (PPCs). AON efficacy was assessed through RNA analysis and was based on correction efficacy, and AONs were grouped and their properties assessed. We (a) identified nine AONs with significant correction efficacies (>50%), (b) confirmed that a single nucleotide mismatch was sufficient to significantly decrease AON efficacy, and (c) found potential correlations between efficacy and some of the parameters analyzed. Overall, our results show that AON-based splicing modulation holds great potential for treating Stargardt disease caused by splicing defects in ABCA4. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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17 pages, 3284 KiB  
Article
AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?
by Iris Barny, Isabelle Perrault, Christel Michel, Nicolas Goudin, Sabine Defoort-Dhellemmes, Imad Ghazi, Josseline Kaplan, Jean-Michel Rozet and Xavier Gerard
Genes 2019, 10(5), 368; https://doi.org/10.3390/genes10050368 - 14 May 2019
Cited by 15 | Viewed by 3988
Abstract
Mutations in CEP290 encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo–lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated [...] Read more.
Mutations in CEP290 encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo–lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated–altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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12 pages, 1772 KiB  
Article
Antisense Oligonucleotide-Based Downregulation of the G56R Pathogenic Variant Causing NR2E3-Associated Autosomal Dominant Retinitis Pigmentosa
by Sarah Naessens, Laurien Ruysschaert, Steve Lefever, Frauke Coppieters and Elfride De Baere
Genes 2019, 10(5), 363; https://doi.org/10.3390/genes10050363 - 10 May 2019
Cited by 17 | Viewed by 4109
Abstract
The recurrent missense variant in Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3), c.166G>A, p.(Gly56Arg) or G56R, underlies 1%–2% of cases with autosomal dominant retinitis pigmentosa (adRP), a frequent, genetically heterogeneous inherited retinal disease (IRD). The mutant NR2E3 protein has a presumed [...] Read more.
The recurrent missense variant in Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3), c.166G>A, p.(Gly56Arg) or G56R, underlies 1%–2% of cases with autosomal dominant retinitis pigmentosa (adRP), a frequent, genetically heterogeneous inherited retinal disease (IRD). The mutant NR2E3 protein has a presumed dominant negative effect (DNE) by competition for dimer formation with Cone-Rod Homeobox (CRX) but with abolishment of DNA binding, acting as a repressor in trans. Both the frequency and DNE of G56R make it an interesting target for allele-specific knock-down of the mutant allele using antisense oligonucleotides (AONs), an emerging therapeutic strategy for IRD. Here, we designed gapmer AONs with or without a locked nucleic acid modification at the site of the mutation, which were analyzed for potential off-target effects. Next, we overexpressed wild type (WT) or mutant NR2E3 in RPE-1 cells, followed by AON treatment. Transcript and protein levels of WT and mutant NR2E3 were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot respectively. All AONs showed a general knock-down of mutant and WT NR2E3 on RNA and protein level, showing the accessibility of the region for AON-induced knockdown. Further modifications are needed however to increase allele-specificity. In conclusion, we propose the first proof-of-concept for AON-mediated silencing of a single nucleotide variation with a dominant negative effect as a therapeutic approach for NR2E3-associated adRP. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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Graphical abstract

12 pages, 2885 KiB  
Article
In Vitro Gene Delivery in Retinal Pigment Epithelium Cells by Plasmid DNA-Wrapped Gold Nanoparticles
by Sònia Trigueros, Elena B. Domènech, Vasileios Toulis and Gemma Marfany
Genes 2019, 10(4), 289; https://doi.org/10.3390/genes10040289 - 09 Apr 2019
Cited by 32 | Viewed by 4928
Abstract
Many rare diseases course with affectation of neurosensory organs. Among them, the neuroepithelial retina is very vulnerable due to constant light/oxidative stress, but it is also the most accessible and amenable to gene manipulation. Currently, gene addition therapies targeting retinal tissue (either photoreceptors [...] Read more.
Many rare diseases course with affectation of neurosensory organs. Among them, the neuroepithelial retina is very vulnerable due to constant light/oxidative stress, but it is also the most accessible and amenable to gene manipulation. Currently, gene addition therapies targeting retinal tissue (either photoreceptors or the retinal pigment epithelium), as a therapy for inherited retinal dystrophies, use adeno-associated virus (AAV)-based approaches. However, efficiency and safety of therapeutic strategies are relevant issues that are not always resolved in virus-based gene delivery and alternative methodologies should be explored. Based on our experience, we are currently assessing the novel physical properties at the nanoscale of inorganic gold nanoparticles for delivering genes to the retinal pigment epithelium (RPE) as a safe and efficient alternative approach. In this work, we present our preliminary results using DNA-wrapped gold nanoparticles (DNA-gold NPs) for successful in vitro gene delivery on human retinal pigment epithelium cell cultures, as a proof-of-principle to assess its feasibility for retina in vivo gene delivery. Our results show faster expression of a reporter gene in cells transfected with DNA-gold NPs compared to DNA-liposome complexes. Furthermore, we show that the DNA-gold NPs follow different uptake, internalization and intracellular vesicle trafficking routes compared to pristine NPs. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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12 pages, 592 KiB  
Article
Adeno-Associated Viral Vectors as a Tool for Large Gene Delivery to the Retina
by Ivana Trapani
Genes 2019, 10(4), 287; https://doi.org/10.3390/genes10040287 - 09 Apr 2019
Cited by 49 | Viewed by 6304
Abstract
Gene therapy using adeno-associated viral (AAV) vectors currently represents the most promising approach for the treatment of many inherited retinal diseases (IRDs), given AAV’s ability to efficiently deliver therapeutic genes to both photoreceptors and retinal pigment epithelium, and their excellent safety and efficacy [...] Read more.
Gene therapy using adeno-associated viral (AAV) vectors currently represents the most promising approach for the treatment of many inherited retinal diseases (IRDs), given AAV’s ability to efficiently deliver therapeutic genes to both photoreceptors and retinal pigment epithelium, and their excellent safety and efficacy profiles in humans. However, one of the main obstacles to widespread AAV application is their limited packaging capacity, which precludes their use from the treatment of IRDs which are caused by mutations in genes whose coding sequence exceeds 5 kb. Therefore, in recent years, considerable effort has been made to identify strategies to increase the transfer capacity of AAV vectors. This review will discuss these new developed strategies, highlighting the advancements as well as the limitations that the field has still to overcome to finally expand the applicability of AAV vectors to IRDs due to mutations in large genes. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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13 pages, 11917 KiB  
Article
Correction of NR2E3 Associated Enhanced S-cone Syndrome Patient-specific iPSCs using CRISPR-Cas9
by Laura R. Bohrer, Luke A. Wiley, Erin R. Burnight, Jessica A. Cooke, Joseph C. Giacalone, Kristin R. Anfinson, Jeaneen L. Andorf, Robert F. Mullins, Edwin M. Stone and Budd A. Tucker
Genes 2019, 10(4), 278; https://doi.org/10.3390/genes10040278 - 05 Apr 2019
Cited by 26 | Viewed by 4544
Abstract
Enhanced S-cone syndrome (ESCS) is caused by recessive mutations in the photoreceptor cell transcription factor NR2E3. Loss of NR2E3 is characterized by repression of rod photoreceptor cell gene expression, over-expansion of the S-cone photoreceptor cell population, and varying degrees of M- and [...] Read more.
Enhanced S-cone syndrome (ESCS) is caused by recessive mutations in the photoreceptor cell transcription factor NR2E3. Loss of NR2E3 is characterized by repression of rod photoreceptor cell gene expression, over-expansion of the S-cone photoreceptor cell population, and varying degrees of M- and L-cone photoreceptor cell development. In this study, we developed a CRISPR-based homology-directed repair strategy and corrected two different disease-causing NR2E3 mutations in patient-derived induced pluripotent stem cells (iPSCs) generated from two affected individuals. In addition, one patient’s iPSCs were differentiated into retinal cells and NR2E3 transcription was evaluated in CRISPR corrected and uncorrected clones. The patient’s c.119-2A>C mutation caused the inclusion of a portion of intron 1, the creation of a frame shift, and generation of a premature stop codon. In summary, we used a single set of CRISPR reagents to correct different mutations in iPSCs generated from two individuals with ESCS. In doing so we demonstrate the advantage of using retinal cells derived from affected patients over artificial in vitro model systems when attempting to demonstrate pathophysiologic mechanisms of specific mutations. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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Review

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40 pages, 4711 KiB  
Review
Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective
by Peter M.J. Quinn and Jan Wijnholds
Genes 2019, 10(12), 987; https://doi.org/10.3390/genes10120987 - 29 Nov 2019
Cited by 24 | Viewed by 7204
Abstract
The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream [...] Read more.
The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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15 pages, 2652 KiB  
Review
Molecular Therapies for Choroideremia
by Jasmina Cehajic Kapetanovic, Alun R. Barnard and Robert E. MacLaren
Genes 2019, 10(10), 738; https://doi.org/10.3390/genes10100738 - 23 Sep 2019
Cited by 14 | Viewed by 3984
Abstract
Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, [...] Read more.
Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, international research community has been engaged in conducting gene therapy trials for another more common inherited retinal disease known as choroideremia and with phase III clinical trials now underway, approval of this therapy is poised to follow suit. This chapter discusses new insights into clinical phenotyping and molecular genetic testing in choroideremia with review of molecular mechanisms implicated in its pathogenesis. We provide an update on current gene therapy trials and discuss potential inclusion of female carries in future clinical studies. Alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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15 pages, 1786 KiB  
Review
Molecular Strategies for RPGR Gene Therapy
by Jasmina Cehajic Kapetanovic, Michelle E McClements, Cristina Martinez-Fernandez de la Camara and Robert E MacLaren
Genes 2019, 10(9), 674; https://doi.org/10.3390/genes10090674 - 04 Sep 2019
Cited by 29 | Viewed by 5796
Abstract
Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%–20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, [...] Read more.
Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%–20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, characteristic for its early onset and rapid progression to blindness in young people. At present there is no cure for RPGR-related retinal disease. Recently, however, there have been important advances in RPGR research from bench to bedside that increased our understanding of RPGR function and led to the development of potential therapies, including the progress of adeno-associated viral (AAV)-mediated gene replacement therapy into clinical trials. This manuscript discusses the advances in molecular research, which have connected the RPGR protein with an important post-translational modification, known as glutamylation, that is essential for its optimal function as a key regulator of photoreceptor ciliary transport. In addition, we review key pre-clinical research that addressed challenges encountered during development of therapeutic vectors caused by high infidelity of the RPGR genomic sequence. Finally, we discuss the structure of three current phase I/II clinical trials based on three AAV vectors and RPGR sequences and link the rationale behind the use of the different vectors back to the bench research that led to their development. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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30 pages, 1977 KiB  
Review
Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges
by Irene Vázquez-Domínguez, Alejandro Garanto and Rob W. J. Collin
Genes 2019, 10(9), 654; https://doi.org/10.3390/genes10090654 - 28 Aug 2019
Cited by 57 | Viewed by 7913
Abstract
Inherited retinal diseases (IRDs) are both genetically and clinically highly heterogeneous and have long been considered incurable. Following the successful development of a gene augmentation therapy for biallelic RPE65-associated IRD, this view has changed. As a result, many different therapeutic approaches are [...] Read more.
Inherited retinal diseases (IRDs) are both genetically and clinically highly heterogeneous and have long been considered incurable. Following the successful development of a gene augmentation therapy for biallelic RPE65-associated IRD, this view has changed. As a result, many different therapeutic approaches are currently being developed, in particular a large variety of molecular therapies. These are depending on the severity of the retinal degeneration, knowledge of the pathophysiological mechanism underlying each subtype of IRD, and the therapeutic target molecule. DNA therapies include approaches such as gene augmentation therapy, genome editing and optogenetics. For some genetic subtypes of IRD, RNA therapies and compound therapies have also shown considerable therapeutic potential. In this review, we summarize the current state-of-the-art of various therapeutic approaches, including the pros and cons of each strategy, and outline the future challenges that lie ahead in the combat against IRDs. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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25 pages, 585 KiB  
Review
Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease
by Siebren Faber and Ronald Roepman
Genes 2019, 10(8), 557; https://doi.org/10.3390/genes10080557 - 24 Jul 2019
Cited by 8 | Viewed by 4128
Abstract
The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, [...] Read more.
The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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16 pages, 1836 KiB  
Review
The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers
by Arianna Tolone, Soumaya Belhadj, Andreas Rentsch, Frank Schwede and François Paquet-Durand
Genes 2019, 10(6), 453; https://doi.org/10.3390/genes10060453 - 14 Jun 2019
Cited by 36 | Viewed by 5648
Abstract
Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of [...] Read more.
Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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15 pages, 1039 KiB  
Review
Retinal miRNA Functions in Health and Disease
by Marta Zuzic, Jesus Eduardo Rojo Arias, Stefanie Gabriele Wohl and Volker Busskamp
Genes 2019, 10(5), 377; https://doi.org/10.3390/genes10050377 - 17 May 2019
Cited by 51 | Viewed by 7900
Abstract
The health and function of our visual system relies on accurate gene expression. While many genetic mutations are associated with visual impairment and blindness, we are just beginning to understand the complex interplay between gene regulation and retinal pathologies. MicroRNAs (miRNAs), a class [...] Read more.
The health and function of our visual system relies on accurate gene expression. While many genetic mutations are associated with visual impairment and blindness, we are just beginning to understand the complex interplay between gene regulation and retinal pathologies. MicroRNAs (miRNAs), a class of non-coding RNAs, are important regulators of gene expression that exert their function through post-transcriptional silencing of complementary mRNA targets. According to recent transcriptomic analyses, certain miRNA species are expressed in all retinal cell types, while others are cell type-specific. As miRNAs play important roles in homeostasis, cellular function, and survival of differentiated retinal cell types, their dysregulation is associated with retinal degenerative diseases. Thus, advancing our understanding of the genetic networks modulated by miRNAs is central to harnessing their potential as therapeutic agents to overcome visual impairment. In this review, we summarize the role of distinct miRNAs in specific retinal cell types, the current knowledge on their implication in inherited retinal disorders, and their potential as therapeutic agents. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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Other

8 pages, 189 KiB  
Commentary
The Foundation Fighting Blindness Plays an Essential and Expansive Role in Driving Genetic Research for Inherited Retinal Diseases
by Ben Shaberman and Todd Durham
Genes 2019, 10(7), 511; https://doi.org/10.3390/genes10070511 - 06 Jul 2019
Cited by 8 | Viewed by 4199
Abstract
The Foundation Fighting Blindness leads a collaborative effort among patients and families, scientists, and the commercial sector to drive the development of preventions, treatments, and cures for inherited retinal diseases (IRDs). When the nonprofit was established in 1971, it sought the knowledge and [...] Read more.
The Foundation Fighting Blindness leads a collaborative effort among patients and families, scientists, and the commercial sector to drive the development of preventions, treatments, and cures for inherited retinal diseases (IRDs). When the nonprofit was established in 1971, it sought the knowledge and insights of leaders in the retinal research field to guide its research funding decisions. While the Foundation’s early investments focused on gaining a better understanding of the genetic causes of IRDs, its portfolio of projects would come to include some of the most innovative approaches to saving and restoring vision, including gene replacement/augmentation therapies, gene editing, RNA modulation, optogenetics, and gene-based neuroprotection. In recent years, the Foundation invested in resources such as its patient registry, natural history studies, and genetic testing program to bolster clinical development and trials for emerging genetic therapies. Though the number of clinical trials for such therapies has surged over the last decade, the Foundation remains steadfast in its commitment to funding the initiatives that hold the most potential for eradicating the entire spectrum of IRDs. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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