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Progress in Retinal and Eye Research Jan 2022Inherited and age-related retinal degeneration is the hallmark of a large group of heterogeneous diseases and is the main cause of untreatable blindness today. Genetic... (Review)
Review
Inherited and age-related retinal degeneration is the hallmark of a large group of heterogeneous diseases and is the main cause of untreatable blindness today. Genetic factors play a major pathogenic role in retinal degenerations for both monogenic diseases (such as retinitis pigmentosa) and complex diseases with established genetic risk factors (such as age-related macular degeneration). Progress in genotyping techniques and back of the eye imaging are completing our understanding of these diseases and their manifestations in patient populations suffering from retinal degenerations. It is clear that whatever the genetic cause, the majority of vision loss in retinal diseases results from the loss of photoreceptor function. The timing and circumstances surrounding the loss of photoreceptor function determine the adequate therapeutic approach to use for each patient. Among such approaches, gene therapy is rapidly becoming a therapeutic reality applicable in the clinic. This massive move from laboratory work towards clinical application has been propelled by the advances in our understanding of disease genetics and mechanisms, gene delivery vectors, gene editing systems, and compensatory strategies for loss of photoreceptor function. Here, we provide an overview of existing modalities of retinal gene therapy and their relevance based on the needs of patient populations suffering from inherited retinal degenerations.
Topics: Genetic Therapy; Humans; Macular Degeneration; Retina; Retinal Degeneration; Retinitis Pigmentosa
PubMed: 34058340
DOI: 10.1016/j.preteyeres.2021.100975 -
Genetics in Medicine : Official Journal... Jun 2020Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be...
PURPOSE
Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy-number variations (CNVs), which have been shown as major contributors to unsolved IRD cases.
METHODS
Five hundred IRD patients were analyzed with targeted next-generation sequencing (NGS). The NGS data were used to detect CNVs with ExomeDepth and gCNV and the results were compared with CNV detection with a single-nucleotide polymorphism (SNP) array. Likely causal CNV predictions were validated by quantitative polymerase chain reaction (qPCR).
RESULTS
Likely disease-causing single-nucleotide variants (SNVs) and small indels were found in 55.6% of subjects. PVs in USH2A (11.6%), RPGR (4%), and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene.
CONCLUSION
CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.
Topics: DNA Copy Number Variations; Eye Proteins; Genes, Recessive; High-Throughput Nucleotide Sequencing; Humans; Retinal Degeneration; Virulence
PubMed: 32037395
DOI: 10.1038/s41436-020-0759-8 -
Science Translational Medicine Jan 2019Considerable progress has been made in testing stem cell-derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD)....
Considerable progress has been made in testing stem cell-derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD). However, the recent reports of oncogenic mutations in induced pluripotent stem cells (iPSCs) underlie the need for robust manufacturing and functional validation of clinical-grade iPSC-derived RPE before transplantation. Here, we developed oncogenic mutation-free clinical-grade iPSCs from three AMD patients and differentiated them into clinical-grade iPSC-RPE patches on biodegradable scaffolds. Functional validation of clinical-grade iPSC-RPE patches revealed specific features that distinguished transplantable from nontransplantable patches. Compared to RPE cells in suspension, our biodegradable scaffold approach improved integration and functionality of RPE patches in rats and in a porcine laser-induced RPE injury model that mimics AMD-like eye conditions. Our results suggest that the in vitro and in vivo preclinical functional validation of iPSC-RPE patches developed here might ultimately be useful for evaluation and optimization of autologous iPSC-based therapies.
Topics: Animals; Disease Models, Animal; Macular Degeneration; Rats; Retinal Degeneration; Retinal Pigment Epithelium; Stem Cells; Swine
PubMed: 30651323
DOI: 10.1126/scitranslmed.aat5580 -
Journal of Neuroinflammation May 2023Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis...
BACKGROUND
Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis‑targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration.
METHODS
Mice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment.
RESULTS
Intraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response.
CONCLUSIONS
This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.
Topics: Mice; Animals; Retinal Degeneration; Inflammation; Nucleotidyltransferases; RNA
PubMed: 37217935
DOI: 10.1186/s12974-023-02804-y -
The New England Journal of Medicine May 2008Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the... (Clinical Trial)
Clinical Trial
Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.
Topics: Adult; Blindness; Carrier Proteins; DNA, Complementary; Dependovirus; Eye Proteins; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Injections; Mutation; Promoter Regions, Genetic; Reflex, Pupillary; Retina; Retinal Degeneration; Visual Acuity; cis-trans-Isomerases
PubMed: 18441370
DOI: 10.1056/NEJMoa0802315 -
International Journal of Molecular... Nov 2022Optogenetics is a recent breakthrough in neuroscience, and one of the most promising applications is the treatment of retinal degenerative diseases. Multiple clinical... (Review)
Review
Optogenetics is a recent breakthrough in neuroscience, and one of the most promising applications is the treatment of retinal degenerative diseases. Multiple clinical trials are currently ongoing, less than a decade after the first attempt at visual restoration using optogenetics. Optogenetic therapy has great value in providing hope for visual restoration in late-stage retinal degeneration, regardless of the genotype. This alternative gene therapy consists of multiple elements including the choice of target retinal cells, optogenetic tools, and gene delivery systems. Currently, there are various options for each element, all of which have been developed as a product of technological success. In particular, the performance of optogenetic tools in terms of light and wavelength sensitivity have been improved by engineering microbial opsins and applying human opsins. To provide better post-treatment vision, the optimal choice of optogenetic tools and effective gene delivery to retinal cells is necessary. In this review, we provide an overview of the advancements in optogenetic therapy for visual restoration, focusing on available options for optogenetic tools and gene delivery methods.
Topics: Humans; Optogenetics; Retinal Degeneration; Retina; Vision, Ocular; Genetic Therapy
PubMed: 36499371
DOI: 10.3390/ijms232315041 -
Frontiers in Immunology 2019The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal... (Review)
Review
The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.
Topics: Animals; Humans; Microglia; Retinal Degeneration
PubMed: 31481963
DOI: 10.3389/fimmu.2019.01975 -
Genetics in Medicine : Official Journal... Feb 2022In Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time consuming process. To address this, we have developed the Mendelian Analysis...
PURPOSE
In Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time consuming process. To address this, we have developed the Mendelian Analysis Toolkit (MATK), a configurable, automated variant ranking program.
METHODS
MATK aggregates variant information from multiple annotation sources and uses expert-designed rules with parameterized weights to produce a ranked list of potentially causal solutions. MATK performance was measured by a comparison between MATK-aided and human-domain expert analyses of 1060 families with inherited retinal degeneration (IRD), analyzed using an IRD-specific gene panel (589 individuals) and exome sequencing (471 families).
RESULTS
When comparing MATK-assisted analysis with expert curation in both the IRD-specific gene panel and exome sequencing (1060 subjects), 97.3% of potential solutions found by experts were also identified by the MATK-assisted analysis (541 solutions identified with MATK of 556 solutions found by conventional analysis). Furthermore, MATK-assisted analysis identified 114 additional potential solutions from the 504 cases unsolved by conventional analysis.
CONCLUSION
MATK expedites the process of identification of likely solving variants in Mendelian traits, and reduces variability stemming from human error and researcher bias. MATK facilitates data reanalysis to keep up with the constantly improving annotation sources and next-generation sequencing processing pipelines. The software is open source and available at https://gitlab.com/matthew_maher/mendelanalysis.
Topics: Automation; High-Throughput Nucleotide Sequencing; Humans; Retinal Degeneration; Software; Exome Sequencing
PubMed: 34906470
DOI: 10.1016/j.gim.2021.09.015 -
Biochemical Pharmacology Sep 2022Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and... (Review)
Review
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
Topics: Carnitine; Humans; Infant, Newborn; Mitochondria; Photoreceptor Cells; Retina; Retinal Degeneration
PubMed: 35835206
DOI: 10.1016/j.bcp.2022.115168 -
Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives.International Journal of Molecular... Aug 2023Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases... (Review)
Review
Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.
Topics: Humans; Retinal Degeneration; Macular Degeneration; Retinitis Pigmentosa; Biomarkers; Blindness; Retina
PubMed: 37685886
DOI: 10.3390/ijms241713079