Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps.
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ABSTRACT:
SUBMITTER: Duncan JL
PROVIDER: S-EPMC6052953 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps.
Duncan Jacque L JL Pierce Eric A EA Laster Amy M AM Daiger Stephen P SP Birch David G DG Ash John D JD Iannaccone Alessandro A Flannery John G JG Sahel José A JA Zack Donald J DJ Zarbin Marco A MA
Translational vision science & technology 20180718 4
Similar Datasets
Project description:Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
| S-EPMC4315917 | biostudies-literature
Project description:Inherited retinal dystrophies/degenerations (IRDs) are the leading cause of visual impairment and incurable familial blindness in the Western world. Given the clinical and genetic heterogeneity, establishing a molecular diagnosis is especially relevant. The aim of this study was to perform the first nationwide survey to understand the prevalence and current management of IRDs in Portugal. A response was obtained from 26 healthcare providers (HCP) (76.5% response rate). Only 4 respondents reported not managing IRD patients. Most HCPs (68.1%) reported managing up to 100 patients, while three currently manage between 501 and 1000 patients. Based on the Portuguese population, an estimated IRD prevalence of 0.031%, i.e., about 1 in 3000 individuals, was calculated. In most HCPs (86.3%), most patients are adults, and non-syndromic retinitis pigmentosa is the most frequent diagnosis. Only 4 HCPs currently use the national, web-based IRD registry (IRD-PT). However, all but one respondent expressed interest in participating in such a registry. Genetic testing is available in 54.5%, with 58.3% HCPs reporting solved rates between 61-80%, but 4 to 9 months to get a genetic test result in 83.4% of cases. Based on this survey, the prevalence of biallelic RPE65-associated disease in Portugal is 0.00031%, i.e., approximately 1:300,000 individuals. Data from this study provide vital background information on national differences in the diagnosis and management of IRD patients. Nationwide implementation of the IRD-PT registry should be encouraged and supported to provide population-based reference data and to identify patients eligible for current and future therapies.
| S-EPMC11401845 | biostudies-literature
Project description:Inherited retinal diseases (IRDs) are associated with mutations in over 250 genes and represent a major cause of irreversible blindness worldwide. While gene augmentation or gene editing therapies could address the underlying genetic mutations in a small subset of patients, their utility remains limited by the great genetic heterogeneity of IRDs and the costs of developing individualised therapies. Gene-agnostic therapeutic approaches target common pathogenic pathways that drive retinal degeneration or provide functional rescue of vision independent of the genetic cause, thus offering potential clinical benefits to all IRD patients. Here, we review the key gene-agnostic approaches, including retinal cell reprogramming and replacement, neurotrophic support, immune modulation and optogenetics. The relative benefits and limitations of these strategies and the timing of clinical interventions are discussed.
| S-EPMC9881597 | biostudies-literature
Project description:Inherited retinal degenerations such as retinitis pigmentosa (RP) affect around one in 4000 people and are the leading cause of blindness in working age adults in several countries. In these typically monogenic conditions, there is progressive degeneration of photoreceptors; however, inner retinal neurons such as bipolar cells and ganglion cells remain largely structurally intact, even in end-stage disease. Therapeutic approaches aiming to stimulate these residual cells, independent of the underlying genetic cause, could potentially restore visual function in patients with advanced vision loss, and benefit many more patients than therapies directed at the specific gene implicated in each disorder. One approach investigated for this purpose is that of optogenetics, a method of neuromodulation that utilises light to activate neurons engineered to ectopically express a light-sensitive protein. Using gene therapy via adeno-associated viral vectors, a range of photosensitive proteins have been expressed in remaining retinal cells in advanced retinal degeneration with in vivo studies demonstrating restoration of visual function. Developing an effective optogenetic strategy requires consideration of multiple factors, including the light-sensitive protein that is used, the vector and method for gene delivery, and the target cell for expression because these in turn may affect the quality of vision that can be restored. Currently, at least four clinical trials are ongoing to investigate optogenetic therapies in patients, with the ultimate aim of reversing visual loss in end-stage disease.
| S-EPMC9804934 | biostudies-literature
Project description:Most patients with inherited retinal degenerations (IRDs) have been waiting for treatments that are "just around the corner" for decades, with only a handful of seminal breakthroughs happening in recent years. Highlighting the difficulties in the quest for curative therapeutics, Luxturna required 16 years of development before finally obtaining United States Food and Drug Administration (FDA) approval and its international equivalents. IRDs are both genetically and phenotypically heterogeneous. While this diversity offers many opportunities for gene-by-gene precision medicine-based approaches, it also poses a significant challenge. For this reason, alternative (or parallel) strategies to identify more comprehensive, across-the-board therapeutics for the genetically and phenotypically diverse IRD patient population are very appealing. Even when gene-specific approaches may be available and become approved for use, many patients may have reached a disease stage whereby these approaches may no longer be viable. Thus, alternate visual preservation or restoration therapeutic approaches are needed at these stages. In this review, we underscore several gene-agnostic approaches that are being developed as therapeutics for IRDs. From retinal supplementation to stem cell transplantation, optogenetic therapy and retinal prosthetics, these strategies would bypass at least in part the need for treating every individual gene or mutation or provide an invaluable complement to them. By considering the diverse patient population and treatment strategies suited for different stages and patterns of retinal degeneration, gene agnostic approaches are very well poised to impact favorably outcomes and prognosis for IRD patients.
| S-EPMC10133473 | biostudies-literature
Project description:PRLΔE1, a retina-specific isoform of prolactin, is expressed in multiple and diverse forms of canine inherited retinal degeneration (IRD). We find that while PRLΔE1 expression in rods is not associated with the initial phase of disease characterized by acute photoreceptor cell death, it is associated with the protracted phase of slow cell loss. Restoration of photoreceptors to a healthy state by gene-specific replacement therapy of individual IRDs successfully suppresses PRLΔE1 expression. Moreover, short-term PRLΔE1 silencing using shRNA results in preservation of outer nuclear layer thickness, suggesting PRLΔE1 drives retinal disease. However, longer-term observations reveal off-target toxic effects of the PRLΔE1 shRNA, precluding determination of its full therapeutic potential. Future research efforts aimed at enhancing the safety and specificity of PRLΔE1-targeting strategies may identify a potential universal intervention strategy for sustaining photoreceptors during the prolonged phase of multiple IRDs.
| S-EPMC11410941 | biostudies-literature
Project description:PurposeTo characterize the progression of vascular changes that occur in each retinal plexus, in three canine models of inherited retinal degeneration.MethodsIn this retrospective cohort study, we examined the retinal imaging records of 44 dogs from a research colony that had undergone optical coherence tomography angiography (OCTA) imaging. Animals enrolled included crd2/NPHP5 and xlpra2/RPGR mutant dogs imaged at different stages of photoreceptor loss, as well as RHOT4R/+ dogs after acute light-induced rod degeneration. Also included were normal controls imaged at similar ages. OCT angiograms of the superficial vascular plexus combined with the intermediate capillary plexus (SVP + ICP), and the deep capillary plexus (DCP) were analyzed using the AngioTool software to calculate vessel density and other vascular parameters.ResultsA reduction in vessel density was seen over time in both the SVP + ICP and DCP in all mutant dogs but was more pronounced in the DCP. Scans were subclassified based on outer nuclear layer (ONL) thinning compared to age-matched normal controls. When ONL loss was 0% to 50%, vessel density in the DCP was significantly lower than in age-matched controls. In all cases, when ONL loss exceeded 87.5%, vessel density in the SVP + ICP was significantly reduced as well. In the acute light-induced rod degeneration model, the vascular regression changes were observed mainly in the DCP.ConclusionsVessel density reduction in dogs undergoing retinal degeneration is first detected by OCTA in the DCP, and only at later stages in the SVP + ICP.
| S-EPMC9672900 | biostudies-literature
Project description:There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD). It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access to potentially applicable therapies. Here we show the current findings of a target capture next-generation sequencing study of over 750 patients from over 520 pedigrees currently situated in Ireland. We also demonstrate how processes can be implemented to retrospectively analyse patient datasets for the detection of structural variants in previously obtained sequencing reads. Pathogenic or likely pathogenic mutations were detected in 68% of pedigrees tested. We report nearly 30 novel mutations including three large structural variants. The population statistics related to our findings are presented by condition and credited to their respective candidate gene mutations. Rediagnosis rates of clinical phenotypes after genotyping are discussed. Possible causes of failure to detect a candidate mutation are evaluated. Future elements of this project, with a specific emphasis on structural variants and non-coding pathogenic variants, are expected to increase detection rates further and thereby produce an even more comprehensive representation of the genetic landscape of IRDs in Ireland.
| S-EPMC5704217 | biostudies-literature
Project description:Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.
| S-EPMC7226744 | biostudies-literature
Project description:Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Dozens of promising proofs of concept have been obtained in animal models of inherited retinal degenerations (IRDs), and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. However, this progress has also generated new questions and posed challenges that need to be addressed to further expand the applicability of gene therapy in the eye, including safe delivery of viral vectors to the outer retina, treatment of dominant IRDs as well as of IRDs caused by mutations in large genes, and, finally, selection of the appropriate IRDs and patients to maximize the efficacy of gene transfer. This review summarizes the strategies that are currently being exploited to overcome these challenges and drive the clinical development of retinal gene therapy.
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