Management of keratoconus: an updated review

Frontiers in Medicine, Journal Year: 2023, Volume and Issue: 10

Published: June 20, 2023

Keratoconus is the most common corneal ectatic disorder. It characterized by progressive thinning with resultant irregular astigmatism and myopia. Its prevalence has been estimated at 1:375 to 1:2,000 people globally, a considerably higher rate in younger populations. Over past two decades, there was paradigm shift management of keratoconus. The treatment expanded significantly from conservative (e.g., spectacles contact lenses wear) penetrating keratoplasty many other therapeutic refractive modalities, including cross-linking (with various protocols/techniques), combined CXL-keratorefractive surgeries, intracorneal ring segments, anterior lamellar keratoplasty, more recently, Bowman's layer transplantation, stromal keratophakia, regeneration. Several recent large genome-wide association studies (GWAS) have identified important genetic mutations relevant keratoconus, facilitating development potential gene therapy targeting keratoconus halting disease progression. In addition, attempts made leverage power artificial intelligence-assisted algorithms enabling earlier detection progression prediction this review, we provide comprehensive overview current emerging propose algorithm for systematically guiding clinical entity.

Language: Английский

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Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 13, 2023

Abstract Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene and editing. We generated LNP variants through the inclusion positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) carboxy-ester (LNPx) modified PEG-lipids, neutral unmodified PEG-lipids (LNP). Subretinal injections LNPa containing Cre in mouse show tdTomato signal retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx LNPz 27% 16% photoreceptor transfection, respectively, with striking localization extending from synaptic pedicle to outer segments, displaying pan-retinal distribution photoreceptors RPE. Cas9 sgAi9 leads formation an oval elongated structure a charge resulting 16.4% editing restricted Surface modifications LNPs PEG alter cellular tropism mRNA. genome retina future be used correct genetic mutations that lead blindness.

Language: Английский

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Gene-agnostic therapeutic approaches for inherited retinal degenerations

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 9, 2023

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 editing therapies could address the underlying genetic small subset patients, their utility remains limited by great heterogeneity IRDs costs developing individualised therapies. Gene-agnostic therapeutic approaches target common pathogenic pathways that drive degeneration provide functional rescue vision independent cause, thus offering potential clinical benefits to all IRD patients. Here, we review key gene-agnostic approaches, including cell reprogramming replacement, neurotrophic support, immune modulation optogenetics. The relative limitations these strategies timing interventions discussed.

Language: Английский

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RNA-targeting strategies as a platform for ocular gene therapy

Progress in Retinal and Eye Research, Journal Year: 2022, Volume and Issue: 92, P. 101110 - 101110

Published: July 13, 2022

Language: Английский

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Self-Reported Functional Vision in USH2A-Associated Retinal Degeneration as Measured by the Michigan Retinal Degeneration Questionnaire

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(6), P. 5 - 5

Published: June 4, 2024

Purpose: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, Michigan Retinal Degeneration Questionnaire (MRDQ), correlate MRDQ scores well-established visual function measurements. Design: An observational cross-sectional (n = 93) participants who had Usher Syndrome Type 2 (USH2, n 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; 38) associated biallelic variants USH2A gene. Methods: protocol approved by all ethics boards informed consent obtained from each participant. Participants completed at 48-month follow-up visit. Disease duration participants. One-way ANOVA used compare subgroups (clinical diagnosis, age, disease duration, full-field stimulus threshold [FST] Blue-Red mediation) on mean per domain. Spearman correlation coefficients were assess associations between domains visual/retinal assessments. Results: Of sample, 58% female median 13 years. sensitive differences clinical FST mediation. correlated static perimetry, microperimetry, testing, best-corrected acuity (BCVA). Conclusions: Self-reported FV measured MRDQ, when applied USH2 ARRP participants, good distributional characteristics well tests. adds new dimension understanding vision-related functioning establishes PRO tool as an informative measure evaluating outcomes.

Language: Английский

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Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(18), P. 5512 - 5512

Published: Sept. 18, 2024

Inherited retinal diseases (IRDs) encompass a wide spectrum of rare conditions characterized by diverse phenotypes associated with hundreds genetic variations, often leading to progressive visual impairment and profound vision loss. Multiple natural history studies clinical trials exploring gene therapy for various IRDs are ongoing. Outcomes ophthalmic measure changes in three main categories-structural, functional, patient-focused outcomes. Since may range from congenital poor central birth affecting the peripheral retina initially progressing insidiously acuity affected late disease course, typical outcome measures such as ocular coherence tomography (OCT) imaging macula not provide adequate representation therapeutic outcomes including alterations course. Thus, alternative unique necessary assess loss vision, color night contrast sensitivity IRDs. These differences have complicated assessment IRD therapies, had design novel specialized endpoints demonstrate treatment efficacy. As engineering techniques continue advance growing investment industry accelerated approval tracks orphan conditions, must improve their assessments safety efficacy new therapies that aim come market. Here, we will an overview current approaches, review measuring function, highlight those utilized recent trials, stage 2 3 through second quarter 2024.

Language: Английский

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Lipid Nanoparticle-Mediated Delivery of mRNA Into the Mouse and Human Retina and Other Ocular Tissues

Translational Vision Science & Technology, Journal Year: 2024, Volume and Issue: 13(7), P. 7 - 7

Published: July 9, 2024

Purpose: Lipid nanoparticles (LNPs) show promise in their ability to introduce mRNA drive protein expression specific cell types of the mammalian eye. Here, we examined encapsulated LNPs with two distinct formulations gene mouse and human retina other ocular tissues. Methods: We introduced mRNA-carrying into biological systems. Intravitreal injections were tested deliver Human retinal pigment epithelium (RPE) explants used assess tissue. analyzed specificity using histology, immunofluorescence, imaging. Results: In mice, mRNAs encoding GFP ciliary neurotrophic factor (CNTF) specifically expressed by Müller glia RPE. Acute inflammatory changes measured microglia distribution (Iba-1) or interleukin-6 (IL-6) not observed 6 hours post-injection. RPE also high levels GFP. cells apical basal processes consistent perivascular macrophages. Conclusions: demonstrated reliably transfect subpopulations eye tissues vivo Of significance, intravitreal sufficient mice. To our knowledge, demonstrate delivery for first time. Translational Relevance: Ocular gene-replacement therapies non-viral vector methods are a promising alternative adeno-associated virus (AAV) vectors. Our studies that LNP can be both without inducing significant inflammation. This methodology could lines, tissue explants, potentially as therapy clinical setting future.

Language: Английский

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Nanoneedles Induce Targeted siRNA Silencing of p16 in the Human Corneal Endothelium

Advanced Science, Journal Year: 2022, Volume and Issue: 9(33)

Published: Oct. 17, 2022

Abstract Nanoneedles can target nucleic acid transfection to primary cells at tissue interfaces with high efficiency and minimal perturbation. The corneal endothelium is an ideal for nanoneedle‐mediated RNA interference therapy aimed enhancing its proliferative capacity, necessary regeneration. This work develops a strategy siRNA nanoninjection the human endothelium. deliver p16‐targeting endothelial in vitro without toxicity. nanoinjection of induces p16 silencing increases cell proliferation, as monitored by ki67 expression. Furthermore, targeting nontoxic ex vivo, silences transfected cells. These data indicate that support targeted treatment dysfunction.

Language: Английский

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Repurposing small molecules for nephronophthisis and related renal ciliopathies

Kidney International, Journal Year: 2023, Volume and Issue: 104(2), P. 245 - 253

Published: May 25, 2023

Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It most common genetic cause of kidney failure in children and young adults. Clinically genetically heterogeneous, it caused variants ciliary genes, resulting either isolated disease or syndromic forms association with other manifestations disorders. No curative treatment currently available. Over past 2 decades, advances understanding mechanisms have identified several dysregulated signaling pathways, some shared cystic diseases. Notably, molecules previously developed target these pathways shown promising beneficial effects orthologous mouse models. In addition knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens "repurposing" libraries small able rescue ciliogenesis defects observed nephronophthisis conditions. Those compounds appeared act on relevant and, when tested, showed nephronophthisis-associated extrarenal mice. this review, we summarized those studies that highlight drug strategies context a rare such as nephronophthisis-related ciliopathies, broad heterogeneity systemic but mechanisms.

Language: Английский

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Phenotypic Distinctions Between EYS- and USH2A-Associated Retinitis Pigmentosa in an Asian Population

Translational Vision Science & Technology, Journal Year: 2025, Volume and Issue: 14(2), P. 16 - 16

Published: Feb. 11, 2025

Purpose: This study compares clinical characteristics of retinitis pigmentosa (RP) associated with mutations in the EYS and USH2A genes a Southeast Asian cohort. Methods: Prospective single-center families EYS- or USH2A-associated RP seen at Singapore National Eye Centre. Comprehensive ophthalmic evaluations, multimodal imaging, genetic testing, longitudinal follow-up identified clinically useful differentiating features between two genotypes. Results: A total 300 were enrolled, RP, accounting for 24.7% all probands 50.7% solved likely cases. cases predominantly nonsyndromic (75%). EYS-associated was more severe functional structural outcomes, patients myopic than (SE −3.31 vs. −0.69; P < 0.0001). displayed peripapillary nasal sparing on autofluorescence imaging frequently (57.6% 26.7%; = 0.006), whereas often had parafoveal ring (73.3% 30.3%; 0.0002). Multiple logistic regression diagnostic 83.2% accuracy distinguishing USH2A, validated second unrelated Conclusions: have overlapping presentations but can be distinguished based constellation phenotypic including disease onset severity, refractive error, fundus autofluorescence. These may support effective strategy these common forms RP. Translational Relevance: Distinct provide valuable tools that inform personalized management facilitate targeted interventions practice.

Language: Английский

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