Gene therapy ophthalmology

A 37-week-old girl underwent ophthalmic examination. Born at 32 weeks, the infant weighed 680 grams and received high-flow nasal cannula for respiratory distress of the newborn. Dilated fundus examination of the right eye revealed an atypical chorioretinal coloboma; the left eye revealed hyperpigmentary changes in the macula. Fluorescein angiography of both eyes showed retinal vascularization to zone II. Genetic testing revealed a heterozygous variant of uncertain significance in the catenin Alpha 1 (CTNNA1) gene...

Inherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached...

Retinal dystrophies are a common health problem worldwide that are currently incurable due to the inability of retinal cells to regenerate. Inherited retinal diseases (IRDs) are a diverse group of disorders characterized by progressive vision loss caused by photoreceptor cell dysfunction. The eye has always been an attractive organ for the development of novel therapies due to its independent access to the systemic pathway. Moreover, anti-sense oligonucleotides (ASOs), which facilitate manipulation of unwanted mRNAs via degradation or splicing, are undergoing rapid development and have been clinically deployed for the treatment of several diseases...

PURPOSE: To analyze the clinical characteristics, natural history, and genetics of PDE6B-associated retinal dystrophy. DESIGN: Retrospective, observational cohort study. METHODS: Review of medical records and retinal imaging, including fundus autofluorescence (FAF) imaging and spectral-domain optical coherence tomography (SD-OCT) of patients with molecularly confirmed PDE6B-associated retinal dystrophy in a single tertiary referral center...

The mechanism of myopia and the associated retinopathy remains unclear, and dysregulated microRNAs (miRNAs) are implicated in this disease. In this research, we purposed to find out the regulatory function that miRNAs play in myopia and the associated retinopathy. We first performed miRNA microarray analysis in a lens-induced myopia mouse model and found that miR-9-5p, miR-96-5p, miR-182-5p, miR-183-5p, and miR-181a-5p were elevated in the myopic retina. Then, we examined the functions and regulatory mechanisms of miR-181a-5p utilizing the human retinal pigment epithelium (RPE) cell line ARPE-19 b y overexpressing miR-181a-5p...

PURPOSE: The present review will summarize FECD-associated genes and pathophysiology, diagnosis, current  therapeutic approaches, and future treatment perspectives. METHODS: Literature review. RESULTS: Fuchs' endothelial corneal dystrophy (FECD) is the most common bilateral corneal dystrophy and accounts for one-third of all corneal transplants performed in the US. FECD is caused by a combination of genetic and non-heritable factors, and there are two types: early-onset FECD, which affects individuals from an early age and is usually more severe, and late-onset FECD, which is more common and typically manifests around the age of 40...

High-throughput sequencing technology, also known as next-generation sequencing technology, can explore new biomarkers and specific gene mutations. It has a pivotal role in promoting the gene research, which can limit the detection area, lessen the time needed for sequencing. Also, it can quickly screen out the suspected pathogenic genes of patients, gain the necessary genetic data, and provide the basis for clinical diagnosis and genetic counseling. In the research of corneal diseases, through the DNA sequencing of patients' diseased cells, it can provide a deeper understanding of corneal diseases and improve the diagnosis, classification and treatment alternatives of various corneal diseases...

Age-related macular degeneration (AMD) stands as a leading cause of irreversible blindness, particularly affecting central vision and impeding daily tasks. This paper provides a thorough exploration of AMD, distinguishing between its two main subtypes-Wet and Dry AMD-while shedding light on the prevalence and risk factors, including age, genetics, and smoking. The focus shifts to the current and future treatment landscape, examining both Dry and Wet AMD. Regarding Dry AMD, interventions such as antioxidant supplementation and ongoing clinical trials offer hope...

Basal cell carcinoma (BCC) is the most common skin malignancy, with a higher prevalence in Caucasians than in East Asians. Although there is a lack of epidemiological data in China, it is generally believed that the incidence of BCC in China is increasing due to the aging population. A variety of risk factors are related to the occurrence of BCC, among which ultraviolet rays and gene mutations play a major role, especially the abnormal activation of Hedgehog (Hh) signaling pathway, which is considered to be the most important pathogenesis of BCC...

A 33-5/7, 1570 g dichorionic diamniotic twin presented with cryptorchidism, failed hearing examination (both ears), poor feeding, profound hypoglycemia, coagulopathy, conjugated hyper-bilirubinemia, hydronephrosis, and hypotension. Microarray sent with results of whole genome SNP microgray analysis detected an interstitial duplication of the chromosomal segment 4q35 1q35.2. On this basis, telemedicine screening was performed to evaluate for ocular abnormalities in association with abnormal gene testing. Unilateral advanced retinopathy was noted affecting the right eye, with mature vascularization in the left eye...

PURPOSE: Pigmentation in uveal melanoma is associated with increased malignancy and is known as a barrier for photodynamic therapy. We investigated the role of pigmentation in tumor behavior and the response to light-activated Belzupacap sarotalocan (Bel-sar) treatment in a pigmented (wild type) and nonpigmented (tyrosinase knock-out [TYR knock-out]) cell line in vitro and in a murine model. METHODS: The B16F10 (TYR knock-out) was developed using CRISPR/Cas9. After the treatment with light-activated Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were measured by flow cytometry...

Heterozygous mutations of orthodenticle homeobox 2 ( OTX2 )can result in ocular malformations, pituitary abnormalities, or hypopituitarism spanning from isolated growth hormone (GH) deficiency to combined pituitary hormone deficiency. We present a patient exhibiting growth and pubertal disturbances, developmental delay, and pigmentary retinopathy. Further examination revealed deficiencies in GH following clonidine stimulation, hypogonadism, and, subsequently, central hypothyroidism. Brain magnetic resonance imaging uncovered hypoplasia of the pituitary and an ectopic pituitary tissue...

Regenerative medicine (RM) has emerged as a promising and revolutionary solution to address a range of unmet needs in healthcare, including ophthalmology. Moreover, RM takes advantage of the body's innate ability to repair and replace pathologically affected tissues. On the other hand, despite its immense promise, RM faces challenges such as ethical concerns, host-related immune responses, and the need for additional scientific validation, among others. The primary aim of this review is to present a high-level overview of current strategies in the domain of RM (cell therapy, exosomes, scaffolds, in vivo reprogramming, organoids, and interspecies chimerism), centering around the field of ophthalmology...

Adeno-associated virus (AAV) is widely used as a vector for delivery of gene therapy. Long term therapeutic benefit depends on perpetual expression of the wild-type gene after transduction of host cells by AAV. To address this issue in a mass population of identified single cells, 4 rats received an injection of a 1:1 mixture of rAAV2-retro-hSyn-EGFP and rAAV2-retro-hSyn-mCherry into each superior colliculus. After the virus was transported retrogradely to both retinas, serial fundus imaging was performed at days 14, 45, 211, and 375 to visualize individual fluorescent ganglion cells...

INTRODUCTION: Most lung cancers are diagnosed at an advanced stage. Common metastatic sites include the brain, bone, liver and adrenal glands. Ocular metastases, however, are extremely rare. We present a case of advanced lung adenocarcinoma presenting exclusively with photopsias attributable to retinal metastases. CASE DESCRIPTION: We describe a woman in her fifties, a lifetime non-smoker with an unremarkable medical and family history, who presented to the emergency department with photopsias for a week...

PURPOSE: Inherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large UK IRD patient cohort. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients with IRD who have attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis has been identified...

PURPOSE: Continuous vision loss due to vasoproliferative eye disease still represents an unsolved issue despite anti-vascular endothelial growth factor (VEGF) therapy. The impact of signal transducer and activator of transcription 3 (STAT3) signaling on retinal angiogenesis and its potential use as a therapeutic target remain controversial. In vitro, oncostatin M (OSM), as a strong STAT3 activator, possesses robust proangiogenic activity. This study investigated to what extent the proangiogenic effects of OSM translate to the in vivo setting of vasoproliferative eye disease...

Human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) therapies are promising alternatives for the treatment of retinal degenerative diseases caused by RPE degeneration. The generation of autologous RPE cells from human adult donors, which has the advantage of avoiding immune rejection and teratoma formation, is an alternative cell resource to gain mechanistic insight into and test potential therapies for RPE degenerative diseases. Here, we found that limbal stem cells (LSCs) from hESCs and adult primary human limbus have the potential to produce RPE cells and corneal stromal stem cells (CSSCs)...

INTRODUCTION: Mutational screening of inherited retinal disorders is prerequisite for gene targeted therapy. Our aim is to report and analyze the proportions of mutations in inherited retinal disease (IRD) causing genes from a single center in Switzerland in order to describe the distribution of IRDs in Western Switzerland. METHODS: We conducted a retrospective study of patient records. Criteria for inclusion were residence in Western Switzerland for patients and relatives presenting a clinical diagnosis of IRDs and an established molecular diagnosis managed by the genetics service of the Jules-Gonin Eye Hospital (JGEH) of Lausanne between January 2002 and December 2022...

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