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Signal Transduction and Targeted Therapy Sep 2023The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve... (Review)
Review
The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
Topics: Humans; Endoplasmic Reticulum Stress; Unfolded Protein Response; Color Vision Defects; Autophagy; Epigenomics
PubMed: 37709773
DOI: 10.1038/s41392-023-01570-w -
Journal of Perinatal Medicine Jul 2023The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal...
The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal neurons or retinal pigment epithelium (RPE) cells alter visual perception and ultimately can lead to blindness. The advent of human stem cells and their exploitation for vision restoration approaches has boosted the field. Traditionally, animal models - mostly rodents - have been generated and used to mimic certain monogenetic hereditary diseases. Of note, some models were extremely useful to develop specific gene therapies, for example for Retinitis Pigmentosa, Leber congenital amaurosis and achromatopsia. However, complex multifactorial diseases are not well recapitulated in rodent models such as age-related macular degeneration (AMD) as rodents lack a macula. Here, human stem cells are extremely valuable to advance the development of therapies. Particularly, cell replacement therapy is of enormous importance to treat retinal degenerative diseases. Moreover, different retinal degenerative disorders require the transplantation of unique cell types. The most advanced one is to substitute the RPE cells, which stabilize the light-sensitive photoreceptors. Some diseases require also the transplantation of photoreceptors. Depending on the disease pattern, both approaches can also be combined. Within this article, I briefly feature the underlying principle of cell replacement therapies, demonstrate some successes and discuss certain shortcomings of these approaches for clinical application.
Topics: Animals; Humans; Retinal Degeneration; Retinal Pigment Epithelium; Retina; Macular Degeneration; Stem Cells; Mammals
PubMed: 36474335
DOI: 10.1515/jpm-2022-0510 -
Stem Cell Research & Therapy Nov 2023Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making... (Review)
Review
Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Retina; Retinal Degeneration; Retinitis Pigmentosa; Organoids
PubMed: 38012786
DOI: 10.1186/s13287-023-03564-5 -
Journal of Personalized Medicine Jul 2023(1) Background: Achromatopsia is a rare disease of which the natural course and impact on life are still unknown to this date. We aimed to assess the morphological,...
(1) Background: Achromatopsia is a rare disease of which the natural course and impact on life are still unknown to this date. We aimed to assess the morphological, functional characteristics, and quality of life in a large sample size of patients with achromatopsia. (2) A total of 94 achromats were included in this retrospective cohort study. Sixty-four were patients of the Department of Ophthalmology, Saarland University Medical Centre in Homburg/Saar, Germany, between 2008 and 2021. Thirty further participants with achromatopsia from the national support group were included using an online questionnaire, which is available under 'Supplementary data'. Statistical analysis was performed using SPSS Version 25; (3) The 94 patients (37 males (39.4%) and 57 females (60.6%)) showed a mean age of 24.23 ± 18.53 years. Visual acuity was stable (SD ± 0.22 logMAR at 1.0 logMAR) over a time of observation from 2008 to 2021. Edge filter glasses were the most used optical aids, while enlarged reading glasses were the most used low vision aids. (4) Conclusions: Our findings give an insight into describing the natural process and the quality of life of achromatopsia. The results demonstrate that achromatopsia is a predominantly stationary disease. The individual prescription of edge filters and low-vision aids is essential following a personalised fitting.
PubMed: 37511719
DOI: 10.3390/jpm13071106 -
Progress in Retinal and Eye Research Jan 2024The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding,... (Review)
Review
The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.
Topics: Humans; Retinal Degeneration; Diabetic Retinopathy; Unfolded Protein Response; Endoplasmic Reticulum Stress; Retina; Endoplasmic Reticulum; Homeostasis
PubMed: 38092262
DOI: 10.1016/j.preteyeres.2023.101231 -
Ophthalmology Dec 2023To describe the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV).
PURPOSE
To describe the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV).
DESIGN
Multicenter retrospective cohort study.
PARTICIPANTS
A total of 67 patients with IRD-related CLV.
METHODS
Review of clinical notes, ophthalmic imaging, and molecular diagnosis from 2 international centers.
MAIN OUTCOME MEASURES
Visual function, retinal imaging, management, and response to treatment were evaluated and correlated.
RESULTS
The prevalence of IRD-related CLV was 0.5%; 54% of patients had isolated retinitis pigmentosa (RP), 21% had early-onset severe retinal dystrophy, and less frequent presentations were syndromic RP, sector RP, cone-rod dystrophy, achromatopsia, PAX6-related dystrophy, and X-linked retinoschisis. The overall age of patients at CLV diagnosis was 30.7 ± 16.9 years (1-83). Twenty-one patients (31%) had unilateral CLV, and the most common retinal features were telangiectasia, exudates, and exudative retinal detachment (ERD) affecting the inferior and temporal retina. Macular edema/schisis was observed in 26% of the eyes, and ERD was observed in 63% of the eyes. Fifty-four patients (81%) had genetic testing, 40 of whom were molecularly solved. Sixty-six eyes (58%) were observed, 17 eyes (15%) were treated with a single modality, and 30 eyes (27%) had a combined approach. Thirty-five eyes (31%) were "good responders," 42 eyes (37%) were "poor responders," 22 eyes (19%) had low vision at baseline and were only observed, and 12 eyes (11%) did not have longitudinal assessment. Twenty-one observed eyes (62%) responded well versus 14 (33%) treated eyes. Final best-corrected visual acuity was significantly worse than baseline (P = 0.002); 40 patients (60%) lost 15 ETDRS letters or more over follow-up in 1 or both eyes, and 21 patients (31%) progressed to more advanced stages of visual impairment.
CONCLUSIONS
Inherited retinal disease-related CLV is rare, sporadic, and mostly bilateral; there is no gender predominance, and it can occur in diverse types of IRD at any point of the disease, with a mean onset in the fourth decade of life. Patients with IRD-related CLV who have decreased initial visual acuity, ERD, CLV changes affecting 2 or more retinal quadrants, and CRB1-retinopathy may be at higher risk of a poor prognosis.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Prevalence; Retrospective Studies; Retina; Retinal Detachment; Retinal Dystrophies; Retinitis Pigmentosa; Cone-Rod Dystrophies; Vision, Low; Eye Proteins; Membrane Proteins; Nerve Tissue Proteins
PubMed: 37544434
DOI: 10.1016/j.ophtha.2023.07.027 -
European Journal of Ophthalmology Nov 2023Achromatopsia is an autosomal recessive cone dysfunction syndrome, characterized by absence of color discrimination, low visual acuity, photophobia, and nystagmus....
BACKGROUND
Achromatopsia is an autosomal recessive cone dysfunction syndrome, characterized by absence of color discrimination, low visual acuity, photophobia, and nystagmus. Achromatopsia constitutes a common cause of visual impairment in children, with a prevalence of 1:30,000 worldwide.
OBJECTIVE
To characterize the clinical characteristics of achromatopsia, the main genes causing the disease in our population and the clinical course of the disease, with an emphasis on visual function stability with increasing age.
METHODS
Retrospective study based on medical charts of patients with achromatopsia. Patients were divided into two groups according to their age at last follow-up: older and younger than 10 years. A subset of patients with long term follow-up were analyzed separately, with patients being described in both age groups.
RESULTS
Seventy-six patients were included in the study. The mean age was 14.28 years. Variants in the CNGA3 gene were the most common (73.6%). Clinical characteristics included photophobia (96.2%), nystagmus (93.6%), hypermetropia (72.3%) and strabismus (51.1%). In the large cohort there was no correlation of age with visual acuity ( = 0.129). In the separate subset cohort with long follow-up there was a relative improvement in visual acuity with age ( < 0.001).
CONCLUSIONS
CNGA3 is the main gene associated with achromatopsia in our population (around ∼ 73%), which is in contrast to the distribution worldwide (∼ 25%). Most achromats suffer from photophobia and nystagmus, and the main refractive error is hypermetropia. Achromatopsia's natural course seems to be stationary, and there may even be a slight improvement in visual acuity with time.
PubMed: 37920903
DOI: 10.1177/11206721231212768 -
Irish Journal of Medical Science Oct 2023Emergency service vehicle (ESV) drivers are an important part of the health, fire and police services. ESV driving is associated with increased crash risk, but little... (Review)
Review
BACKGROUND
Emergency service vehicle (ESV) drivers are an important part of the health, fire and police services. ESV driving is associated with increased crash risk, but little guidance exists in the literature on relevant medical conditions among drivers and their potential for adding to higher crash risks.
AIMS
We undertook a narrative review to examine the role of medical and other conditions in crash risk of ESV drivers.
METHOD
A literature search was conducted using the ScienceDirect and Transport Research International Documentation (TRID) databases. There was no time frame for the search, and results were restricted to review and research articles.
RESULTS
Of 570 papers identified, 13 remained after screening and full-text review. A range of factors have been shown to have an impact on increased crash risk, including the nature of the task, physical features of the equipment, training, experience, environmental conditions and secondary tasks. There was scant information on medical conditions other than alcohol use disorders.
CONCLUSIONS
Given issues of speed, vehicle and environment, it would seem prudent to mandate levels of medical fitness to drive similar to and sometimes exceeding (i.e. colour blindness for traffic signals and alerts, hearing impairment as first responders) those for group 2 drivers with extra stipulations relating to specific service needs such as enhanced visual (such as colour blindness and contrast sensitivity) and auditory function. Further research is needed on the prevalence and emergence of relevant medical conditions among ESV drivers, with due consideration of their application to the driving tasks in each service.
Topics: Humans; Automobile Driving; Accidents, Traffic; Alcoholism; Color Vision Defects; Ambulances
PubMed: 36752949
DOI: 10.1007/s11845-023-03301-0