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Indian Journal of Ophthalmology Jul 2022Inherited retinal diseases (IRD) are genotypically and phenotypically varied disorders that lead to progressive degeneration of the outer retina and the retinal pigment... (Review)
Review
Inherited retinal diseases (IRD) are genotypically and phenotypically varied disorders that lead to progressive degeneration of the outer retina and the retinal pigment epithelium (RPE) eventually resulting in severe vision loss. Recent research and developments in gene therapy and cell therapy have shown therapeutic promise in these hitherto incurable diseases. In gene therapy, copies of a healthy gene are introduced into the host cells via a viral vector. Clinical trials for several genes are underway while treatment for RPE65 called voretigene neparvovec, is already approved and commercially available. Cell therapy involves the introduction of stem cells that can replace degenerated cells. These therapies are delivered to the target tissues, namely the photoreceptors (PR) and RPE via subretinal, intravitreal, or suprachoroidal delivery systems. Although there are several limitations to these therapies, they are expected to slow the disease progression and restore some visual functions. Further advances such as gene editing technologies are likely to result in more precise and personalized treatments. Currently, several IRDs such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, choroideremia, achromatopsia, and Usher syndrome are being evaluated for possible gene therapy or cell therapy. It is important to encourage patients to undergo gene testing and maintain a nationwide registry of IRDs. This article provides an overview of the basics of these therapies and their current status.
Topics: Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Retina; Retinal Diseases; Retinitis Pigmentosa
PubMed: 35791112
DOI: 10.4103/ijo.IJO_82_22 -
Pediatric Research Jul 2021
Topics: Color; Color Vision Defects; Female; Humans; Male; Publishing
PubMed: 33173171
DOI: 10.1038/s41390-020-01258-9 -
Current Biology : CB Sep 2023A new study describes a set of behavioural experiments that assess whether gene therapy can restore colour vision in patients with congenital achromatopsia.
A new study describes a set of behavioural experiments that assess whether gene therapy can restore colour vision in patients with congenital achromatopsia.
Topics: Humans; Color Vision Defects; Color Vision
PubMed: 37699345
DOI: 10.1016/j.cub.2023.07.065 -
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 -
Journal of AAPOS : the Official... Apr 2020To describe the nystagmus characteristics of subjects with molecularly confirmed CNGB3-associated achromatopsia and report the spectral domain optical coherence...
PURPOSE
To describe the nystagmus characteristics of subjects with molecularly confirmed CNGB3-associated achromatopsia and report the spectral domain optical coherence tomography (SD-OCT) findings in these individuals.
METHODS
Adults and children with CNGB3-achromatopsia underwent visual acuity testing, ocular motility assessments, video nystagmography, and SD-OCT imaging. Qualitative assessment of foveal structure was performed by grading SD-OCT images into one of five categories.
RESULTS
A total of 18 subjects (11 adults) were included. The majority demonstrated a phoria, with manifest strabismus present in only 3 subjects. The predominant nystagmus waveform within the cohort was pure pendular. Nine individuals demonstrated a mixture of waveforms. Nystagmus frequencies were 4-8 cycles/second, with no notable differences in eye movements between adults and children. SD-OCT imaging revealed a continuous ellipsoid zone (EZ) at the fovea in 2 subjects (grade 1) and EZ disruption (grade 2) in the remaining 16. Retinal structure characteristics were symmetrical in both eyes in each subject.
CONCLUSIONS
In our study cohort, nystagmus in CNGB3-associated achromatopsia had distinctive features, and the majority of subjects had retinal abnormalities at the fovea on SD-OCT. Early use of SD-OCT in the clinical work-up may eliminate the need for more invasive investigations, such as neuro-imaging.
Topics: Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Fovea Centralis; Humans; Nystagmus, Pathologic; Tomography, Optical Coherence
PubMed: 32151571
DOI: 10.1016/j.jaapos.2019.11.013 -
Cells Apr 2020Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches,... (Review)
Review
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.
Topics: Animals; Disease Models, Animal; Inheritance Patterns; Light Signal Transduction; Mutation; Photoreceptor Cells, Vertebrate; Retinal Degeneration
PubMed: 32260251
DOI: 10.3390/cells9040882 -
Cold Spring Harbor Perspectives in... Feb 2024Naturally occurring inherited retinal diseases (IRDs) in cats and dogs provide a rich source of potential models for human IRDs. In many cases, the phenotypes between... (Review)
Review
Naturally occurring inherited retinal diseases (IRDs) in cats and dogs provide a rich source of potential models for human IRDs. In many cases, the phenotypes between the species with mutations of the homologous genes are very similar. Both cats and dogs have a high-acuity retinal region, the area centralis, an equivalent to the human macula, with tightly packed photoreceptors and higher cone density. This and the similarity in globe size to that of humans means these large animal models provide information not obtainable from rodent models. The established cat and dog models include those for Leber congenital amaurosis, retinitis pigmentosa (including recessive, dominant, and X-linked forms), achromatopsia, Best disease, congenital stationary night blindness and other synaptic dysfunctions, -associated retinopathy, and Stargardt disease. Several of these models have proven to be important in the development of translational therapies such as gene-augmentation therapies. Advances have been made in editing the canine genome, which necessitated overcoming challenges presented by the specifics of canine reproduction. Feline genome editing presents fewer challenges. We can anticipate the generation of specific cat and dog IRD models by genome editing in the future.
Topics: Animals; Dogs; Cats; Humans; Cat Diseases; Dog Diseases; Retinal Diseases; Eye Diseases, Hereditary; Retinitis Pigmentosa; Proteins; Mutation
PubMed: 37217283
DOI: 10.1101/cshperspect.a041286 -
Journal of Applied Genetics May 2020Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which... (Review)
Review
Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for several human diseases, such as Leber's congenital amaurosis 2-LCA2 (caused by a mutation of RPE65), X-linked retinitis pigmentosa-XLRP (caused by mutation RPGR), and achromatopsia (caused by mutation of CNGB3). Promising results were also obtained for canine as follows: hemophilia (A and B), mucopolysaccharidoses (MPS I, MPS IIIB, MPS VII), leukocyte adhesion deficiency (CLAD), and muscular dystrophy (a counterpart of human Duchenne dystrophy). Present knowledge on molecular background of canine monogenic diseases and their successful gene therapies prove that dogs have an important contribution to preclinical studies.
Topics: Animals; Dog Diseases; Dogs; Eye Diseases; Genetic Diseases, Inborn; Genetic Therapy; Genome; Hemophilia A; Lysosomal Storage Diseases; Muscular Dystrophy, Animal; Mutation; Retinitis Pigmentosa
PubMed: 32189222
DOI: 10.1007/s13353-020-00554-8 -
Investigative Ophthalmology & Visual... Feb 2021Psychophysical and genetic testing provide substantial information about color vision phenotype and genotype. However, neither reveals how color vision phenotypes and...
PURPOSE
Psychophysical and genetic testing provide substantial information about color vision phenotype and genotype. However, neither reveals how color vision phenotypes and genotypes manifest themselves in individual cones, where color vision and its anomalies are thought to originate. Here, we use adaptive-optics phase-sensitive optical coherence tomography (AO-PSOCT) to investigate these relationships.
METHODS
We used AO-PSOCT to measure cone function-optical response to light stimulation-in each of 16 human subjects with different phenotypes and genotypes of color vision (five color-normal, three deuteranopic, two protanopic, and six deuteranomalous trichromatic subjects). We classified three spectral types of cones (S, M, and L), and we measured cone structure-namely cone density, cone mosaic arrangement, and spatial arrangement of cone types.
RESULTS
For the different phenotypes, our cone function results show that (1) color normals possess S, M, and L cones; (2) deuteranopes are missing M cones but are normal otherwise; (3) protanopes are missing L cones but are normal otherwise; and (4) deuteranomalous trichromats are missing M cones but contain evidence of at least two subtypes of L cones. Cone function was consistent with the subjects' genotype in which only the first two M and L genes in the gene array are expressed and was correlated with the estimated spectral separation between photopigments, including in the deuteranomalous trichromats. The L/M cone ratio was highly variable in the color normals. No association was found between cone density and the genotypes and phenotypes investigated, and the cone mosaic arrangement was altered in the dichromats.
CONCLUSIONS
AO-PSOCT is a novel method for assessing color vision phenotype and genotype in single cone cells.
Topics: Adult; Color Perception; Color Vision; Color Vision Defects; Female; Genotype; Humans; Male; Middle Aged; Phenotype; Retinal Cone Photoreceptor Cells; Retinal Pigments; Tomography, Optical Coherence; Young Adult
PubMed: 33544131
DOI: 10.1167/iovs.62.2.8 -
BMC Medical Genomics Jul 2024Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we...
Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.
BACKGROUND
Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals.
METHODS
Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022.
RESULTS
All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis.
CONCLUSIONS
Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.
Topics: Humans; Color Vision Defects; Cyclic Nucleotide Phosphodiesterases, Type 6; Male; Female; Pedigree; Exome Sequencing; Adult; Hearing Loss; Mutation; Consanguinity; Child; Iran; Phenotype; Eye Proteins
PubMed: 38956522
DOI: 10.1186/s12920-024-01942-3