The human retina is a highly complex tissue that makes up an integral part of our central nervous system. It is astonishing that our retina works seamlessly to provide one of our most critical ...senses, and it is equally devastating when a disease destroys a portion of the retina and robs people of their vision. After decades of research, scientists are beginning to understand retinal cells in a way that can benefit the millions of individuals suffering from inherited blindness. This understanding has come about in part with the ability to culture human embryonic stem cells and the innovation of induced pluripotent stem cells, which can be cultured from patients and used to model their disease. In this review, we highlight the successes of specific disease modelling studies and resulting molecular discoveries. The greatest strides in cellular modelling have come from mutations in genes with established and well-understood cellular functions in the context of the retina. We believe that the future of cellular modelling depends on emphasising reproducible production of retinal cell types, demonstrating functional rescue using site-specific programmable nucleases, and shifting towards unbiased screening using next generation sequencing.
Inherited retinal diseases (IRDs) are a leading cause of irreversible visual loss in the developed world. The primary driver of pathology in IRDs is pathogenic genetic variant. However, there is ...increasing evidence, from recent studies, for a role of the immune system in disease mechanism, particularly retinal microglia. Microglia are the primary immune cells in the retina and actively contribute to disease pathogenesis when activated locally by phagocytosing photoreceptors, inducing inflammation and signaling infiltration of circulating monocytes. In this article, we discuss the evidence for the contribution of retinal microglia to IRD pathogenesis reported so far using mice model.
Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal ...degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic
mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.
Importance
This novel endpoint tracks functional vision changes in patients with inherited retinal dystrophies (IRDs) over time.
Background
The aims of the study were to determine whether a ...multi‐luminance mobility test (MLMT) can detect functional vision changes over time in subjects with IRDs and to assess natural history and potential effects of investigational agents.
Design
This is a prospective, observational study.
Participants
Sixty‐two subjects were enrolled. Sixty (29 normal sighted and 31 visually impaired) were eligible; 54 (28 visually impaired and 26 normal‐sighted) completed all testing visits.
Methods
Subjects navigated MLMT courses three times over 1 year. At each visit, subjects completed testing using individual eyes, and both eyes, at up to nine standardized, increasing luminance levels (range 1 to 400 lux). Accuracy and speed were evaluated and compared with visual acuity (VA), visual field (VF) and a visual function questionnaire.
Main Outcome Measures
Accuracy and speed of normal and visually impaired subjects on MLMT, and reliability and content validity of MLMT were the main outcome measures.
Results
MLMT distinguished normal‐sighted from visually impaired subjects. All control subjects passed all MLMT attempts at all tested light levels. Visually impaired subjects' performance varied widely; some declined over 1 year. Performance declined markedly below certain VA and VF thresholds. Concordance on performance on two baseline visits was high: correlations for accuracy were 94% and 98% for lowest common and highest common lux levels.
Conclusions and Relevance
MLMT differentiated visually impaired from control populations and, in visually impaired subjects, identified a range of performances; and tracked performance declines over time, consistent with these progressive conditions.
Gut microbiome and retinal diseases: an updated review Nadeem, Urooba; Boachie-Mensah, Michael; Zhang, Jason ...
Current opinion in ophthalmology,
2022-May-01, 2022-05-00, 20220501, Volume:
33, Issue:
3
Journal Article
The gut microbiome, trillions of microorganisms residing in our digestive tract, is now believed to play a significant role in retinal diseases. Breakthroughs in computational biology and specialized ...animal models have allowed researchers not only to characterize microbes associated with retinal diseases, but also to provide early insights into the function of the microbiome in relation to biological processes in the retinal microenvironment. This review aims to provide an update on recent advances in the current knowledge on the relationship between the gut microbiome and retinal disorders.
Recent work demonstrates distinct gut microbial compositions associated with retinal diseases such as agerelated macular degeneration and retinopathy of prematurity. Currently, it is believed that gut dysbiosis leads to increased gut permeability, elevated circulation of bacterial products, microbial metabolites and inflammatory mediators that result in immune dysregulation at distant anatomic sites including the retina.
Emerging evidence for the gut-retina axis can elucidate previously unknown pathways involved in retinal diseases and also presents an exciting potential therapeutic avenue. Further preclinical and clinical studies are necessary to establish causation and delineate the precise relationship of the gut microbiome with retinal disorders.
Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal ...products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.
exemplifies the remarkable clinical and genetic heterogeneity observed in inherited retinal dystrophies. Our research describes the clinical and molecular characteristics of a patient manifesting an ...atypical retinal dystrophy pattern, marked by the identification of both a previously unreported and a rarely encountered
variant.
Whole-exome sequencing was performed to identify potential causative variants. The pathogenicity of the identified
variants was evaluated through
predictors and a minigene splice assay, specifically designed to assess the effect of the unreported
variant.
We identified two
gene variants in a patient exhibiting unusual and symmetrical alterations in both retinas, characterized by an increase in autofluorescence along the distribution of retinal vessels. These variants included a known rare missense variant, c.1376T>C, and a novel splice site variant, c.822G>T. For the latter variant (c.822G>T), we conducted a minigene splice assay that demonstrated the incorporation of a premature stop codon. This finding suggests a likely activation of the nonsense-mediated mRNA decay mechanism, ultimately resulting in the absence of protein production from this allele. Segregation analysis confirmed that these variants were in
.
Our data support that individuals with biallelic
variants may present with a unique pattern of macular degeneration and periarteriolar vascular pigmentation. This study highlights the importance of further clinical and molecular characterization of
variants to elucidate genotype-phenotype correlations in the context of inherited retinal dystrophies.
To assess the efficacy of voretigene neparvovec (VN) treatment by objective fixation stability and chromatic pupillometry testing in clinical practice.
Retrospective cohort study with longitudinal ...follow-up.
Twelve patients (aged 7–34 years) with RPE65-related inherited retinal dystrophies were treated at the same center with VN in both eyes.
Patients treated at the same center with VN were evaluated over a 12-month posttreatment follow-up by subjective and objective tests. Furthermore, patients treated with VN who developed atrophy were compared with those who did not.
Best-corrected visual acuity (BCVA), full-field stimulus threshold test (FST), semiautomated kinetic visual field (SKVF), microperimetry, and chromatic pupillometry over a 12-month follow-up.
Significant improvements of BCVA (P < 0.001), SKVF (P < 0.05), and FST (P < 0.001) were already observed 45 days after treatment and were maintained at the 12-month timepoint. Fixation stability, assessed by microperimetry, improved significantly (P < 0.05) after treatment. Chromatic pupillometry showed significant improvements (P < 0.05) at the 6- and 12-month timepoints. The increase in maximum pupillary constriction significantly (P < 0.001) correlated with higher retinal sensitivity in FST. Four patients developed multifocal retinal atrophy in both eyes, detected at the 6-month timepoint, but this atrophy was not generally associated with worse visual function outcomes.
This study explores objective outcomes in order to demonstrate the efficacy of VN treatment in addition to the tests normally performed in clinical practice. Our findings show a significant improvement of retinal function both in subjective assessments, such as BCVA, SKVF, and FST, and in objective measurements of fixation stability and maximum pupillary constriction. Moreover, the significant correlation between maximum pupillary constriction and light sensitivity thresholds corroborates the introduction of chromatic pupillometry as an objective test to better assess treatment outcomes in patients with inherited retinal dystrophies.
Proprietary or commercial disclosure may be found after the references in the Footnotes and Disclosures at the end of this article.
Retinitis pigmentosa (RP) belongs to a group of pigmentary retinopathies. It is the most common form of inherited retinal dystrophy, characterized by progressive degradation of photoreceptors that ...leads to nyctalopia, and ultimately, complete vision loss. RP is distinguished by the continuous retinal degeneration that progresses from the mid-periphery to the central and peripheral retina. RP was first described and named by Franciscus Cornelius Donders in the year 1857. It is one of the leading causes of bilateral blindness in adults, with an incidence of 1 in 3000 people worldwide. In this review, we are going to focus on the genetic heterogeneity of this disease, which is provided by various inheritance patterns, numerosity of variations and inter-/intra-familial variations based upon penetrance and expressivity. Although over 90 genes have been identified in RP patients, the genetic cause of approximately 50% of RP cases remains unknown. Heterogeneity of RP makes it an extremely complicated ocular impairment. It is so complicated that it is known as "fever of unknown origin". For prognosis and proper management of the disease, it is necessary to understand its genetic heterogeneity so that each phenotype related to the various genetic variations could be treated.
MER tyrosine kinase (MERTK) encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium. It plays a critical role in photoreceptor outer segment internalization ...prior to phagocytosis. Mutations in MERTK have been associated with severe autosomal recessive retinal dystrophies in the RCS rat and in humans. We present here a comprehensive review of all reported MERTK disease causing variants with the associated phenotype. In addition, we provide further data and insights of a large cohort of 1,195 inherited retinal dystrophies (IRD) index cases applying state‐of‐the‐art genotyping techniques and summarize current knowledge. A total of 79 variants have now been identified underlying rod‐cone dystrophy and cone‐rod dystrophy including 11 novel variants reported here. The mutation spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, 2 small insertion–deletions, 3 small duplications, and 2 exonic and 3 gross deletions. Altogether, mutations in MERTK account for ∼2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell‐based therapy.
We provide a mutation update for MER tyrosine kinase (MERTK) which encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium critical for photoreceptor outer segment phagocytosis. A total of 79 variants have been identified underlying inherited retinal diseases of which 11 are reported for the first time. Altogether, mutations in MERTK account for ∼2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell based therapy.
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