Patient experiences and perceived value of genetic testing in inherited retinal diseases: a cross-sectional survey.

This study evaluated patient experiences with genetic testing for inherited retinal diseases (IRDs) and the association between underlying knowledge, testing outcomes, and the perceived value of the results. An online survey was distributed to adults with IRDs and parents/guardians of dependents with IRDs who had had genetic testing. Data included details of genetic testing, pre- and post- test perceptions, Decision Regret Scale, perceived value of results, and knowledge of gene therapy. Of 135 responses (85% from adults with IRDs), genetic testing was primarily conducted at no charge through public hospitals (49%) or in a research setting (30%). Key motivations for genetic testing were to confirm IRD diagnosis and to contribute towards research. Those who had received a genetic diagnosis (odds ratio: 6.71; p < 0.001) and those self-reported to have good knowledge of gene therapy (odds ratio: 2.69; p = 0.018) were more likely to have gained confidence in managing their clinical care. For over 80% of respondents, knowing the causative gene empowered them to learn more about their IRD and explore opportunities regarding clinical trials. Key genetic counselling information needs include resources for family communications, structured information provision, and ongoing genetic support, particularly in the context of emerging ocular therapies, to enhance consistency in information uptake.

Gender differences in retinal diseases: A review.

Gender medicine is a medical specialty that addresses gender differences in health and disease. Traditionally, medical research and clinical practice have often been focused on male subjects and patients. As a result, gender differences in medicine have been overlooked. Gender medicine considers the biological, psychological, and social differences between the genders and how these differences affect the development, diagnosis, treatment, and prevention of disease. For ophthalmological diseases epidemiological differences are known. However, there are not yet any gender-based ophthalmic treatment approaches for women and men. This review provides an overview of gender differences in retinal diseases. It is intended to make ophthalmologists, especially retinologists, more sensitive to the topic of gender medicine. The goal is to enhance comprehension of these aspects by highlighting fundamental gender differences. Integrating gender medicine into ophthalmological practice helps promote personalized and gender-responsive health care and makes medical research more accurate and relevant to the entire population.

Recent Progress in Retinal Pigment Epithelium Cell-Based Therapy for Retinal Disease.

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of retinal pigment epithelial cells and/or photoreceptors as a treatment for these conditions are underway. In this review, we summarize recent progress in the field of retinal pigment epithelium transplantation, including some pertinent clinical trial results as well as preclinical studies that address issues of transplant immunology, cell delivery, and cell manufacturing.

Allele-specific antisense oligonucleotides for the treatment of BEST1-related dominantly inherited retinal diseases: An in vitro model.

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. The primary aim of this study was to establish a reliable in vitro model utilizing induced photoreceptor-like cells (PRCs) for assessing the efficacy and safety of ASOs targeting the BEST1 gene. Despite advances in gene therapy, effective treatments for a broad range of IRDs remain limited. An additional aim was to develop an in vitro model for evaluating RNA-based therapeutics, specifically ASOs, for the treatment in IRDs. Firstly, a cell culture model was established by induction of PRCs from dermal fibroblasts via direct programming. The induced PRCs were characterized at both the transcriptomic and protein level. Then, a common single nucleotide polymorphism (SNP) was identified in the BEST1 gene (rs1800007) for targeting with ASOs. ASOs were designed using the GapmeR strategy to target multiple alleles of this SNP, which is potentially suitable for a large proportion of the population. The efficacy and possible off-target effects of these ASOs were also analyzed in the induced PRC model. The findings show that the selected ASOs achieved allele-specific mRNA degradation with virtually no off-target effects on the global transcriptome profile, indicating their potential as safe and effective therapeutic agents. The presented in vitro model is a valuable platform for testing personalized IRD treatments and should inspire further research on RNA-based therapeutics. To the best of our knowledge this study is the first to test RNA-based therapeutics involving the use of ASOs in an induced PRC model. Based on the present findings, it will be possible to establish an ex vivo disease model using dermal fibroblast samples from affected individuals. In other words, the disease model and the ASOs that were successfully designed in this study can serve as a useful platform for the testing of personalized treatments for IRDs.

Noninvasive electrical stimulation as a neuroprotective strategy in retinal diseases: a systematic review of preclinical studies.

BACKGROUND: Electrical activity has a crucial impact on the development and survival of neurons. Numerous recent studies have shown that noninvasive electrical stimulation (NES) has neuroprotective action in various retinal disorders. OBJECTIVE: To systematically review the literature on in vivo studies and provide a comprehensive summary of the neuroprotective action and the mechanisms of NES on retinal disorders. METHODS: Based on the PRISMA guideline, a systematic review was conducted in PubMed, Web of Science, Embase, Scopus and Cochrane Library to collect all relevant in vivo studies on "the role of NES on retinal diseases" published up until September 2023. Possible biases were identified with the adopted SYRCLE's tool. RESULTS: Of the 791 initially gathered studies, 21 articles met inclusion/exclusion criteria for full-text review. The results revealed the neuroprotective effect of NES (involved whole-eye, transcorneal, transscleral, transpalpebral, transorbital electrical stimulation) on different retinal diseases, including retinitis pigmentosa, retinal degeneration, high-intraocular pressure injury, traumatic optic neuropathy, nonarteritic ischemic optic neuropathy. NES could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and visual function with high security, and its mechanism of action might be related to promoting the secretion of neurotrophins and growth factors, decreasing inflammation, inhibiting apoptosis. The quality scores of included studies ranged from 5 to 8 points (a total of 10 points), according to SYRCLE's risk of bias tool. CONCLUSION: This systematic review indicated that NES exerts neuroprotective effects on retinal disease models mainly through its neurotrophic, anti-inflammatory, and anti-apoptotic capabilities. To assess the efficacy of NES in a therapeutic setting, however, well-designed clinical trials are required in the future.

Cell therapy for retinal disease.

PURPOSE OF REVIEW: This review presents an update on completed stem cell therapy trials aimed at retinal diseases. RECENT FINDINGS: In recent years, several clinical trials have been conducted examining the safety and role of cell therapy in diseases, including age-related macular degeneration, Stargardt's macular dystrophy, and retinitis pigmentosa. Studies have utilized a variety of cell lines, modes of delivery, and immunosuppressive regimens. The prevalence of fraudulent cell therapy clinics poses threats to patients. SUMMARY: Clinical trials have begun to characterize the safety of cell therapy in retinal disease. While studies have described the potential benefits of cell therapy, larger studies powered to evaluate this efficacy are required to continue progressing toward preventing retinal disease. Nonapproved cell therapy clinics require regulation and patient education to avoid patient complications.

Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey.

Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.

Toward low-cost gene therapy: mRNA-based therapeutics for treatment of inherited retinal diseases.

Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss.

Retinogenesis in a Dish: Bibliometric Analysis and Visualization of Retinal Organoids From 2011 to 2022.

Retinal organoid (RO) is the three-dimensional (3D) retinal culture derived from pluripotent or embryonic stem cells which recapitulates organ functions, which was a revolutionary milestone in stem cell technology. The purpose of this study is to explore the hotspots and future directions on ROs, as well as to better understand the fields of greatest research opportunities. Eligible publications related to RO from 2011 to 2022 were acquired from the Web of Science (WoS) Core Collection database. Bibliometric analysis was performed by using software including VOSviewer, CiteSpace, and ArcGIS. A total of 520 articles were included, and the number of annual publications showed a rapid increase with an average rate of 40.86%. The United States published the most articles (241/520, 46.35%) with highest total citation frequencies (5,344). University College London (UK) contributed the largest publication output (40/520, 7.69%) and received highest total citation frequencies. Investigative Ophthalmology & Visual Science was the most productive journal with 129 articles. Majlinda Lako contributed the most research with 32 articles, while Olivier Goureau has the strongest collaboration work. Research could be subdivided into four keyword clusters: "culture and differentiation," "morphogenesis and modeling," "gene therapy," and "transplantation and visual restoration," and evolution of keywords was identified. Last decade has witnessed the huge progress in the field of RO, which is a young and promising research area with extensive and in-depth studies. More attention should be paid to RO-related models and therapies based on specific retinal diseases, especially inherited retinopathies.

Neuroprotective Effects of Human Adipose-Derived Mesenchymal Stem Cells in Oxygen-Induced Retinopathy.

This study was designed to provide evidence of the neuroprotective of human adipose-derived mesenchymal stem cells (hADSCs) in oxygen-induced retinopathy (OIR). In vivo, hADSCs were intravitreally injected into OIR mice. Various assessments, including HE (histological evaluation), TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, electroretinogram (ERG) analysis, and retinal flat-mount examination, were performed separately at postnatal days 15 (P15) and 17 (P17) to evaluate neurological damage and functional changes. Western blot analysis of ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) was conducted at P17 to elucidate the neuroprotective mechanism. The P17 OIR group exhibited a significant increase in vascular endothelial cell nuclei and neovascularization that breached the ILM (inner limiting membrane) to the P17 control group. In addition, the retinal nonperfusion areas in the P17 OIR group and the number of apoptotic retinal cells in the P15 OIR group were significantly higher than in the corresponding hADSCs treatment group and control group. There was no significant thickness change in the inner nuclear layer (INL) but the outer nuclear layer (ONL) in the P17 OIR treatment group compared with the P17 OIR group. The cell density in the INL and ONL at P17 in the hADSCs treatment group was not significantly different from the OIR group. The amplitude of a-wave and b-wave in scotopic ERG analysis for the P17 OIR group was significantly lower than in the P17 hADSCs treatment group and the P17 control group. Furthermore, the latency of the a-wave and b-wave in the P17 OIR group was significantly longer than in the P17 hADSCs treatment group and the P17 control group. In addition, the expression levels of CNTF and BDNF in the P17 OIR group were statistically higher than those in the P17 control group, whereas the expression of GDNF was statistically lower in the P17 OIR group, compared with the P17 control group. The expression of CNTF and GDNF in the P17 hADSCs treatment group was statistically higher than in the P17 OIR group. However, the expression of BDNF in the P17 hADSCs treatment group was statistically lower than in the P17 OIR group. This study provides evidence for the neuroprotective effects of hADSCs in OIR.

Deep learning for precision medicine: Guiding laser therapy in ischemic retinal diseases.

In this issue of Cell Reports Medicine, Zhao and colleagues1 report a multi-tasking artificial intelligence system that can assist the whole process of fundus fluorescein angiography (FFA) imaging and reduce the reliance on retinal specialists in FFA examination.

Low rates of optical coherence tomography utilization in the diagnosis and management of retinovascular diseases in a lower middle-income economy.

Background: Optical coherence tomography (OCT) is widely used as the standard of care in evaluating macular and retinovascular diseases. However, the degree of OCT utilization is yet to be researched in a resource-limited country where wide gaps exist in access to healthcare. Aim: To determine the rate of utilization of the OCT in diagnosis, pre-treatment, and post-treatment evaluation of macular and retinovascular diseases treated with intravitreal anti-vascular endothelial growth factor injection (IVI). Patients and Methods: Retrospective, consecutive, and non-comparative case series of eyes diagnosed and treated from Jan 2017 to Jan 2022 for seven macular and retinovascular diseases in five eye clinics in Nigeria. Data extracted include demographics, indication for IVI, eye treated, use or non-use of OCT at the diagnosis (pre-treatment) and after the last IVI (post-treatment), and central macular thickness (CMT) of pre-treatment OCT scans. Results: Seven hundred and forty two eyes were diagnosed with retinovascular and macular diseases (389 right eyes and 353 left eyes).The male to female ratio was 430: 312 eyes. The mean age was, 63.89 years (SD 12.58). Four hundred and fifty two eyes (60.9%) had a pre-treatment OCT, 235 eyes (31.7%) had a post-treatment OCT, and 190 eyes (25.6%) had both pre- and post-treatment OCTs. The rate of pre-treatment OCT varied with the diagnosis (P = 0.000); DME had the highest rate, 74.4%, and HRVO had the lowest, 40%. Post-treatment OCT rate varied with the diagnosis (P = 0.009); non-AMD CNVM had the highest rate, 49.1%, and PCV had the lowest, 24.6%. Pre-treatment OCT rate was influenced by clinic location (P = 0.000); higher in clinics having an OCT. Post-treatment OCT was not influenced by clinic location (P = 0.37). A CRVO eye had the highest maximum CMT (1031 microns) of all the pre treatment eyes and the lowest minimum CMT of all the pre treatment eyes was in a BRVO eye (138 microns). Mean CMT was highest in HRVO (475.33 microns) and lowest in CNVM (307.62 microns). Conclusion: Though OCT is the standard of care for managing retinovascular and macular diseases, this research quantifies the extent of its use in Nigeria and finds it to be low. A post-treatment OCT rate of 32% suggests that urgent steps are required to improve access to OCT for IVI patients.

[Nanotechnologies in ophthalmology]. / Nanotekhnologii v oftal'mologii.

Application of new materials and methods in the diagnosis and treatment of eye diseases is one of the promising research areas in modern ophthalmology. Significant progress has been made in understanding the pathogenesis, diagnosis and treatment of eye diseases using nanotechnologies and nanomaterials. This paper presents the main achievements and results of original research on this issue. It has been shown that nanoparticles are able to overcome biological barriers, deliver drugs to the target site, and provide the required drug release rate. Modern nanotechnological approaches in tissue engineering are also being actively introduced into ophthalmology, making it possible to create nanoframeworks for growing three-dimensional cellular structures, including arrays of pigment epithelium cells and retinal ganglion cells for the treatment of retinal damage caused by degenerative diseases, injuries and infections.

The genetic counselor workforce in inherited retinal disease clinics: a descriptive assessment.

BACKGROUND: Genetic counselors (GCs) have practiced in Inherited Retinal Disease (IRD) clinics for several decades. In this small subspecialty of genetic counseling, GCs are critical for patient understanding of genetic information, which can have prognostic, systemic, family planning and therapeutic implications. Recently, both access to genetic testing for IRDs and the number of genes associated with IRDs (>350) has increased dramatically. However, the practice models and roles of IRD GCs have not been previously described. MATERIALS AND METHODS: GCs working in academic IRD clinics were surveyed to assess their experience, clinical practices, and roles performed. The collected data was compared to the broader genetic counseling profession and to other specialties using publicly available data on GC professional practices. RESULTS: While roles of IRD GCs were overlapping with those of the overall genetic counseling profession, all survey respondents reported diverse roles that included both clinical and non-clinical duties, spending up to half their time on research and educational responsibilities. Most respondents (89%) felt that their clinic's MD to GC ratio was too high, while clinical load varied. IRD GCs report varying degrees of prior genetic counseling and ophthalmology-specific experience but unanimously desire additional subspecialty-specific training. CONCLUSIONS: This descriptive assessment of a small subspecialty suggests a need for growth in the number of GCs practicing in IRD clinics and could help to inform development of new GC positions in IRD centers. It also highlights the desire for additional GC-specific education and may be relevant to curriculum development within GC programs.

Gene Augmentation for Autosomal Dominant CRX-Associated Retinopathies.

The cone-rod homeobox (CRX) protein is a key transcription factor essential for photoreceptor function and survival. Mutations in human CRX gene are linked to a wide spectrum of blinding diseases ranging from mild macular dystrophy to severe Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). These diseases are still incurable and mostly inherited in an autosomal dominant form. Dysfunctional mutant CRX protein interferes with the function of wild-type CRX protein, demonstrating the dominant negative effect. At present, gene augmentation is the most promising treatment strategy for hereditary diseases. This study aims to review the pathogenic mechanisms of various CRX mutations and propose two therapeutic strategies to rescue sick photoreceptors in CRX-associated retinopathies, namely, Tet-On-hCRX system and adeno-associated virus (AAV)-mediated gene augmentation. The outcome of proposed studies will guide future translational research and suggest guidelines for therapy evaluation in terms of treatment safety and efficacy.

Connexins Biology in the Pathophysiology of Retinal Diseases.

Connexins (Cx) are a family of transmembrane proteins that form gap junction intercellular channels that connect neighboring cells. These channels allow the passage of ions and other biomolecules smaller than 1 kDa, thereby synchronizing the cells both electrically and metabolically. Cxs are expressed in all retinal cell types and the diversity of Cx isoforms involved in the assembly of the channels provides a functional syncytium required for visual transduction. In this chapter, we summarize the status of current knowledge regarding Cx biology in retinal tissues and discuss how Cx dysfunction is associated with retinal disease pathophysiology. Although the contribution of Cx deficiency to retinal degeneration is not well understood, recent findings present Cx as a potential therapeutic target. Therefore, we will briefly discuss pharmacological approaches and gene therapies that are being explored to modulate Cx function and fight sight-threatening eye diseases.

Retinal Organoids: A Human Model System for Development, Diseases, and Therapies.

Inherited retinal degenerations (IRD) encompasses a group of heterogeneous disorders causing debilitating visual diseases and blindness, affecting more than two million people worldwide, in all age groups. The inheritance patterns vary from autosomal dominant, autosomal recessive, X-linked, and sporadic with mutations in over 260 genes identified to date. Despite the significant advances in clinical diagnosis, there is no effective treatment available. Human-induced pluripotent stem cells (hiPSC) derived in vitro 3D retinal organoids offer a powerful preclinical tool to investigate the molecular mechanism(s) of inherited diseases. Organoids have the potential for the development of personalized therapies by modeling the disease-specific and patient-specific IRD. This mini-review will elaborate on the utility of the advanced culture model system by focusing on staging the in vitro human retinogenesis, modeling retinal diseases, and as a tool for testing potential therapeutic approaches to restore or prevent vision loss in affected individuals.

Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration.

A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to partially restore vision in patients with retinal diseases that have resulted in the loss of photoreceptors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been major breakthroughs in retinal prosthesis technology, with the creation of numerous types of implants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate the remaining cells in the retina with electric signals to create a visual sensation. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying electronic retinal prostheses. Engineering aspects are explored, including electrode-retina alignment, electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events, visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing debate over whether implantable retinal devices still offer a promising approach for the treatment of retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as optogenetics. This review compares retinal prostheses with these alternative therapies, providing a balanced perspective on their advantages and limitations. The recent advancements in retinal prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of retinal prostheses. While acknowledging the challenges and complexities of the technology, this article highlights the significant potential of retinal prostheses for vision restoration in individuals with retinal diseases and calls for continued research and development to refine and enhance their performance, ultimately improving patient outcomes and quality of life.

Paracentral acute middle maculopathy in a fasting patient after cataract surgery and its response to hyperbaric oxygen therapy.

INTRODUCTION: Paracentral acute middle maculopathy (PAMM) is a structural optical coherence tomography (OCT) sign secondary to ischemia in the intermediate and deep retinal vascular network, characterized by hyperreflectivity in the inner nuclear layer (INL). AIM: Our objective is to demonstrate PAMM development following uncomplicated cataract surgery, possibly triggered by fasting and dehydration. We also aim to emphasize the potential role of hyperbaric oxygen therapy in treating PAMM. CASE PRESENTATION: A 66-year-old man with a past medical history of Neurofibromatosis type 1 and cardiovascular disease underwent uncomplicated cataract surgery in the left eye. The patient was also fasting due to Ramadan. The patient complained of very low vision during the routine postoperative examination on the third day. His-best-corrected visual acuity (BCVA) was counting fingers at 1 meter. His-anterior and posterior segment examination was unremarkable. In infrared imaging, a large hyporeflective area was observed in the parafoveal region, and structural OCT also showed increased hyperreflectivity in the middle retinal layers corresponding to the junction of INL and outer plexiform layer (OPL) involving the entire INL which suggested PAMM. Following 14 sessions of hyperbaric oxygen therapy, the patient's BCVA increased to 0.9 on the 14th day of diagnosing PAMM. CONCLUSION: To the best of our knowledge, this is the first case representing a patient with  PAMM triggered by fasting and cataract surgery who responded positively to hyperbaric oxygen therapy. However, triggering of PAMM by fasting is entirely unproven and that this observation occurred in a highly complex case with many other possible contributing factors. Also, the triggering of PAMM by some manipulation during surgery is equally unproven.