Usher syndrome (USH) is the most common cause of deafblindness. USH is autosomal recessively inherited and characterized by rod-cone dystrophy or retinitis pigmentosa (RP), often accompanied by sensorineural hearing loss. Variants in >15 genes have been identified as causative for clinically and genetically distinct subtypes. Among the ultra-rare and recently discovered genes is ARSG, coding for the lysosomal sulfatase Arylsulfatase G. This subtype was assigned as \"USH IV\" with a late onset of RP and usually late-onset progressive SNHL without vestibular involvement. Here, we describe nine new subjects and the clinical description of four cases with the USH IV phenotype bearing seven novel and two known pathogenic variants. Functional experiments indicated the complete loss of sulfatase enzymatic activity upon ectopic expression of mutated ARSG cDNA. Interestingly, we identified a homozygous missense variant, p.(Arg99His), previously described in dogs with neuronal ceroid lipofuscinosis. Our study expands the genetic landscape of ARSG-USH IV and the number of known subjects by more than 30%. These findings highlight that USH IV likely has been underdiagnosed and emphasize the need to test molecularly unresolved subjects with deafblindness syndrome. Finally, testing of ARSG should be considered for the genetic work-up of apparent isolated inherited retinal diseases.

Mutations in the KIF7 gene have been implicated in autosomal recessive conditions such as Joubert syndrome, acrocallosal syndrome, and fetal hydrolethalus, as well as in retinal degeneration and other ocular manifestations due to their effect on primary cilia. In this study, we report that the full-field electroretinogram (ERG) test showed non-recordable scotopic ERG responses, while photopic ERG responses were diminished bilaterally. This is a case report of a 62-year-old female patient with painless, progressive vision loss in both eyes. Fundus examination revealed a pale optic nerve head, vessel attenuation, and macular thinning without peripheral pigmentary changes. The full-field electroretinogram (ERG) test showed non-recordable scotopic ERG responses, while photopic ERG responses were diminished bilaterally. Based on these ocular findings, the patient was clinically diagnosed with retinitis pigmentosa (RP) sine pigmento. Genetic testing identified a pathogenic heterozygous mutation in the KIF7 gene with the variant c.61C>T (p.Arg21*). Our case suggests that this pathologic variant may be associated with RP sine pigmento. Further studies are warranted to better understand the role of the KIF7 gene in retinal dystrophies.

The prevalence of retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, has been increasing globally and is linked to the aging population and improved life expectancy. These diseases are characterized by chronic, progressive neuronal damage or depletion of the photoreceptor cells in the retina, and limited effective treatment options are currently available. Mesenchymal stem cell-derived exosomes (MSC-EXOs) containing cytokines, growth factors, lipids, mRNA, and miRNA, which act as mediators of intercellular communication transferring bioactive molecules to recipient cells, offer an appealing, non-cellular nanotherapeutic approach for retinal degenerative diseases. However, treatment specificity is compromised due to their high heterogeneity in size, content, functional effects, and parental cellular source. To improve this, engineered MSC-EXOs with increased drug-loading capacity, targeting ability, and resistance to bodily degradation and elimination have been developed. This review summarizes the recent advances in miRNAs of MSC-EXOs as a treatment for retinal degeneration, discussing the strategies and methods for engineering therapeutic MSC-EXOs. Notably, to address the single functional role of engineered MSC-EXOs, we propose a novel concept called \"Compound Engineered MSC-EXOs (Co-E-MSC-EXOs)\" along with its derived potential therapeutic approaches. The advantages and challenges of employing Co-E-MSC-EXOs for retinal degeneration in clinical applications, as well as the strategies and issues related to them, are also highlighted.

Retinitis Pigmentosa (RP) is an inherited retinal dystrophy (IRD) that causes progressive visual loss. Patients suffering from RP have a substantial influence on their everyday activities, social contacts, and jobs, lowering their quality of life. Frequent referral delays, as well as the lack of a standard therapy for the majority of patients, contribute to the significant unmet demand for RP. Any retinal injury has the potential to result in total blindness and visual impairment. Despite the fact that there is no cure for RP, people can manage it using rehabilitation programs and low-vision gadgets. The purpose of this research is to characterize the expanding treatment landscape for RP, as well as the justification for advanced therapy medicinal products (ATMPs). Vitamin A supplements can help prevent the sluggish visual loss caused by a prevalent kind of RP. The presence of visual purple in the rods and the underlying vascular choroid causes the retina to look purplish red. The major portion of the retina damaged is the rod photoreceptor electric cell; the development of diverse diseases is progressive. Because of the retina\'s accessibility, immunological privilege, and compartmentalization, hereditary retinal diseases are amenable to cell and gene therapy. Therapeutic techniques that attempt to rescue photoreceptors (gene therapies) require the existence of non-functional target cells, but other therapies (cell therapies) do not require the presence of live photoreceptors. To provide successful therapy choices for RP patients at all disease phases, the development pipeline must be continually diversified and advanced, as well as ongoing efforts to encourage early patient identification and quick diagnosis. Future research will focus on avoiding vision loss in genetic eye illnesses and assisting patients in regaining their eyesight. Retinal implants, cell therapies, supplementary medications, and gene therapies may become common treatments for reducing vision loss in the future.

UNASSIGNED: Radix Salviae (Danshen)-Angelicae Sinensis Radix (Danggui)-Lycii Fructus (Gouqizi)-Rehmanniae Radix Praeparata (Shudihuang)-Ginkgo Folium (Yinxinye) (RALRG) are commonly used herbs in China that have shown positive effects on retinitis pigmentosa (RP). However, little research has been performed on the impact of RALRG and RP. Herein, this study aimed to predict the mechanism and potential components of RALRG in treating RP.
UNASSIGNED: The ingredients of RALRG were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP); the potential targets of RP and RALRG were obtained from TCMSP, GeneCards, and the Online Mendelian Inheritance in Man (OMIM) database. A protein-protein interaction (PPI) network was constructed to visualize PPIs. The functional enrichment was performed with the R program. A visual RALRG-RP-pathway pharmacology network was established by Cytoscape 3.9.1. Molecular docking was used to perform molecular docking and calculate the binding affinity.
UNASSIGNED: A total of 132 effective active ingredients in RALRG with 248 target genes were screened; 92 intersection target genes were acquired from the intersection of RP- and RALRG-related genes. Gene Ontology (GO) enrichment indicated that these intersection targets were mainly involved in oxidative stress, metal ion response, and chemical stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the PI3K-AKT, cellular senescence, and MAPK signaling pathways were closely related to the therapy of RP. In addition, a potential pharmacology network for RALRG-RP-pathway was constructed. AKT1 and JUN were considered the primary targets. Luteolin, quercetin, and kaempferol were identified as the vital three active ingredients.
UNASSIGNED: RALRG was found to be the main regulator for oxidative stress and PI3K/AKT signaling pathways. Luteolin, quercetin, and kaempferol were three promising complementary ingredients for RP treatment. This study may provide a theoretical basis for applying RALRG to screen potential drugs for RP.

Inherited retinal dystrophies (IRDs) are a heterogeneous group of visual disorders caused by different pathogenic mutations in genes and regulatory sequences. The endoplasmic reticulum (ER) membrane protein complex (EMC) subunit 3 (EMC3) is the core unit of the EMC insertase that integrates the transmembrane peptides into lipid bilayers, and the function of its cytoplasmic carboxyl terminus remains to be elucidated. In this study, an insertional mutation c.768insT in the C-terminal coding region of EMC3 was identified and associated with dominant IRDs in a five-generation family. This mutation caused a frameshift in the coding sequence and a gain of an additional 16 amino acid residues (p.L256F-fs-ext21) to form a helix structure in the C-terminus of the EMC3 protein. The mutation is heterozygous with an incomplete penetrance, and cosegregates in all patients examined. This finding indicates that the C-terminus of EMC3 is essential for EMC functions and that EMC3 may be a novel candidate gene for retinal degenerative diseases.

Stem cell therapy is a promising therapeutic approach for inherited retinal diseases (IRDs). This study aims to quantitatively examine the effectiveness and safety of stem cell therapy for patients with IRDs, including retinitis pigmentosa and Stargardt disease (STGD).
We searched PubMed, EMBASE, Web of Science, Cochrane Library databases, and the ClinicalTrials.gov website. The latest retrieval time was August 20, 2023. The primary outcomes were rates and mean difference (MD) of best-corrected visual acuity (BCVA) improvement. Subgroup analyses were conducted according to administration routes and stem cell types. This study was registered with PROSPERO (CRD42022349271).
Twenty-one prospective studies, involving 496 eyes (404 RP and 92 STGD) of 382 patients (306 RP and 76 STGD), were included in this study. For RP, the rate of BCVA improvement was 49% and 30% at 6 months and 12 months, respectively, and the BCVA was significantly improved in the operative eyes at 6 months post-treatment (MD = - 0.12 logMAR, 95% CI .17 to - 0.06 logMAR; P < 0.001), while there was no significant difference at 12 months post-treatment (MD = -0.06 logMAR; 95% CI - 0.13 to 0.01 logMAR; P = 0.10). For STGD, the rate of BCVA improvement was 60% and 55% at 6 months and 12 months, respectively, and the BCVA was significantly improved in the operative eyes at 6 months (MD = - 0.14 logMAR, 95% CI - 0.22 to - 0.07 logMAR; P = 0.0002) and 12 months (MD = - 0.17 logMAR, 95% CI - 0.29 to - 0.04 logMAR; P = 0.01). Subgroup analyses showed suprachoroidal space injection of stem cells may be more efficient for RP. Eleven treated-related ocular adverse events from three studies and no related systemic adverse events were reported.
This study suggests stem cell therapy may be effective and safe for patients with RP or STGD. The long-term vision improvement may be limited for RP patients. Suprachoroidal space injection of stem cells may be a promising administration route for RP patients. Limited by the low grade of evidence, large sample size randomized clinical trials are required in the future.

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47-0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression.

Retinal angiomatous proliferation (RAP) and other types of choroidal neovascularization (CNV) are very rarely reported in patients with retinitis pigmentosa (RP). We present a case report of a 91-year-old patient with an obvious RP phenotype, who presented with a sudden onset of vision worsening and metamorphopsia in the left eye. Genetic testing on the UK inherited retinal disease panel did not identify a pathogenic variant. Multimodal imaging comprising optical coherence tomography (OCT), OCT angiography, and fluorescein and indocyanine green angiography showed a RAP lesion in the left macula. The patient received three treatments of monthly injections of aflibercept, with excellent morphological and functional outcomes. Taking into account the patient\'s age at presentation of the RAP lesion, it is not clear whether the RAP was associated or coincidental with RP. This case report highlights the importance of possessing an awareness that RAP lesions can occur in RP. Moreover, due to a good response and potential safety concerns with continuous anti-VEGF injections in RP patients, a pro re nata (PRN) regimen might be the safest option.

Mutations in the Crumbs-homologue-1 (CRB1) gene lead to a spectrum of severe inherited retinal diseases, including retinitis pigmentosa (RP). The establishment of a genotype-phenotype correlation in CRB1 patients has been difficult due to the substantial variability and phenotypic overlap between CRB1-associated diseases. This phenotypic modulation may be due to several factors, including genetic modifiers, deep intronic mutations, isoform diversity, and copy number variations. Induced pluripotent stem cell (iPSC)-derived patient retinal organoids are novel tools that can provide sensitive, quantitative, and scalable phenotypic assays. CRB1 RP patient iPSC-derived retinal organoids have shown reproducible phenotypes compared to healthy retinal organoids. However, having genetically defined iPSC isogenic controls that take into account potential phenotypic modulation is crucial. In this study, we generated iPSC from an early-onset CRB1 patient and developed a correction strategy for the c.2480G>T, p.(Gly827Val) CRB1 mutation using CRISPR/Cas9-mediated homology-directed repair.