Multimodal Imaging-Guided Stem Cell Ocular Treatment.

Stem cell therapies are gaining traction as promising treatments for a variety of degenerative conditions. Both clinical and preclinical studies of regenerative medicine are hampered by the lack of technologies that can evaluate the migration and behavior of stem cells post-transplantation. This study proposes an innovative method to longitudinally image in vivo human-induced pluripotent stem cells differentiated to retinal pigment epithelium (hiPSC-RPE) cells by multimodal photoacoustic microscopy, optical coherence tomography, and fluorescence imaging powered by ultraminiature chain-like gold nanoparticle cluster (GNC) nanosensors. The GNC exhibits an optical absorption peak in the near-infrared regime, and the 7-8 nm size in diameter after disassembly enables renal excretion and improved safety as well as biocompatibility. In a clinically relevant rabbit model, GNC-labeled hiPSC-RPE cells migrated to RPE degeneration areas and regenerated damaged tissues. The hiPSC-RPE cells' distribution and migration were noninvasively, longitudinally monitored for 6 months with exceptional sensitivity and spatial resolution. This advanced platform for cellular imaging has the potential to enhance regenerative cell-based therapies.

Autoantibodies Against Bestrophin in Non-Paraneoplastic Acute Exudative Polymorphous Vitelliform Maculopathy.

Acute exudative polymorphous vitelliform maculopathy (AEPVM) has recently been identified as a paraneoplastic manifestation of various cancers. Yet, the first reported cases of AEPVM in the literature were reported in seemingly healthy individuals. It is not clear whether those individuals harbored unidentified mutations or occult cancers, or truly represented a separate subset of AEPVM. Here, we report two cases of mutation-negative, autoantibody-positive non-paraneoplastic AEPVM. We present multimodal ocular imaging to demonstrate the presentation of this subset of AEPVM. [Ophthalmic Surg Lasers Imaging Retina 2024;55:51-54.].

Oxidative stress differentially impacts apical and basolateral secretion of angiogenic factors from human iPSC-derived retinal pigment epithelium cells.

The retinal pigment epithelium (RPE) is a polarized monolayer that secretes growth factors and cytokines towards the retina apically and the choroid basolaterally. Numerous RPE secreted proteins have been linked to the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine the differential apical and basolateral secretome of RPE cells, and the effects of oxidative stress on directional secretion of proteins linked to AMD and angiogenesis. Tandem mass tag spectrometry was used to profile proteins in human iPSC-RPE apical and basolateral conditioned media. Changes in secretion after oxidative stress induced by H2O2 or tert-butyl hydroperoxide (tBH) were investigated by ELISA and western analysis. Out of 926 differentially secreted proteins, 890 (96%) were more apical. Oxidative stress altered the secretion of multiple factors implicated in AMD and neovascularization and promoted a pro-angiogenic microenvironment by increasing the secretion of pro-angiogenic molecules (VEGF, PTN, and CRYAB) and decreasing the secretion of anti-angiogenic molecules (PEDF and CFH). Apical secretion was impacted more than basolateral for PEDF, CRYAB and CFH, while basolateral secretion was impacted more for VEGF, which may have implications for choroidal neovascularization. This study lays a foundation for investigations of dysfunctional RPE polarized protein secretion in AMD and other chorioretinal degenerative disorders.

Real-world outcomes of voretigene neparvovec treatment in pediatric patients with RPE65-associated Leber congenital amaurosis.

PURPOSE: To investigate real-world safety and efficacy of voretigene neparvovec gene therapy administration in pediatric patients with biallelic RPE65 disease-causing variants. METHODS: A retrospective study of 27 eyes of 14 patients with RPE65-associated Leber congenital amaurosis examined postoperative complications and longitudinal changes in photoreceptor function following treatment with subretinal injection of voretigene neparvovec. Full-field stimulus threshold testing (FST), Goldmann visual fields (GVF), best-corrected visual acuity (BCVA), and central subfield thickness (CST) on optical coherence tomography (OCT) scans were collected preoperatively and up to 12 months posttreatment. RESULTS: Baseline through 6-12 month follow-up FST and GVF data were obtained for 13 eyes of 7 patients. FST improved for each eye after treatment with a mean improvement of 2.1 log-units (P < 0.001) and GVF improved for each eye with a mean improvement of 221 sum degrees (P < 0.001). BCVA improved from logMAR 0.98 at baseline to logMAR 0.83 at last follow-up (P < 0.001). Across 19 eyes of 10 patients included in CST analysis, there was a small but statistically significant 9-µ decrease in mean CST from baseline to last follow-up (P < 0.001). The most common postoperative issues included elevation in intraocular pressure (59%), persistent intraocular inflammation (15%), and vitreous opacities (26%) that resolved over a period of months. CONCLUSIONS: This report provides some of the earliest longitudinal real-world evidence of the pediatric safety and efficacy of voretigene neparvovec using multiple functional and structural measures of the retina. Outcomes demonstrate significant improvements in visual function consistent with clinical trial results.

Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome.

Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

Coats-like Exudative Vitreoretinopathy in Retinitis Pigmentosa: Ocular Manifestations and Treatment Outcomes.

PURPOSE: To provide a comprehensive review of the ocular manifestations, outcomes, and genetic findings in patients with Coats-like retinitis pigmentosa (RP). DESIGN: Multicenter, retrospective, nonconsecutive case series. PARTICIPANTS: Patients with a diagnosis of RP demonstrating Coats-like exudative vitreoretinopathy between January 1, 2008, and October 1, 2019. METHODS: Evaluation of ocular findings at RP diagnosis and at time of presentation of Coats-like exudative vitreoretinopathy, pedigree analysis, genetic testing, retinal imaging, and anatomic outcomes after treatment. MAIN OUTCOME MEASURES: Visual acuity, ophthalmoscopy results, OCT results, fluorescein angiography results, and identification of genetic mutations. RESULTS: Nine patients diagnosed with RP and demonstrating Coats-like exudative vitreoretinopathy were included. Median age at time of RP diagnosis was 8 years (range, 1-22 years), and median age at presentation of Coats-like exudative vitreoretinopathy was 18 years (range, 1-41 years). Seven patients were female, and 2 were male. The genetic cause of disease was identified in 6 patients. Three patients demonstrated Coats-like fundus findings at the time of RP diagnosis. Exudative retinal detachment (ERD) localized to the infratemporal periphery was present in all patients, with bilateral disease observed in 7 patients. In all treated patients, focal laser photocoagulation was used to treat leaking telangiectasias and to limit further ERD expansion. Cystoid macular edema refractory to carbonic anhydrase inhibitor therapy and ultimately amenable to treatment with intravitreal anti-vascular endothelial growth factor injection was observed in 4 patients. CONCLUSIONS: Coats-like vitreoretinopathy is present in up to 5% of all RP patients. The term Coats-like RP is used colloquially to describe this disease state, which can present at the time of RP diagnosis or, more commonly, develops late during the clinical course of patients with longstanding RP. Coats-like RP is distinct from Coats disease in that exudative pathologic features occur exclusively in the setting of a coexisting RP diagnosis, is restricted to the infratemporal retina, can affect both eyes, and does not demonstrate a male gender bias. Given the risk of added vision loss posed by exudative vitreoretinopathy in patients with RP, a heightened awareness of this condition is critical in facilitating timely intervention.

Rapid visual field constriction in a patient with retinitis pigmentosa and pituitary adenoma.

PURPOSE: To report a case of pituitary adenoma in a patient with retinitis pigmentosa (RP) and consequent rapid constriction of the visual field in each eye, which is atypical for either of these pathologies. OBSERVATIONS: A 45-year old male, with a long-standing history of RP, presented with rapid vision loss over 3 months. Examination revealed a severe drop in visual acuity and significant progression of concentric visual field constriction in each eye compared to 3 months prior. MRI revealed a pituitary macroadenoma compressing the optic chiasm. The patient underwent endoscopic trans-sphenoidal resection of the tumor and experienced partial recovery of visual acuity but not visual field. CONCLUSIONS AND IMPORTANCE: The visual field deficit in this patient was atypical for pituitary adenoma or optic neuropathy. The pattern was most consistent with RP, but the rate of progression was not. In a patient with chiasmal pathology in the setting of pre-existing retinopathy, visual field progression may not be limited exclusively to the bitemporal regions. Rapid constriction of the visual field in a patient with RP should prompt a work-up for alternative etiologies which includes neuro-imaging.

Autoimmune retinopathy associated with monoclonal gammopathy of undetermined significance: a case report.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia and precursor to multiple myeloma. It has known ocular manifestations, but has not previously been shown to have an association with autoimmune retinopathy. CASE PRESENTATION: A 57 year-old female presented with 1 year of progressive, bilateral, peripheral vision loss, photopsias, and nyctalopia. Her fundus examination and extensive ancillary testing were concerning for hereditary versus autoimmune retinopathy. The patient was found to have anti-retinal antibodies against carbonic anhydrase II and enolase proteins with a negative genetic retinal dystrophy panel. Malignancy work-up was negative, but the patient was diagnosed with MGUS, a premalignant condition. The patient was treated with immunosuppressive therapies, with rituximab demonstrating the most robust therapeutic response with respect to patient symptoms and ophthalmic testing. CONCLUSIONS: MGUS should be considered as a potential etiology of autoimmune retinopathy in patients without other autoimmune or malignant disease processes. Immunosuppressive therapy may be helpful in limiting disease progression, with rituximab showing efficacy in retinopathy refractory to other agents.

Development of a Gene Therapy Vector for RDH12-Associated Retinal Dystrophy.

Early-onset severe retinal dystrophy (EOSRD) is a genetically heterogeneous group of diseases resulting in serious visual disability in children. A significant number of EOSRD cases, often diagnosed as Leber congenital amaurosis (LCA13), are associated with mutations in the gene encoding retinol dehydrogenase 12 (RDH12). RDH12 is a member of the enzyme family of short-chain dehydrogenases/reductases. In the retina, RDH12 plays a critical role in reducing toxic retinaldehydes generated by visual cycle activity that is required for the light response of the photoreceptor cells. Individuals with RDH12 deficiency exhibit widespread retinal degeneration impacting both rods and cones. Although Rdh12-deficient (Rdh12-/-) mice do not exhibit retinal degeneration, functional deficits relevant to visual cycle function can be demonstrated. In the present study, we describe the development and preclinical testing of a recombinant adeno-associated viral (rAAV) vector that has the potential for use in treating EOSRD due to RDH12 mutations. Wild-type and Rdh12-/- mice that received a subretinal injection of rAAV2/5 carrying a human RDH12 cDNA driven by a human rhodopsin-kinase promoter exhibited transgene expression that was stable, correctly localized, and did not cause retinal toxicity. In addition, administration of the vector reconstituted retinal reductase activity in the retinas of Rdh12-/- mice and decreased susceptibility to light damage associated with Rdh12 deficiency, thus demonstrating potential therapeutic efficacy in an animal model that does not exhibit a retinal degeneration phenotype. These findings support further efforts to develop gene replacement therapy for individuals with RDH12 mutations.

Comparison of ophthalmic training in 6 English-speaking countries.

OBJECTIVE: To compare key characteristics of ophthalmology training programs in 6 different English-speaking countries: Australia, New Zealand, Canada, Ireland, the United Kingdom, and the United States. PARTICIPANTS: Seven ophthalmologists with personal knowledge of all 6 systems contributed. METHODS: The main features examined were career pathway, duration of training, surgical training, governing bodies, and examination structure. Data were collected from the literature, online resources, and personal experience. RESULTS: Several differences were highlighted, including length of training (ranging from 4 to 9 years after medical school), number of surgical procedures such as cataracts (ranging from minimum 86 to approximately 600), and structure of fellowship training. CONCLUSIONS: As trainees increasingly seek international experience to enhance their knowledge and skills, the similarities and differences between training programs in different countries have become more relevant. Some of these differences may reflect differing needs of different patient populations and different healthcare delivery systems across the globe. However, these differences should also prompt educators to more carefully scrutinize their own training system and search for potential improvements.

Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection.

IMPORTANCE Ocriplasmin cleaves fibronectin and laminin, components of the vitreous gel, and is used as a pharmacologic treatment for vitreomacular traction. Laminin is also found throughout multiple retinal layers. Ocriplasmin injection may lead to acute panretinal dysfunction in some eyes, but the mechanism of this toxic reaction has not been described. OBSERVATIONS We evaluated a 63-year-old woman demonstrating acute panretinal dysfunction after intravitreous ocriplasmin injection for a small macular hole with vitreomacular adhesion. Findings included visual acuity loss, visual field constriction, pupillary abnormalities, attenuated retinal arteries, loss of outer retinal signals on spectral-domain optical coherence tomography, and severely reduced electroretinography responses. B-waves were reduced more than A-waves were, suggesting postreceptoral dysfunction and decreased photoreceptor activity. CONCLUSIONS AND RELEVANCE Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.

Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.

Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.