Association of sodium-glucose cotransporter-2 inhibitors and the risk of retinal vascular occlusion: A real-world retrospective cohort study in Taiwan.

AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are proposed to alleviate the development of inflammatory eye diseases. However, the association between SGLT2i and retinal vascular occlusion remains unclear. Therefore, this study aims to explore the effects of SGLT2i on the incidence of retinal vascular occlusion. MATERIALS AND METHODS: This retrospective cohort study analysed electronic medical records data from the largest multi-institutional database in Taiwan. Individuals who initiated SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) between 2016 and 2019 were included in our analysis. To conduct a homogenous comparison, inverse probability of treatment weighting with propensity scoring was employed. The primary outcome was retinal vascular occlusion, and the secondary outcomes were retinal vascular occlusion-related complications (macular oedema, vitreous haemorrhage, and tractional retinal detachment) and conditions requiring vitreoretinal intervention (intravitreal injection, retinal laser therapy, and vitrectomy). RESULTS: In total, 12,074 SGLT2i users and 39,318 DPP4i users were included. The incidence rate of retinal vascular occlusion in the SGLT2i and DPP4i groups was 1.2 (95% confidence interval [CI], 0.9-1.4) and 1.6 (95% CI, 1.3-1.8) events per 1000 person-years, respectively, which yielded a subdistribution hazard ratio (SHR) of 0.74 (95% CI, 0.55-0.99). Similar risk reductions were observed in the retinal vascular occlusion-related complications (SHR, 0.76; 95% CI, 0.69-0.84) and conditions requiring vitreoretinal intervention (SHR, 0.84; 95% CI, 0.77-0.94). CONCLUSIONS: In this multi-institutional study in Taiwan, SGLT2i use was associated with a reduced risk of retinal vascular occlusion. Further prospective studies are required to ascertain this association.

Semiautomated design and soluble expression of a chimeric antigen TbpAB01 from Glaesserella parasuis.

Pathogenic bacterial membrane proteins (MPs) are a class of vaccine and antibiotic development targets with widespread clinical application. However, the inherent hydrophobicity of MPs poses a challenge to fold correctly in living cells. Herein, we present a comprehensive method to improve the soluble form of MP antigen by rationally designing multi-epitope chimeric antigen (ChA) and screening two classes of protein-assisting folding element. The study uses a homologous protein antigen as a functional scaffold to generate a ChA possessing four epitopes from transferrin-binding protein A of Glaesserella parasuis. Our engineered strain, which co-expresses P17 tagged-ChA and endogenous chaperones groEL-ES, yields a 0.346 g/L highly soluble ChA with the property of HPS-positive serum reaction. Moreover, the protein titer of ChA reaches 4.27 g/L with >90% soluble proportion in 5-L bioreactor, which is the highest titer reported so far. The results highlight a timely approach to design and improve the soluble expression of MP antigen in industrially viable applications.

Retinal detachment and mortality in patients with cytomegalovirus retinitis: A multicenter study in taiwan.

PURPOSE: To characterize patients with cytomegalovirus (CMV) retinitis and identify risk factors for retinal detachment (RD) and mortality in this Taiwanese patient population. METHODS: This retrospective study included patients diagnosed with CMV retinitis between 2007 and 2019. The diagnosis was confirmed through aqueous polymerase chain reaction (PCR). Relevant data were collected from the Chang Gung Research Database. Univariate Cox regression was performed to identify the associations of RD and mortality risks with various patient characteristics, including demographic features, comorbidities, laboratory results, and medication use patterns. RESULTS: In total, 32 patients with CMV retinitis were included. Among these patients, 78.1% had an immunocompromised status, including 56.3% with high-dose systemic steroid use, 21.9% with HIV infection, 12.5% with hematologic malignancy, and 9.4% with renal transplantation. Approximately 21.9% of patients had RD 2.4 ± 2.1 months after CMV retinitis diagnosis, and 34.4% died within 6.2 [4.2, 38.2] months after diagnosis. Patients with RD had a statistically significant, but likely not clinically significant, later initiation of anti-CMV medications compared to their non-RD counterparts (8 [5, 23] days vs. 2 [1, 11] days, p = 0.039). Mortality was significantly associated with older age (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.02-1.10), hematologic malignancy (HR: 5.92; 95% CI: 1.44-24.37), and positivity for CMV on blood PCR (HR: 4.93; 95% CI: 1.49-16.35). CONCLUSION: Our study suggests that older age, hematologic malignancy, and positivity for CMV on blood PCR are risk factors for mortality in patients with CMV retinitis. KEY MESSAGES: What is known Cytomegalovirus (CMV) retinitis is the predominant sight-threatening opportunistic ocular infection in patients with acquired immunodeficiency syndrome (AIDS). What is new In the era of highly active antiretroviral therapy for AIDS, the majority of CMV retinitis patients are those receiving immunomodulatory therapy for underlying diseases. Older age, hematologic malignancy, and positive blood polymerase chain reaction for CMV are potential risk factors for mortality in patients with CMV retinitis.

LONGITUDINAL CHANGES IN CHOROIDAL THICKNESS IN CHILDREN WITH A HISTORY OF PREMATURITY: An 18-Month Prospective Cohort Study.

PURPOSE: To evaluate choroidal changes over time in school-age children with a history of prematurity. METHODS: A study of 416 eyes of 208 eligible participants, including 88, 190, 36, 56, and 46 eyes in the full-term control, preterm, spontaneously regressed retinopathy of prematurity, intravitreal bevacizumab (injection of bevacizumab)-treated retinopathy of prematurity, and laser-treated retinopathy of prematurity groups, respectively, were enrolled in this study. The choroidal thickness was measured 4 times at 6-month intervals using optical coherence tomography. RESULTS: Of all the groups, the laser-treated children had the thinnest choroid compared with full-term children (-52.3 µ m, P = 0.04). Preterm children exhibited greater attenuation in choroidal thickness over time than did full-term children (-6.3 ± 26.9 and -1.1 ± 12.8 µ m/year, P = 0.03), whereas no difference was observed between injection of bevacizumab and laser treatments (-4.6 ± 18.9 and -2.0 ± 15.7 µ m/year, P = 0.46). In all groups, the changes in axial length were negatively associated with the changes in choroidal thickness (all P < 0.05). CONCLUSION: A greater attenuation in choroid thickness over time was observed in preterm children than in full-term children, but this attenuation did not differ between injection of bevacizumab and laser treatments. Axial elongation was associated with choroidal thinning in school-age children.

Neonatal gut microbiota profile and the association with retinopathy of prematurity in preterm infants.

BACKGROUND: To explore the role of gut microbiota in preterm infants at high risk of developing retinopathy of prematurity (ROP). METHODS: Preterm infants with gestational age (GA) < 32 weeks and/or birth weight (BW) < 1500 g born between 2020 and 2021 were prospectively enrolled. Their faecal samples were collected and analysed at different postnatal ages of life using 16S rRNA gene sequencing on the Miseq platform. The main outcome measures were the microbial diversity, taxonomy, relative abundance, bacterial predicted functional analysis, and their associations with different ROP groups. Subgroup analyses were performed by matching their GA and BW across different ROP groups. RESULTS: A total of 268 stool samples were collected from 110 preterm infants, including 13 with type 1 ROP, 44 with type 2 or mild ROP, and 53 without ROP. Type 1 ROP showed no significant difference in microbial diversity up to 8 postnatal weeks (p = 0.057), while type 2 and no ROP groups displayed increased diversity (p = 0.0015 and p = 0.049, respectively). Bifidobacterium genera was notably less abundant in type 1 ROP group at first postnatal week (p = 0.022) and remained low in subsequent weeks. Predicted functional analysis revealed enriched pathways in membrane transport, carbohydrate metabolism, amino acid metabolism, and replication and repair. CONCLUSIONS: Reduced gut microbial diversity may be associated with ROP development in high-risk preterm infants. Further research is needed to comprehend how early-life Bifidobacterium reduction affects metabolism and how targeting microbiome may help for ROP prevention and management.

Exploring the Location of Corneal Pigmented Arc and Myopia Control Efficacy in Orthokeratology-Treated Children Using Pentacam Measurements.

OBJECTIVES: To determine the location and intensity of the corneal pigmented arc in orthokeratology (ortho-k)-treated children and its relationship with annual axial length (AL) change using Pentacam. METHODS: This retrospective cohort study enrolled children aged 9 to 15 years who had been followed up for at least one year after ortho-k treatment for myopia control. A Pentacam was used to determine the location and intensity of pigmented arc after lens wear. Annual AL changes were further used as the outcome measurement to determine their relationships with the location and intensity of pigmented arc using generalized estimating equations (GEE). RESULTS: In total, 62 eyes from 33 patients (mean age 10.9 years) were included in our final analysis. The mean follow-up time was 30.6 months. The mean annual AL changes were 0.10 mm. Age statistically correlated with annual AL change (GEE, P= 0.033). In addition, the annual AL change was negatively associated with the relative vertical distance of the lowest density of pigmented arc point based on the visual center, pupil center, and corneal thinnest point after adjustment with age ( P =0.005, P =0.004, and P< 0.001, respectively). CONCLUSIONS: Pentacam could be a useful tool for evaluating the location and intensity of the corneal pigmented arc. In addition, there was a negative correlation between the vertical distance of the pigmented arc and annual AL change. These findings may provide important information regarding myopia control, next-generation ortho-k design, and prescription.

Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress.

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

LONG-TERM CLINICAL OUTCOMES AND GENOTYPE-PHENOTYPE CORRELATION IN FAMILIAL EXUDATIVE VITREORETINOPATHY IN A TERTIARY REFERRAL CENTER.

BACKGROUND/PURPOSE: To evaluate clinical outcomes and assess genotype-phenotype correlations in patients with familial exudative vitreoretinopathy (FEVR). METHODS: Clinical charts of 40 patients with FEVR were reviewed. FEVR was staged per Pendergast and Trese, and retinal dragging and folds further classified per Yaguchi et al. We performed whole-exome sequencing and compared clinical characteristics between genetic-positive and genetic-negative groups. RESULTS: The mean duration of follow-up was 5.4 years (range: 0.33, 15) for genetic-positive and 6.9 (range: 1, 20) for genetic-negative patients. The mean age at diagnosis was 5.6 years (0.25, 27) for genetic-positive and 6.0 (0, 32) for genetic-negative patients. Genetic-positive patients reported 100% full-term births and genetic-negative patients reported 45% full-term births ( P = 0.0012). There were more patients with retinal folds with all major vessels affected (Yaguchi's Group 4) in genetic-positive compared with genetic-negative patients (21.4% vs. 2.6%, P = 0.045). TSPAN12 was the most common (57.1%) genetic mutation in our population of which 50% exhibited asymmetric presentation. CONCLUSION: Patients who test positive for a typical FEVR gene mutation reported more term births and had more severe disease by Yaguchi's classification. TSPAN12 was the most common genetic mutation in our population and had highly asymmetrical disease.

Retrospective Analysis of Surgical Outcomes on Axial Length Elongation in Eyes with Posterior and Combined Persistent Fetal Vasculature.

This study aims to investigate the outcomes and risk factors associated with poor vision (vision less than counting fingers, 2.0 logMAR, Snellen vision 20/2000) in patients with posterior or combined persistent fetal vasculature (PFV), with or without surgery. We retrospectively reviewed the medical records of patients who were diagnosed with PFV from January 2008 to April 2021. We included 51 eyes of 44 patients who presented with PFV, of which 38 eyes underwent surgical correction (pars plicata/plana vitrectomy, with or without lensectomy, and intraocular lens implantation) at the median age of 6.0 months (range: 0.7 to 82.0). The mean follow-up was 68.8 months ± 38.0 months. The axial length change in the eyes undergoing surgery was significantly higher than the eyes without surgery (p = 0.025). Initial anterior chamber collapse and retinal detachment were associated with poor vision (p = 0.006 and p = 0.002, respectively). In addition, 37% of eyes with posterior or combined PFV had vision better than counting fingers. Surgery for eyes with PFV could result in better eye growth. Visual outcomes remained poor and were associated with the level of macular abnormality. Initial anterior chamber collapse and retinal detachment at presentation were the risk factors for poor visual outcomes. Vitrectomy for selected PFV eyes is valuable and associated with a better cosmetic outcome (better eye growth).

COMPARISON BETWEEN ORAL AND INTRAVENOUS ULTRAWIDE-FIELD FLUORESCEIN ANGIOGRAPHY IN THE CLINICAL FOLLOW-UP OF CHILDREN WITH A HISTORY OF RETINOPATHY OF PREMATURITY OR PREMATURITY.

PURPOSE: To compare between oral and intravenous (IV) ultrawide-field fluorescein angiography in pediatric patients with a history of prematurity of retinopathy or prematurity. METHODS: Pediatric patients (<18 year old; n = 107 patients) who underwent ultrawide-field fluorescein angiography for retinopathy of prematurity were categorized into oral and IV fluorescein angiography (FA) groups. Quality of FA images was graded on the order of retinal vessels visible. Reported outcomes were proportions of graded FA images, peak fluorescein intensity, and the time to first dye appearance and to reach peak fluorescence. RESULTS: Image quality analysis revealed that 91.5% of IV FA images had excellent image quality compared with only 55.6% of oral FA images (P < 0.01). There were still 83.3% of oral-contrast images with good or excellent image quality. The average time required for first dye appearance and peak fluorescence were significantly shorter in the IV FA group than in the oral FA group (P < 0.01). Peak intensity was greater in the IV group (141.41 ± 29.09) than in the oral group (111.25 ± 45.68; P < 0.01). Adverse reaction rates were similar between the two groups (P = 0.22). CONCLUSION: Ultrawide-field fluorescein angiography provides excellent-quality imaging of the retina in the pediatric population. Overall, oral FA is still an effective and useful alternative to IV FA in children with prematurity history.

SURGICAL OUTCOME AND PROGNOSTIC FACTORS AFTER OPHTHALMIC SURGERY IN ABUSIVE HEAD TRAUMA.

PURPOSE: To analyze the clinical characteristics, surgical outcomes, and risk factors associated with visual outcomes in patients with abusive head trauma (AHT). METHODS: We retrospectively reviewed surgical outcomes of patients with AHT who underwent vitrectomy from 2001 to 2019. The patients' demographics, comprehensive preoperative and postoperative ocular findings, surgical treatments, visual outcomes, and postoperative complications in the medical records were reviewed. Univariable and multivariable analyses were performed to identify the prognostic factors associated with visual outcomes. RESULTS: Fourteen children (18 eyes) diagnosed with AHT who underwent vitrectomy were evaluated. The most common surgical indication was vitreous hemorrhage (n = 6, 33%). Retinal attachment at the final visit was noted in 17 eyes (94%). Thirteen eyes (72%) had a best-corrected visual acuity less than 20/200 after vitrectomy. In the multivariable analysis, optic nerve atrophy (n = 9, 50%) was significantly associated with a poor visual prognosis (final best-corrected visual acuity worse than 20/200) after vitrectomy in children with AHT (95% confidence interval, 1.041-517.963, P = 0.0471). CONCLUSION: The general visual prognosis was poor for patients with AHT needing vitrectomy, although a high rate of retinal attachment was observed. Optic nerve atrophy is a prognostic factor for poor visual outcomes in patients with AHT who received ophthalmic surgery.

Case report: novel PCDH15 variant causes usher syndrome type 1F with congenital hearing loss and syndromic retinitis pigmentosa.

BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder primarily responsible for deaf-blindness. Patients with subtype Usher syndrome type 1 (USH1) typically experience congenital sensorineural hearing loss, abnormal vestibular function, and retinitis pigmentosa (RP). Here we present a case of Usher syndrome type 1F (USH1F) with a novel homozygous variant in the calcium-dependent cell-cell adhesion protocadherin-15 (PCDH15) gene. CASE PRESENTATION: Ophthalmic examinations were evaluated over a course of 10 years and the disease-causing variant was identified by whole exome sequencing (WES). Initial and follow-up examination of color fundus photos after 10 years revealed an increase in bone spicule pigment deposits in both eyes. A parafoveal hyper-AF ring in both eyes was shown in fundus autofluorescence (FAF) with a progressive diameter-wise constriction observed over 8 years. Outer nuclear layer (ONL) loss was observed in parafoveal and perifoveal regions of both eyes on spectral domain-optical coherence tomography (SD-OCT). Full-field electroretinography (ffERG) showed extinguished global retinal function. WES identified a novel two-base-pair deletion, c.60_61del (p.Phe21Ter), in the PCDH15 gene, confirming the diagnosis of USH1F. CONCLUSIONS: We report a novel homozygous PCDH15 pathogenic variant expected to lead to nonsense-mediated decay (NMD) of PCDH15 mRNA. The patient exhibits a loss of function with USH1F, experiencing congenital hearing loss and syndromic RP.

Effects of TIMP-2 Polymorphisms on Retinopathy of Prematurity Risk, Severity, Recurrence, and Treatment Response.

Tissue inhibitors of metalloproteinases (TIMPs) play a crucial role in endogenous angiogenesis besides the regulation of matrix metalloproteinase (MMP) activity. Associations between TIMP-2 gene polymorphisms and the risk of retinopathy of prematurity (ROP) were examined. Premature infants born between 2009 and 2018 were included. Five single-nucleotide polymorphisms (SNPs) of TIMP-2 were analyzed with real-time polymerase chain reaction (PCR). Multivariate logistic regression was applied to model associations between TIMP-2 polymorphisms and ROP susceptibility and severity. The GA+AA genotype in individuals with the TIMP-2 polymorphism of rs12600817 was associated with a higher risk of ROP (odds ratio [OR]: 1.518, 95% confidence interval [CI]: 1.028-2.242) compared with their wild-type genotypes. The AA genotype (OR: 1.962, 95% CI: 1.023-3.762) and the AA+GA genotype (OR: 1.686, 95% CI: 1.030-2.762) in individuals with the rs12600817 polymorphism had higher risks of severe, treatment-requiring ROP relative to their wild-type counterparts. In patients with treatment-requiring ROP, the AG+GG genotypes in the TIMP-2 polymorphism of rs2889529 were correlated with the treatment response (p = 0.035). The TIMP-2 polymorphism of rs12600817 help in predicting ROP risks in preterm infants, while the polymorphism of rs2889529 can serve as a genetic marker in evaluating the ROP treatment response.

Congenital Stationary Night Blindness: Clinical and Genetic Features.

Congenital stationary night blindness (CSNB) is an inherited retinal disease (IRD) that causes night blindness in childhood with heterogeneous genetic, electrophysical, and clinical characteristics. The development of sequencing technologies and gene therapy have increased the ease and urgency of diagnosing IRDs. This study describes seven Taiwanese patients from six unrelated families examined at a tertiary referral center, diagnosed with CSNB, and confirmed by genetic testing. Complete ophthalmic exams included best corrected visual acuity, retinal imaging, and an electroretinogram. The effects of identified novel variants were predicted using clinical details, protein prediction tools, and conservation scores. One patient had an autosomal dominant CSNB with a RHO variant; five patients had complete CSNB with variants in GRM6, TRPM1, and NYX; and one patient had incomplete CSNB with variants in CACNA1F. The patients had Riggs and Schubert-Bornschein types of CSNB with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. This is the first report of CSNB patients in Taiwan with confirmed genetic testing, providing novel perspectives on molecular etiology and genotype-phenotype correlation of CSNB. Particularly, variants in TRPM1, NYX, and CACNA1F in our patient cohort have not previously been described, although their clinical significance needs further study. Additional study is needed for the genotype-phenotype correlation of different mutations causing CSNB. In addition to genetic etiology, the future of gene therapy for CSNB patients is reviewed and discussed.

CNGB1-related rod-cone dystrophy: A mutation review and update.

Cyclic nucleotide-gated channel ß1 (CNGB1) encodes the 240-kDa ß subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.

Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration.

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.

Role of growth factors and internal limiting membrane constituents in müller cell migration.

This study investigated the effects of growth factors and internal limiting membrane components on Müller cell migration. We studied the effects of epidermal growth factor (EGF), fibroblast growth factor (FGF), somatomedin (IGF-1), platelet derived growth factor (PDGF), and stromal cell-derived factor-1 alpha (SDF-1α) as well as collagen IV, laminin, and fibronectin on the proliferative and migratory activities of rat Müller cells in vitro. A water soluble tetrazolium-1 assay was used to quantify the viability of Müller cells in respective cultures, and analysis was performed using an enzyme-linked immunosorbent assay reader. All the factors examined had significant proliferative effects on cultured Müller cells (p < .05). A two-well Ibidi silicone culture insert was used to assess Müller cell migration. Müller cells cultured in EGF, FGF, IGF-1, collagen IV, and laminin but not in SDF, PDGF, or fibronectin effectively increased the cell migratory activity (p < .001). In addition, combined EGF and collagen IV, combined FGF and collagen IV, and combined IGF-1 and laminin exhibited more significant (p < .001) effects on Müller cell migration compared with culture a single factor. In summary, this study revealed the combinatorial effects of various growth factors and individual internal limiting membrane constituents. This may assist Müller cell migration together with the macular hole healing process.

Predicting visual acuity in Bietti crystalline dystrophy: evaluation of image parameters.

BACKGROUND: To analyze multiple imaging modalities in patients with Bietti crystalline dystrophy (BCD) and to investigate which factors from these modalities are associated with best corrected visual acuity (BCVA). METHODS: In this retrospective study, 40 eyes from 22 patients with BCD were included and were separated into group 1 (BCVA ≤20/200) and group 2 (BCVA > 20/200). Data including BCVA and characteristic findings from near-infrared reflectance (NIR) imaging, fundus autofluorescence (FAF), and spectral domain-optic coherence tomography (SD-OCT) were analyzed and compared. The outcome measures of multimodal imaging were evaluated for correlation with BCVA. RESULTS: NIR is a good diagnostic tool for detecting either crystalline or sclerotic vessels in BCD. Patients in group 1 tended to have a thinner choroid (P = 0.047) with ellipsoid zone (EZ) disruption (P = 0.011). Calculation of the area under the curve indicated that EZ disruption detected on SD-OCT could be a good predictor of legal blindness in BCD. CONCLUSION: For the diagnosis of BCD, NIR could be a good diagnostic tool. Of the studied imaging modalities, we found that EZ disruption at the fovea were strongly associated with legal blindness, which could be easily assessed by SD-OCT.

Mouse Models of Achromatopsia in Addressing Temporal "Point of No Return" in Gene-Therapy.

Achromatopsia is characterized by amblyopia, photophobia, nystagmus, and color blindness. Previous animal models of achromatopsia have shown promising results using gene augmentation to restore cone function. However, the optimal therapeutic window to elicit recovery remains unknown. Here, we attempted two rounds of gene augmentation to generate recoverable mouse models of achromatopsia including a Cnga3 model with a knock-in stop cassette in intron 5 using Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR) and targeted embryonic stem (ES) cells. This model demonstrated that only 20% of CNGA3 levels in homozygotes derived from target ES cells remained, as compared to normal CNGA3 levels. Despite the low percentage of remaining protein, the knock-in mouse model continued to generate normal cone phototransduction. Our results showed that a small amount of normal CNGA3 protein is sufficient to form "functional" CNG channels and achieve physiological demand for proper cone phototransduction. Thus, it can be concluded that mutating the Cnga3 locus to disrupt the functional tetrameric CNG channels may ultimately require more potent STOP cassettes to generate a reversible achromatopsia mouse model. Our data also possess implications for future CNGA3-associated achromatopsia clinical trials, whereby restoration of only 20% functional CNGA3 protein may be sufficient to form functional CNG channels and thus rescue cone response.

PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. The genetic heterogeneity of RP necessitates a broad therapy that is able to provide treatment in a gene- and mutation- non-specific manner. In this study, we identify the therapeutic benefits of metabolic reprogramming by targeting pyruvate kinase M2 (PKM2) in a Pde6ß preclinical model of RP. The genetic contributions of PKM2 inhibition in retinal degeneration were evaluated through histology and electroretinogram (ERG) followed by a statistical analysis using a linear regression model. Notably, PKM2 ablation resulted in thicker retinal layers in Pde6ß-mutated mice as compared to the controls, suggesting greater photoreceptor survival. Consistent with these anatomical findings, ERG analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with intact Pkm2, indicating enhanced photoreceptor function. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.