Investigative ophthalmology & visual science最新文献

{"title":"Senolytic Treatment Alleviates Corneal Allograft Rejection Through Upregulation of Angiotensin-Converting Enzyme 2 (ACE2).","authors":"Hao Chi, Li Ma, Fanxing Zeng, Xiaolei Wang, Peng Peng, Xiaofei Bai, Ting Zhang, Wenhui Yin, Yaoyao Yu, Lingling Yang, Qingjun Zhou, Chao Wei, Weiyun Shi","doi":"10.1167/iovs.66.2.15","DOIUrl":"10.1167/iovs.66.2.15","url":null,"abstract":"<p><strong>Purpose: </strong>Allograft rejection remains a major cause of failure in high-risk corneal transplants, but the underlying mechanisms are not fully understood. This study aimed to investigate the contribution of transplantation stress-induced cellular senescence to corneal allograft rejection and to elucidate the associated molecular mechanisms.</p><p><strong>Methods: </strong>Age-matched murine corneal transplantation models were established. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, and immunofluorescence staining. The role of cellular senescence in corneal allograft rejection was analyzed using p16 knockout mice and adoptive transfer experiments. Senolytic treatment with ABT-263 was administered intraperitoneally to evaluate its effects on corneal allograft rejection. RNA sequencing and pharmacological approaches were employed to identify the underlying mechanisms.</p><p><strong>Results: </strong>Surgical injury induced a senescence-like phenotype in both donor corneas and recipient corneal beds, characterized by an increased accumulation of SA-β-Gal-positive cells in the corneal endothelium and stroma and elevated expression of senescence markers p16 and p21. Using genetic and adoptive transfer models, transplantation stress-induced senescence was shown to exacerbate corneal allograft rejection. Importantly, clearance of senescent cells by ABT-263 significantly suppressed ocular alloresponses and immune rejection. Mechanistically, RNA sequencing and loss-of-function experiments demonstrated that the anti-rejection effects of senolytic treatment were closely dependent on angiotensin-converting enzyme 2 (ACE2).</p><p><strong>Conclusions: </strong>These findings highlight transplantation stress-induced senescence as a pivotal pathogenic factor in corneal allograft rejection. Senolytic therapy emerges as a potential novel strategy to mitigate transplant rejection and improve corneal allograft survival.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"15"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, Genetic, Imaging and Electrophysiological Findings in a Cohort of Patients With GUCA1A-Associated Retinopathy.","authors":"Gilad Allon, Siying Lin, Anthony G Robson, Gavin Arno, Magella M Neveu, Pirro G Hysi, Michel Michaelides, Andrew R Webster, Omar A Mahroo","doi":"10.1167/iovs.66.2.50","DOIUrl":"10.1167/iovs.66.2.50","url":null,"abstract":"<p><strong>Purpose: </strong>To report findings in GUCA1A-associated retinopathy, a rare autosomal-dominant retinopathy.</p><p><strong>Methods: </strong>Clinical features and investigations from molecularly confirmed patients at a large referral center were analyzed (retrospective cohort study).</p><p><strong>Results: </strong>Nineteen patients (14 families), with five different variants, were included: p.(Tyr99Cys) in 10 families and p.(Leu84Phe), p.(Ile107Thr), p.(Glu111Ala), and p.(leu176Phe) in 1 family each. Mean (SD) ages at first and last visits were 38 (17) and 48 (15) years, respectively. Mean (SD) logMAR visual acuities at the first and last visits were 0.67 (0.61) and 0.94 (0.58) for right eyes and 0.63 (0.63) and 0.95 (0.74) for left eyes. Acuities ranged from 0.00 logMAR to no light perception. Most described progressive problems with central and color vision. Across 144 patient visits, logMAR acuity correlated with age (Spearman coefficients of 0.43 and 0.54 for right and left eyes, P < 0.001), with a high interocular correlation (coefficient 0.90, P < 0.001). Optical coherence tomography showed irregularity and then loss of the central ellipsoid zone. Ultra-widefield imaging showed peripheral degeneration in some patients. Electrophysiology (n = 13) was consistent with cone dystrophy (n = 11) or macular dystrophy (n = 2). Compared with the common p.(Tyr99Cys) variant, patients with p.(Glu111Ala) (n = 2) had worse vision; those with p.(Leu84Phe) (n = 3) were younger with earlier-onset visual loss. Patients with p.(Ile107Thr) (n = 2) showed later presentation, with milder acuity reduction.</p><p><strong>Conclusions: </strong>We present genotypic and phenotypic findings from the largest cohort with GUCA1A retinopathy. Most had progressive visual loss and electrophysiologic evidence of cone dystrophy. Possible genotype-phenotype correlations emerged, but subgroups were small for four of five variants.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"50"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung Function as a Biomarker for Glaucoma: The UK Biobank Study.","authors":"Jun Yu, Yuzhou Zhang, Ka Wai Kam, Mary Ho, Alvin L Young, Chi Pui Pang, Clement C Tham, Jason C Yam, Li Jia Chen","doi":"10.1167/iovs.66.2.48","DOIUrl":"10.1167/iovs.66.2.48","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the associations of lung function with glaucoma and related traits, explore the interactions between glaucoma genetic risk and lung function, and assess the causal relationships using Mendelian randomization (MR).</p><p><strong>Methods: </strong>This cross-sectional study involved 85,369 participants with lung function measurements at baseline from the UK Biobank. Associations between lung function parameters and glaucoma and related traits were tested by multivariable logistic and linear regression. Two-sample MR analyses were conducted using summary statistics from large genetic datasets.</p><p><strong>Results: </strong>Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC ratio were inversely associated with glaucoma, with the lowest quartiles conferring odds ratios (ORs) of 1.51 (95% confidence interval [CI], 1.31-1.74; P = 7.6 × 10-8), 1.58 (95% CI, 1.37-1.81; P = 4.7 × 10-10) and 1.20 (95% CI, 1.08-1.34; P = 0.002), respectively, compared with the highest quartiles (P trends < 0.001 observed for each). Similar associations were found for impaired lung function (FEV1 <80% Global Lung Initiative predicted FEV1: OR, 1.22, 95% CI, 1.11-1.33; P = 1.2 × 10-5; FEV1/FVC <0.7: OR, 1.13, 95% CI, 1.03-1.24; P = 0.01). Lower lung function was associated with lower intraocular pressure (IOP), thinner macular retinal nerve fiber layer thickness, and thinner ganglion cell-inner plexiform layer thickness. No interactions were observed between glaucoma genetic risk and lung function. MR analyses did not suggest causal relationships.</p><p><strong>Conclusions: </strong>Lower FVC, FEV1, FEV1/FVC, and impaired lung function are potential biomarkers for glaucoma risk. These findings may facilitate clinical strategies for glaucoma management, particularly for individuals with impaired lung function.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"48"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Alleviates Age-Related Lacrimal Gland Dysfunction Via SIRT-1/NLRP3 Pathway.","authors":"Chao Wang, Yu-Zhi Li, Huan Guo, Shi-Rui Zhou, Xi Peng, Jia-Song Wang, Hua-Tao Xie, Ming-Chang Zhang","doi":"10.1167/iovs.66.2.51","DOIUrl":"10.1167/iovs.66.2.51","url":null,"abstract":"<p><strong>Purpose: </strong>As a consequence of the natural aging process, the lacrimal glands may become dysfunctional. The present study aimed to investigate the potential role of melatonin (MLT) in the alleviation of age-related lacrimal gland dysfunction and to elucidate the underlying mechanism.</p><p><strong>Methods: </strong>In this study, lacrimal glands of 2-month-old, 18-month-old, and MLT intraperitoneally injected 18-month-old mice were obtained for immunofluorescence, immunohistochemistry experiments, and Western blotting to detect inflammatory factors and AQP5 expression, and for electron microscopy to detect mitochondrial structure and dense granules. Lacrimal glands from 18-month-old mice were taken for cell culture, and PCR and Western blotting were performed to detect the signaling pathways in which MLT acts. In addition, the human lacrimal gland explant cultures were performed to validate the role of MLT and the SIRT-1/NLRP3 signaling pathways.</p><p><strong>Results: </strong>In this study, we discovered that aging increased the inflammatory response, decreased secretory function, and led to mitochondrial dysregulation in lacrimal gland. Compared with 2-month-old mice, SIRT-1/3/6 gene transcript levels were significantly decreased in 18-month-old mice. MLT reduced inflammatory factors (IL-1β, IL-6, and TNF-α) and increased AQP5 expression via the SIRT-1/NLRP3 signaling pathway in aged lacrimal gland of human and mouse. Furthermore, MLT restored mitochondrial structure and increased dense granules in aged mouse lacrimal gland. In explants of human lacrimal gland, MLT relieved fibrosis.</p><p><strong>Conclusions: </strong>The present study demonstrated that MLT alleviates age-related lacrimal dysfunction in mice and humans via the SIRT-1/NLRP3 pathway. MLT alleviated the inflammatory response and the decline in the secretory function of the aged lacrimal gland.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"51"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"kexB Gene Correlates With Aspergillus flavus Keratitis Severity: A Whole-Genome Analysis.","authors":"Jiamin Liu, Min Kang, Yuan Wei, Zijun Zhang, Jinding Pang, Qiankun Chen, Xizhan Xu, Zhenyu Wei, Yang Zhang, Kexin Chen, Zhiqun Wang, Xinxin Lu, Qingfeng Liang","doi":"10.1167/iovs.66.2.42","DOIUrl":"10.1167/iovs.66.2.42","url":null,"abstract":"<p><strong>Purpose: </strong>Fungal keratitis caused by Aspergillus flavus (A. flavus) can result in severe inflammation and corneal stromal melting, leading to visual impairment. This study aimed to identify virulent genes correlated with the severity of A. flavus keratitis using whole-genome sequencing.</p><p><strong>Methods: </strong>Whole-genome sequencing of 21 clinical A. flavus strains from cornea was performed to elucidate the pathogenesis of A. flavus in infectious keratitis, followed by pan-genome analysis and virulence analysis. To further understand the results from the previous analyses, growth phenotypes and virulence effect of mutant strains were validated experimentally, including the spore counting, growth pattern under different conditions, and clinical and pathological evaluation of A. flavus keratitis in mice models.</p><p><strong>Results: </strong>The A. flavus pan-genome was composed of 17,326 gene clusters with a core genome of 5378 (31.0% of the pan-genome) orthogroups in all 21 isolates. Virulence gene analysis revealed 183 genes contributing to A. flavus pathogenesis and mutation of the kexB gene was associated with the severity of keratitis. The kexB mutant (ΔkexB) strains showed significantly reduced conidia formation and lower growth rates in the presence of the cell-wall perturbing agents. Further, the mice models validated that clinical score, and corneal perforation rates significantly decreased in the group infected by ΔkexB strains. Infiltration of immune cells, gene expression of cytokines, and matrix metalloproteinase (MMP) were also decreased in the mutant group.</p><p><strong>Conclusions: </strong>The role of kexB gene in A. flavus keratitis was identified through whole-genome sequencing. Its mutation impairs conidia formation, cell wall integrity, and invasion, leading to milder clinical symptoms.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"42"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11824512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does Age Modify the Relation Between Genetic Predisposition to Glaucoma and Various Glaucoma Traits in the UK Biobank?","authors":"Jihye Kim, Jae H Kang, Janey L Wiggs, Hetince Zhao, Keva Li, Nazlee Zebardast, Ayellet Segrè, David S Friedman, Ron Do, Anthony P Khawaja, Hugues Aschard, Louis R Pasquale","doi":"10.1167/iovs.66.2.57","DOIUrl":"10.1167/iovs.66.2.57","url":null,"abstract":"<p><strong>Purpose: </strong>Glaucoma polygenic risk scores could guide glaucoma public health screening initiatives. We investigated how age influences the relationship between a multitrait glaucoma polygenic risk score (mtGPRS) and primary open-angle glaucoma indicators, including intraocular pressure (IOP), retinal structure, and glaucoma prevalence.</p><p><strong>Methods: </strong>We analyzed UK Biobank participants with demographic and genetic data, assessing IOP (n = 118,153), macular retinal nerve fiber layer thickness (mRNFL; n = 42,132), macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 42,042), and prevalent glaucoma status (8982 cases among 192,283 participants). An mtGPRS was constructed using 2673 genetic variants. We used multivariable linear regression to assess how age modifies the relationship between mtGPRS and glaucoma traits (IOP, mRFNL, and mGCIPL) and multivariable logistic regression for prevalent glaucoma risk. We analyzed age quartiles (Q1 = <51, Q2 = 51-57, Q3 = 58-62, and Q4 = ≥63 years) - glaucoma trait interaction tests with the Wald test. All analyses were adjusted for confounders, including nonlinear age effects.</p><p><strong>Results: </strong>Age significantly modified the relationship between the mtGPRS and IOP (Pinteraction = 2.7e-27). Mean IOP differences (millimeters of mercury [mm Hg]) per standard deviation (SD) of mtGPRS were 0.95, 1.02, 1.18, and 1.24 across age quartiles. Similar trends were observed for glaucoma risk (odds ratio per SD of mtGPRS = 2.38, 2.57, 2.80, and 2.75; Pinteraction = 1.0e-06). Relationships between mtGPRS and inner retinal thickness (mRNFL and mGCIPL) across age strata were inconsistently modified by age (Pinteraction ≥ 0.01).</p><p><strong>Conclusions: </strong>With increasing age, an mtGPRS was a better predictor of higher IOP and glaucoma prevalence. It is useful to consider chronological age with genetic information in designing glaucoma screening strategies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"57"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11855177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the Genetic Basis for Inherited Retinal Disease: Lessons Learned From the Foundation Fighting Blindness Clinical Consortium's Gene Poll.","authors":"Kari Branham, Lassana Samarakoon, Isabelle Audo, Allison R Ayala, Janet K Cheetham, Stephen P Daiger, Patty Dhooge, Jacque L Duncan, Todd A Durham, Abigail T Fahim, Rachel M Huckfeldt, Robert B Hufnagel, Susanne Kohl, Ramiro S Maldonado, Michele Melia, Michel Michaelides, Mark E Pennesi, José-Alain Sahel, Juliana M Ferraz Sallum, Mandeep S Singh, Dror Sharon, Kimberly Stepien, Kaylie Jones, Christina Y Weng","doi":"10.1167/iovs.66.2.12","DOIUrl":"10.1167/iovs.66.2.12","url":null,"abstract":"<p><strong>Purpose: </strong>The Foundation Fighting Blindness (FFB) Consortium is a collaboration of 41 international clinical centers that manage patients affected with inherited retinal diseases (IRDs). The annual Consortium gene poll was initiated in 2020 to capture the genetic cause of disease in patients with IRD and associated clinical practices of Consortium sites. Data from the 2022 gene poll are reported here.</p><p><strong>Methods: </strong>In 2022, academic, private practice, and government ophthalmology clinics that are members of the Consortium centers were polled to identify per-case IRD genetic causality from a list of 387 syndromic and nonsyndromic IRD genes. The survey also assessed how genetic testing was obtained and clinical practices of the sites.</p><p><strong>Results: </strong>Thirty centers responded and reported genetic data from 33,834 patients (27,561 families). Disease-causing variants were reported in 293 of 387 genes. The most common genetic etiologies were ABCA4 (17%), USH2A (9%), RPGR (6%), PRPH2 (5%), and RHO (4%). The top 100 genes accounted for the genetic cause of disease in 94.4% of patients. Two-thirds of the centers had at least one genetic counselor. In the 21 US sites, genetic testing was commonly obtained through sponsored programs (95%, FFB-My Retina Tracker Programs or Spark-ID Your IRD), whereas in the 9 non-US sites, genetic testing was commonly obtained using either patient- or public health system-funded testing pipelines. Clinical work-up of patients with IRD most commonly included updating history, eye examination, and optical coherence tomography.</p><p><strong>Conclusions: </strong>This report provides the largest assessment of genetic causality in the IRD patient population across multiple continents to date.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"12"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship of OCT-Based Diabetic Retinal Neurodegeneration to the Development and Progression of Diabetic Retinopathy: A Cohort Study.","authors":"Ziqi Tang, Dawei Yang, Truong X Nguyen, Shuyi Zhang, Danqi Fang, Victor T T Chan, Clement C Tham, Elliott H Sohn, Ken K Tsang, Cherie Y K Wong, Vivian W K Hui, Amy H Y Yu, Julia T W Lam, Carmen K M Chan, Timothy Y Y Lai, Simon K H Szeto, Carol Y Cheung","doi":"10.1167/iovs.66.2.32","DOIUrl":"10.1167/iovs.66.2.32","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the relationship between diabetic retinal neurodegeneration (DRN), as quantified by optical coherence tomography (OCT), to the development of diabetic retinopathy (DR), progression of DR, and development of proliferative DR (PDR).</p><p><strong>Methods: </strong>This was a prospective cohort study, including 385 eyes with no DR or nonproliferative DR at baseline. The thicknesses of the macular ganglion cell-inner plexiform layer (m-GCIPL), macular retinal nerve fiber layer, and peripapillary RNFL (p-RNFL) were measured using Cirrus OCT (Carl Zeiss Meditec, Dublin, CA, USA). DR outcomes were determined from macula- and optic disc-centered fundus photographs, following the modified Airlie House classification system. Cox proportional hazards models were used to estimate hazard ratio (HR) adjusting for age, mean arterial blood pressure, diabetes mellitus duration, HbA1c, diabetic kidney disease, axial length, OCT signal strength, and disc area (for p-RNFL only).</p><p><strong>Results: </strong>After a median follow-up of 6.2 years (range 5.0-7.7 years), 79 eyes developed DR, 99 eyes developed DR progression, and 38 eyes developed PDR. Thinner mean and sectorial m-GCIPL thicknesses were significantly associated with higher risk of DR development, with HRs ≥ 1.373 (1.023-1.843), except for the superonasal and superotemporal sectors. Similar to DR development, thinner m-GCIPL thicknesses were significantly associated with DR progression and PDR development, with HRs ranging from 1.306 (1.094-1.559) to 2.331 (1.524-3.566). Additionally, the inclusion of inferior m-GCIPL thickness significantly improved the predictive discrimination for DR development (C statistics: 0.661 vs. 0.705, P < 0.001), and DR progression (C statistics: 0.704 vs. 0.729, P < 0.001), as well as inferotemporal m-GCIPL for PDR development (C statistic: 0.917 vs. 0.930, P < 0.001) beyond established risk factors.</p><p><strong>Conclusions: </strong>OCT measurements that elucidate DRN may enhance prognostic identification and predictive discrimination of DR development, DR progression, and PDR development beyond established risk factors.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"32"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional Alterations in Müller Cell Protein Expression in Human and a Rat Model of Geographic Atrophy.","authors":"Poonam Naik, D Scott McLeod, Imran A Bhutto, Malia M Edwards","doi":"10.1167/iovs.66.2.21","DOIUrl":"10.1167/iovs.66.2.21","url":null,"abstract":"<p><strong>Purpose: </strong>Despite being crucial to neuronal survival, the role Müller cells play in geographic atrophy (GA) has only recently been considered. We investigated whether Müller cells retain their normal functional profile or form a fibrotic scar when remodeling in human GA eyes and our subretinal sodium iodate (NaIO3) model.</p><p><strong>Methods: </strong>Sprague Dawley rats given subretinal injections of NaIO3 (5 mg/mL) were sacrificed at 3 and 12 weeks. Cryosections and retinal flatmounts from rats and cryosections from human GA eyes were stained with antibodies against the Müller cell proteins glutamine synthetase (GS), inwardly rectifying potassium channel 4.1 (Kir4.1), aquaporin 4 (AQP4), cellular retinaldehyde-binding protein 1 (CRALBP), and glial fibrillary acidic protein (GFAP), as well as alpha smooth muscle actin (α-SMA), fibronectin, and collagens I and IV. The immunofluorescence intensity of AQP4 and Kir4.1 was quantified using Image J, and Kir4.1 protein levels were verified by western blot.</p><p><strong>Results: </strong>In both human GA eyes and NaIO3-injected rats, Müller cell processes at the external limiting membrane (ELM) descent and in the subretinal membrane exhibited increased GS expression. GFAP was elevated throughout the Müller cells. AQP4 staining at the ELM descent was particularly pronounced throughout the radial processes, including those extending into the subretinal space. In NaIO3-injected rats, perivascular Kir4.1 expression significantly decreased in the atrophic retina, but expression increased in the subretinal glial membrane. α-SMA and extracellular matrix proteins were not detected in the subretinal membrane.</p><p><strong>Conclusions: </strong>Our findings underscore the persistence of homeostatic proteins, albeit altered, in Müller cells as they remodel and extend into the subretinal space.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"21"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Penetrable AAV2 Capsid Variant for Efficient Intravitreal Gene Delivery to the Retina.","authors":"Xiaoyu He, Yidian Fu, Yangfan Xu, Liang Ma, Peiwei Chai, Hanhan Shi, Yizheng Yao, Shengfang Ge, Renbing Jia, Xuyang Wen, Zhi Yang, Xianqun Fan","doi":"10.1167/iovs.66.1.6","DOIUrl":"https://doi.org/10.1167/iovs.66.1.6","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to identify a novel recombinant adeno-associated virus (rAAV) capsid variant that can widely transfect the deep retina through intravitreal injection and to assess their effectiveness and safety in gene delivery.</p><p><strong>Methods: </strong>By adopting the sequences of various cell-penetrating peptides and inserting them into the capsid modification region of AAV2, we generated several novel variants. The green fluorescent protein (GFP)-carrying variants were screened following intravitreal injection. Gene therapy experiments were conducted via intravitreal injection of rd1 mice. We validated the therapeutic effects utilizing the pupillary light reflex and visual cliff test. Assessment of retinal structure and Pde6b gene levels in rd1 mice after gene therapy further was confirmed through transcriptome sequencing to validate the gene therapy efficacy.</p><p><strong>Results: </strong>We observed enhanced transduction and penetration efficiency of the AAV variant AAV2.CPP.21 after intravitreal injection which can target all layers of the retinas. Normal doses of AAV2.CPP.21 administered via intravitreal injection achieved effective gene therapy for retinitis pigmentosa in rd1 mice, with no increased risk of transgenic leakage in peripheral organs.</p><p><strong>Conclusions: </strong>Our study identified another new, safe, and efficient AAV vector for gene therapy via intravitreal injection for retinal diseases. This new vector holds promise for clinical application and improvement of the efficacy of gene therapy for inherited retinal diseases.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}