{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T06:07:45Z","timestamp":1776751665180,"version":"3.51.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY01651 , EY031044 , EY001765"],"award-info":[{"award-number":["EY01651 , EY031044 , EY001765"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Ophthalmol."],"abstract":"<jats:p>Choroideremia (CHM) is a recessive, X-linked disease that affects 1 in 50,000 people worldwide. CHM causes night blindness in teenage years with vision loss progressing over the next two to three decades. While CHM is known to cause progressive loss of retinal pigment epithelial (RPE) cells, photoreceptors and choroidal vessels, little attention has been given to retinal glial changes in eyes with CHM. In addition, while choroidal loss has been observed clinically, no histopathologic assessment of choroidal loss has been done. We investigated glial remodeling and activation as well as choriocapillaris changes and their association with RPE loss in postmortem eyes from two donors with CHM. Eyes were fixed and cryopreserved or the retina and choroid\/RPE were processed as flatmounts with a small piece cut for transmission electron microscopy. A dense glial membrane, made up of vimentin and GFAP double-positive cells, occupied the subretinal space in the area of RPE and photoreceptor loss of both eyes. The membranes did not extend into the far periphery, where RPE and photoreceptors were viable. A glial membrane was also found on the vitreoretinal surface. Transmission electron microscopy analysis demonstrated prominence and disorganization of glial cells, which contained exosome-like vesicles. UEA lectin demonstrated complete absence of choriocapillaris in areas with RPE loss while some large choroidal vessels remained viable. In the far periphery, where the RPE monolayer was intact, choriocapillaris appeared normal. The extensive glial remodeling present in eyes with CHM should be taken into account when therapies such as stem cell replacement are considered as it could impede cells entering the retina. This gliosis would also need to be reversed to some extent for M\u00fcller cells to perform their normal homeostatic functions in the retina. Future studies investigating donor eyes as well as clinical imaging from carriers or those with earlier stages of CHM will prove valuable in understanding the glial changes, which could affect disease progression if they occur early. This would also provide insights into the progression of disease in the photoreceptor\/RPE\/choriocapillaris complex, which is crucial for identifying new treatments and finding the windows for treatment.<\/jats:p>","DOI":"10.3389\/fopht.2022.994566","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T07:42:00Z","timestamp":1665733320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Glial remodeling and choroidal vascular pathology in eyes from two donors with Choroideremia"],"prefix":"10.3389","volume":"2","author":[{"given":"Malia M.","family":"Edwards","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. Scott","family":"McLeod","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rhonda","family":"Grebe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imran A.","family":"Bhutto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Dahake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"Crumley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard A.","family":"Lutty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"B1","article-title":"The pathologic findings in two cases of choroideremia","volume":"54","author":"McCullough","year":"1950","journal-title":"Trans Am Acad Ophthalmol Otolaryngol"},{"key":"B2","article-title":"Choroideremia; a hereditary and clinical study","volume":"43","author":"McCullough","year":"1950","journal-title":"Arch Ophthal"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.36.10.547","article-title":"Choroideremia; clinical and genetic aspects","volume":"36","author":"Sorsby","year":"1952","journal-title":"Br J Ophthalmol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.86.6.658","article-title":"Retrospective, longitudinal, and cross sectional study of visual acuity impairment in choroideraemia","volume":"86","author":"Roberts","year":"2002","journal-title":"Br J Ophthalmol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1997)9:2<110::AID-HUMU2>3.0.CO;2-D","article-title":"Molecular basis of choroideremia (CHM): mutations involving the rab escort protein-1 (REP-1) gene","volume":"9","author":"van den Hurk","year":"1997","journal-title":"Hum Mutat"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-18364","article-title":"Correlation of optical coherence tomography and autofluorescence in the outer retina and choroid of patients with choroideremia","volume":"57","author":"Xue","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2018.1484448","article-title":"Choroideremia: molecular mechanisms and development of AAV gene therapy","volume":"18","author":"Patricio","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2017.242","article-title":"Identifying characteristic features of the retinal and choroidal vasculature in choroideremia using optical coherence tomography angiography","volume":"32","author":"Abbouda","year":"2018","journal-title":"Eye (Lond)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3928\/23258160-20170829-05","article-title":"Quantitative and qualitative features of spectral-domain optical coherence tomography provide prognostic indicators for visual acuity in patients with choroideremia","volume":"48","author":"Abbouda","year":"2017","journal-title":"Ophthal Surg Lasers Imaging Retina"},{"key":"B10","doi-asserted-by":"publisher","first-page":"57","DOI":"10.3109\/13816810.2011.620056","article-title":"Choroideremia: a review of general findings and pathogenesis","volume":"33","author":"Coussa","year":"2012","journal-title":"Ophthal Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.06-0424","article-title":"Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations","volume":"47","author":"Jacobson","year":"2006","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/2515841418817490","article-title":"Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments","volume":"10","author":"Mitsios","year":"2018","journal-title":"Ther Adv Ophthalmol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-27378-1_23","article-title":"Multimodal imaging in choroideremia","volume":"1185","author":"Foote","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/13816810.2019.1711429","article-title":"En face OCT in choroideremia","volume":"40","author":"Murro","year":"2019","journal-title":"Ophthal Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-022-01953-3","article-title":"Outer retinal and choriocapillaris modifications in choroideremia: three differentially impaired retinal regions and the potential diagnostic role of the external limiting membrane","author":"Arrigo","year":"2022","journal-title":"Eye (Lond)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2020-316528","article-title":"Reduced vessel density in deep capillary plexus correlates with retinal layer thickness in choroideremia","volume":"105","author":"Arrigo","year":"2021","journal-title":"Br J Ophthalmol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.10.022","article-title":"Natural history of the central structural abnormalities in choroideremia: A prospective cross-sectional study","volume":"124","author":"Aleman","year":"2017","journal-title":"Ophthalmology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-21229","article-title":"Subretinal glial membranes in eyes with geographic atrophy","volume":"58","author":"Edwards","year":"2017","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B19","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.exer.2015.07.016","article-title":"Idiopathic preretinal glia in aging and age-related macular degeneration","volume":"150","author":"Edwards","year":"2016","journal-title":"Exp Eye Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1167\/iovs.61.8.27","article-title":"Retinal glial and choroidal vascular pathology in donors clinically diagnosed with stargardt disease","volume":"61","author":"Edwards","year":"2020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0042-6989(02)00680-6","article-title":"Muller Cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery: a review and reconsideration of recent data","volume":"43","author":"Fisher","year":"2003","journal-title":"Vision Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.03.018","article-title":"Retinal remodeling in human retinitis pigmentosa","volume":"150","author":"Jones","year":"2016","journal-title":"Exp Eye Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(87)33479-7","article-title":"Histopathologic observations in choroideremia with emphasis on vascular changes of the uveal tract","volume":"94","author":"Cameron","year":"1987","journal-title":"Ophthalmology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1167\/iovs.15-18865","article-title":"Relationship between presumptive inner nuclear layer thickness and geographic atrophy progression in age-related macular degeneration","volume":"57","author":"Ebneter","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2010.199216","article-title":"C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration Comparative Study","volume":"95","author":"Bhutto","year":"2011","journal-title":"Br J Ophthalmol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2019.02.018","article-title":"Ultrastructural analysis of submacular choriocapillaris and its transport systems in AMD and aged control eyes","volume":"181","author":"Grebe","year":"2019","journal-title":"Exp Eye Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-20049","article-title":"Distribution and quantification of choroidal macrophages in human eyes with age-related macular degeneration","volume":"57","author":"McLeod","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"107939","DOI":"10.1016\/j.exer.2020.107939","article-title":"Choriocapillaris dropout in early age-related macular degeneration","volume":"192","author":"Lutty","year":"2020","journal-title":"Exp Eye Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-3639","article-title":"Relationship between RPE and choriocapillaris in age-related macular degeneration","volume":"50","author":"McLeod","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.533375","article-title":"Retinal thickness and microvascular pattern in early parkinson's disease","volume":"11","author":"Rascuna","year":"2020","journal-title":"Front Neurol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1001\/jamaophthalmol.2016.0874","article-title":"Optical coherence tomography angiography in choroideremia: Correlating choriocapillaris loss with overlying degeneration","volume":"134","author":"Jain","year":"2016","journal-title":"JAMA Ophthalmol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-13454","article-title":"High-resolution adaptive optics retinal imaging of cellular structure in choroideremia","volume":"55","author":"Morgan","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(00)00643-6","article-title":"Evaluation of retinal photoreceptors and pigment epithelium in a female carrier of choroideremia","volume":"108","author":"Syed","year":"2001","journal-title":"Ophthalmology"},{"key":"B34","article-title":"The fate of muller's glia following experimental retinal detachment: nuclear migration, cell division, and subretinal glial scar formation","volume":"16","author":"Lewis","year":"2010","journal-title":"Mol Vision"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2005.03.006","article-title":"Retinal remodeling during retinal degeneration","volume":"81","author":"Jones","year":"2005","journal-title":"Exp Eye Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2013.01.013","article-title":"Macular hole surgery in patients with end-stage choroideremia","volume":"120","author":"Zinkernagel","year":"2013","journal-title":"Ophthalmology"}],"container-title":["Frontiers in Ophthalmology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2022.994566\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T07:42:06Z","timestamp":1665733326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2022.994566\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":36,"alternative-id":["10.3389\/fopht.2022.994566"],"URL":"https:\/\/doi.org\/10.3389\/fopht.2022.994566","relation":{},"ISSN":["2674-0826"],"issn-type":[{"value":"2674-0826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]},"article-number":"994566"}}