{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:29:16Z","timestamp":1791221356438,"version":"4.1.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,4,26]]},"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>RPE65<\/jats:italic>\n                    , a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from\n                    <jats:italic>RPE65<\/jats:italic>\n                    mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution\n                    <jats:italic>in vivo<\/jats:italic>\n                    microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many\n                    <jats:italic>RPE65<\/jats:italic>\n                    -mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned\n                    <jats:italic>RPE65<\/jats:italic>\n                    -mutant retina with photoreceptor loss would respond to treatment. Gene therapy in\n                    <jats:italic>Rpe65<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with\n                    <jats:italic>RPE65<\/jats:italic>\n                    mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0500646102","type":"journal-article","created":{"date-parts":[[2005,4,18]],"date-time":"2005-04-18T20:25:21Z","timestamp":1113855921000},"page":"6177-6182","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":195,"title":["Identifying photoreceptors in blind eyes caused by\n                    <i>RPE65<\/i>\n                    mutations: Prerequisite for human gene therapy success"],"prefix":"10.1073","volume":"102","author":[{"given":"Samuel G.","family":"Jacobson","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas S.","family":"Aleman","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur V.","family":"Cideciyan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Sumaroka","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon B.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A. M.","family":"Windsor","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias I.","family":"Traboulsi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; 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Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; and Howard Hughes Medical Institute and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann H.","family":"Milam","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Physiological Optics, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195; 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