{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:46:54Z","timestamp":1788385614078,"version":"build-2803163510"},"reference-count":47,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T00:00:00Z","timestamp":1527811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T00:00:00Z","timestamp":1527811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T00:00:00Z","timestamp":1513641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["268970"],"award-info":[{"award-number":["268970"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1000268\/1"],"award-info":[{"award-number":["G1000268\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N012992\/1"],"award-info":[{"award-number":["MR\/N012992\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Therapy - Methods &amp; Clinical Development"],"published-print":{"date-parts":[[2018,6]]},"DOI":"10.1016\/j.omtm.2017.12.002","type":"journal-article","created":{"date-parts":[[2017,12,21]],"date-time":"2017-12-21T20:57:48Z","timestamp":1513889868000},"page":"192-202","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":29,"special_numbering":"C","title":["Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice"],"prefix":"10.1016","volume":"9","author":[{"given":"Jasmina","family":"Cehajic-Kapetanovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Milosavljevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bedford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul N.","family":"Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.omtm.2017.12.002_bib1","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1056\/NEJMoa0802268","article-title":"Effect of gene therapy on visual function in Leber\u2019s congenital amaurosis","volume":"358","author":"Bainbridge","year":"2008","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.omtm.2017.12.002_bib2","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1056\/NEJMoa0802315","article-title":"Safety and efficacy of gene transfer for Leber\u2019s congenital amaurosis","volume":"358","author":"Maguire","year":"2008","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.omtm.2017.12.002_bib3","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1089\/hum.2008.107","article-title":"Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial","volume":"19","author":"Hauswirth","year":"2008","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib4","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/S0140-6736(09)61836-5","article-title":"Age-dependent effects of RPE65 gene therapy for Leber\u2019s congenital amaurosis: a phase 1 dose-escalation trial","volume":"374","author":"Maguire","year":"2009","journal-title":"Lancet"},{"key":"10.1016\/j.omtm.2017.12.002_bib5","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1056\/NEJMoa1414221","article-title":"Long-term effect of gene therapy on Leber\u2019s congenital amaurosis","volume":"372","author":"Bainbridge","year":"2015","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.omtm.2017.12.002_bib6","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1073\/pnas.0500646102","article-title":"Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success","volume":"102","author":"Jacobson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.omtm.2017.12.002_bib7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nrg2717","article-title":"Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait","volume":"11","author":"Wright","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"10.1016\/j.omtm.2017.12.002_bib8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1001\/archophthalmol.2011.298","article-title":"Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years","volume":"130","author":"Jacobson","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"10.1016\/j.omtm.2017.12.002_bib9","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.ymthe.2006.03.005","article-title":"Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection","volume":"13","author":"Jacobson","year":"2006","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib10","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/archophthalmol.2011.295","article-title":"Functional and anatomic consequences of subretinal dosing in the cynomolgus macaque","volume":"130","author":"Nork","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"10.1016\/j.omtm.2017.12.002_bib11","first-page":"1771","article-title":"Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2","volume":"17","author":"Cehajic-Kapetanovic","year":"2011","journal-title":"Mol. Vis."},{"key":"10.1016\/j.omtm.2017.12.002_bib12","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1038\/mt.2009.181","article-title":"Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous","volume":"17","author":"Dalkara","year":"2009","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib13","doi-asserted-by":"crossref","first-page":"7827","DOI":"10.1073\/pnas.0802866105","article-title":"Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses","volume":"105","author":"Zhong","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.omtm.2017.12.002_bib14","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/mt.2008.269","article-title":"High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors","volume":"17","author":"Petrs-Silva","year":"2009","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib15","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/mt.2010.234","article-title":"Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina","volume":"19","author":"Petrs-Silva","year":"2011","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib16","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1167\/iovs.10-6250","article-title":"Intravitreal injection of AAV2 transduces macaque inner retina","volume":"52","author":"Yin","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.omtm.2017.12.002_bib17","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/gt.2011.151","article-title":"Novel adeno-associated viral vectors for retinal gene therapy","volume":"19","author":"Vandenberghe","year":"2012","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/hgtb.2012.194","article-title":"Bioengineering of AAV2 capsid at specific serine, threonine, or lysine residues improves its transduction efficiency in\u00a0vitro and in\u00a0vivo","volume":"24","author":"Gabriel","year":"2013","journal-title":"Hum. Gene Ther. Methods"},{"key":"10.1016\/j.omtm.2017.12.002_bib19","doi-asserted-by":"crossref","first-page":"e62097","DOI":"10.1371\/journal.pone.0062097","article-title":"Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors","volume":"8","author":"Kay","year":"2013","journal-title":"PLoS ONE"},{"key":"10.1016\/j.omtm.2017.12.002_bib20","doi-asserted-by":"crossref","first-page":"e59142","DOI":"10.1371\/journal.pone.0059142","article-title":"Optimization of the capsid of recombinant adeno-associated virus 2 (AAV2) vectors: the final threshold?","volume":"8","author":"Aslanidi","year":"2013","journal-title":"PLoS ONE"},{"key":"10.1016\/j.omtm.2017.12.002_bib21","doi-asserted-by":"crossref","first-page":"e7467","DOI":"10.1371\/journal.pone.0007467","article-title":"A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat M\u00fcller cells","volume":"4","author":"Klimczak","year":"2009","journal-title":"PLoS ONE"},{"key":"10.1016\/j.omtm.2017.12.002_bib22","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/gt.2012.20","article-title":"Directed evolution of novel adeno-associated viruses for therapeutic gene delivery","volume":"19","author":"Bartel","year":"2012","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib23","doi-asserted-by":"crossref","first-page":"189ra76","DOI":"10.1126\/scitranslmed.3005708","article-title":"In\u00a0vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous","volume":"5","author":"Dalkara","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.omtm.2017.12.002_bib24","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/mt.2010.273","article-title":"Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa","volume":"19","author":"Pang","year":"2011","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib25","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/gt.2008.178","article-title":"Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection","volume":"16","author":"Hellstr\u00f6m","year":"2009","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib26","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/0092-8674(95)90354-2","article-title":"Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene","volume":"80","author":"Masu","year":"1995","journal-title":"Cell"},{"key":"10.1016\/j.omtm.2017.12.002_bib27","doi-asserted-by":"crossref","first-page":"7748","DOI":"10.1523\/JNEUROSCI.0397-08.2008","article-title":"A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression","volume":"28","author":"Kim","year":"2008","journal-title":"J.\u00a0Neurosci."},{"key":"10.1016\/j.omtm.2017.12.002_bib28","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/nn.2117","article-title":"Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration","volume":"11","author":"Lagali","year":"2008","journal-title":"Nat. Neurosci."},{"key":"10.1016\/j.omtm.2017.12.002_bib29","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1038\/mt.2011.69","article-title":"Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness","volume":"19","author":"Doroudchi","year":"2011","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib30","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.15252\/emmm.201404077","article-title":"Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter","volume":"6","author":"Cronin","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.omtm.2017.12.002_bib31","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/mt.2014.154","article-title":"Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice","volume":"23","author":"Mac\u00e9","year":"2015","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib32","doi-asserted-by":"crossref","first-page":"6511","DOI":"10.1167\/iovs.11-7909","article-title":"Mapping the differential distribution of glycosaminoglycans in the adult human retina, choroid, and sclera","volume":"52","author":"Clark","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.omtm.2017.12.002_bib33","doi-asserted-by":"crossref","first-page":"7528","DOI":"10.1167\/iovs.12-10797","article-title":"Mapping the differential distribution of proteoglycan core proteins in the adult human retina, choroid, and sclera","volume":"53","author":"Keenan","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.omtm.2017.12.002_bib34","first-page":"1760","article-title":"Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential","volume":"14","author":"Li","year":"2008","journal-title":"Mol. Vis."},{"key":"10.1016\/j.omtm.2017.12.002_bib35","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1128\/JVI.72.2.1438-1445.1998","article-title":"Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions","volume":"72","author":"Summerford","year":"1998","journal-title":"J.\u00a0Virol."},{"key":"10.1016\/j.omtm.2017.12.002_bib36","doi-asserted-by":"crossref","first-page":"11072","DOI":"10.1128\/JVI.77.20.11072-11081.2003","article-title":"Identification of a heparin-binding motif on adeno-associated virus type 2 capsids","volume":"77","author":"Kern","year":"2003","journal-title":"J.\u00a0Virol."},{"key":"10.1016\/j.omtm.2017.12.002_bib37","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000223939","article-title":"Vitreous as a substrate for vitreolysis","volume":"44","author":"Bishop","year":"2009","journal-title":"Dev. Ophthalmol."},{"key":"10.1016\/j.omtm.2017.12.002_bib38","first-page":"2345","article-title":"The safety of intravitreal hyaluronidase. A clinical and histologic study","volume":"31","author":"Gottlieb","year":"1990","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.omtm.2017.12.002_bib39","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1080\/02713680490516747","article-title":"Enzyme-assisted vitrectomy in enucleated pig eyes: a comparison of hyaluronidase, chondroitinase, and plasmin","volume":"29","author":"Staubach","year":"2004","journal-title":"Curr. Eye Res."},{"key":"10.1016\/j.omtm.2017.12.002_bib40","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.ajo.2005.04.018","article-title":"Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage","volume":"140","author":"Kuppermann","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"10.1016\/j.omtm.2017.12.002_bib41","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/BF02150029","article-title":"Structure and composition of the inner limiting membrane of the retina. SEM on frozen resin-cracked and enzyme-digested retinas of Macaca mulatta","volume":"224","author":"Heegaard","year":"1986","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"10.1016\/j.omtm.2017.12.002_bib42","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/j.cub.2015.07.029","article-title":"Restoration of Vision with Ectopic Expression of Human Rod Opsin","volume":"25","author":"Cehajic-Kapetanovic","year":"2015","journal-title":"Curr. Biol."},{"key":"10.1016\/j.omtm.2017.12.002_bib43","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/gt.2014.115","article-title":"Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates","volume":"22","author":"Kotterman","year":"2015","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib44","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/mt.2010.258","article-title":"Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration","volume":"19","author":"Maclachlan","year":"2011","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib45","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1089\/humc.2015.076","article-title":"Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin","volume":"26","author":"Ye","year":"2015","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"10.1016\/j.omtm.2017.12.002_bib46","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1089\/hum.2016.085","article-title":"Highly Efficient Delivery of Adeno-Associated Viral Vectors to the Primate Retina","volume":"27","author":"Boye","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2017.12.002_bib47","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1177\/0748730411409719","article-title":"A \u201cmelanopic\u201d spectral efficiency function predicts the sensitivity of melanopsin photoreceptors to polychromatic lights","volume":"26","author":"Enezi","year":"2011","journal-title":"J.\u00a0Biol. Rhythms"}],"container-title":["Molecular Therapy - Methods &amp; Clinical Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2329050117301274?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2329050117301274?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:51:57Z","timestamp":1778867517000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2329050117301274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6]]},"references-count":47,"alternative-id":["S2329050117301274"],"URL":"https:\/\/doi.org\/10.1016\/j.omtm.2017.12.002","relation":{},"ISSN":["2329-0501"],"issn-type":[{"value":"2329-0501","type":"print"}],"subject":[],"published":{"date-parts":[[2018,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice","name":"articletitle","label":"Article Title"},{"value":"Molecular Therapy - Methods & Clinical Development","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.omtm.2017.12.002","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2018 The Authors.","name":"copyright","label":"Copyright"}]}}