{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:20Z","timestamp":1792785920459,"version":"4.5.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"23","license":[{"start":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T00:00:00Z","timestamp":1567728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R025134\/1"],"award-info":[{"award-number":["MR\/R025134\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"RP Fighting Blindness","award":["GR576"],"award-info":[{"award-number":["GR576"]}]},{"DOI":"10.13039\/100010446","name":"Batten Disease Family Association","doi-asserted-by":"publisher","award":["1084908"],"award-info":[{"award-number":["1084908"]}],"id":[{"id":"10.13039\/100010446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23\u00a0months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.<\/jats:p>","DOI":"10.1093\/hmg\/ddz210","type":"journal-article","created":{"date-parts":[[2019,8,28]],"date-time":"2019-08-28T15:23:02Z","timestamp":1567005782000},"page":"3867-3879","source":"Crossref","is-referenced-by-count":27,"title":["Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease"],"prefix":"10.1093","volume":"28","author":[{"given":"Sophia-Martha","family":"kleine Holthaus","sequence":"first","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul","family":"Herranz-Martin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London WC1N 1AX, UK"},{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (UAM-CSIC) and Departamento de Biolog\u00eda Molecular, Universidad Aut\u00f3noma de Madrid (UAM), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Massaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Aristorena","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Hoke","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryea","family":"Maswood","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olha","family":"Semenyuk","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Basche","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna Z","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela P","family":"Klaska","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E","family":"Mole","sequence":"additional","affiliation":[{"name":"MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK"},{"name":"UCL Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK"},{"name":"UCL Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahad A","family":"Rahim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin R","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"},{"name":"NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,6]]},"reference":[{"key":"2020011802062925900_ref1","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.bbadis.2013.04.008","article-title":"NCL diseases\u2014clinical perspectives","volume":"1832","author":"Schulz","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"2020011802062925900_ref2","volume-title":"The Neuronal Ceroid Lipofuscinoses Batten Disease","author":"Mole","year":"2011"},{"key":"2020011802062925900_ref3","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1016\/j.bbadis.2015.04.027","article-title":"Cell biology of the NCL proteins: what they do and don\u2019t do","volume":"1852","author":"C\u00e1rcel-Trullols","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"2020011802062925900_ref4","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.yexcr.2004.04.042","article-title":"CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein","volume":"298","author":"Mole","year":"2004","journal-title":"Exp. Cell Res."},{"key":"2020011802062925900_ref5","first-page":"316","article-title":"Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations","volume-title":"Neurology","author":"Canafoglia","year":"2015"},{"key":"2020011802062925900_ref6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.ajhg.2011.04.004","article-title":"Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6","volume":"88","author":"Arsov","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2020011802062925900_ref7","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/(SICI)1096-8628(19980526)77:4<289::AID-AJMG8>3.0.CO;2-I","article-title":"Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9","volume":"77","author":"Bronson","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"2020011802062925900_ref8","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1086\/338708","article-title":"The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein","volume":"70","author":"Wheeler","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2020011802062925900_ref9","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1086\/338190","article-title":"Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse","volume":"70","author":"Gao","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2020011802062925900_ref10","doi-asserted-by":"crossref","first-page":"e78694","DOI":"10.1371\/journal.pone.0078694","article-title":"A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease","volume":"8","author":"Morgan","year":"2013","journal-title":"PLoS One"},{"key":"2020011802062925900_ref11","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1056\/NEJMoa1407309","article-title":"Long-term safety and efficacy of factor IX gene therapy in hemophilia B","volume":"371","author":"Nathwani","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2020011802062925900_ref12","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. Engl. J. Med."},{"key":"2020011802062925900_ref13","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2020011802062925900_ref14","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1089\/hum.2017.167","article-title":"Advances in gene therapy for hemophilia","volume":"28","author":"Nathwani","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"2020011802062925900_ref15","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0140-6736(17)31868-8","article-title":"Articles efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial","volume":"390","author":"Russel","year":"2017","journal-title":"Lancet"},{"key":"2020011802062925900_ref16","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1089\/hum.2008.022","article-title":"Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA","volume":"1074","author":"Worgall","year":"2008","journal-title":"Hum. 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