{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:36:13Z","timestamp":1793414173680,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the<jats:italic>CLN5<\/jats:italic>gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intracerebroventricular (ICV) delivery of an adeno-associated viral vector encoding ovine<jats:italic>CLN5<\/jats:italic>(scAAV9\/oCLN5) in a naturally occurring sheep model of CLN5 disease. CLN5 affected (CLN5<jats:sup>\u2212\/\u2212<\/jats:sup>) sheep received low, moderate, or high doses of scAAV9\/oCLN5 at three disease stages. The treatment delayed disease progression, extended survival and slowed stereotypical brain atrophy in most animals. Of note, one high dose treated animal only developed mild disease symptomology and survived to 60.1 months of age, triple the natural life expectancy of an untreated CLN5<jats:sup>\u2212\/\u2212<\/jats:sup>sheep. Eyesight was not preserved at any administration age or dosage. Histopathologic examination revealed that greater transduction efficiency was achieved through higher ICV doses, and this resulted in greater amelioration of disease pathology. Together with other pre-clinical data from CLN5<jats:sup>\u2212\/\u2212<\/jats:sup>sheep, the safety and efficacy data from these investigational new drug (IND)-enabling studies supported the initiation of the first in-human CLN5 gene therapy clinical study using the ICV delivery route for the treatment of CLN5 NCL.<\/jats:p><jats:p><jats:bold>Clinical Trial Registration:<\/jats:bold><jats:ext-link>https:\/\/clinicaltrials.gov\/<\/jats:ext-link>, identifier NCT05228145<\/jats:p>","DOI":"10.3389\/fgene.2023.1212228","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T07:57:36Z","timestamp":1691481456000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Nadia L.","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P.","family":"Wellby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham K.","family":"Barrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina N.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley R.","family":"Deane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Wynyard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine J.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anila","family":"Pulickan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillipa M.","family":"Prendergast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Widler","family":"Casy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/mt.2015.114","article-title":"Gene augmentation therapy restores retinal function and visual behavior in a sheep model of CNGA3 achromatopsia","volume":"23","author":"Banin","year":"2015","journal-title":"Mol. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4735","DOI":"10.1007\/s00018-021-03813-x","article-title":"A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis","volume":"78","author":"Basak","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.omtm.2020.04.001","article-title":"Intra-CSF AAV9 and AAVrh10 administration in nonhuman primates: Promising routes and vectors for which neurological diseases?","volume":"17","author":"Bey","year":"2020","journal-title":"Mol. Ther. - Methods Clin. Dev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1016\/j.mri.2012.05.001","article-title":"3D Slicer as an image computing platform for the quantitative imaging network","volume":"30","author":"Federov","year":"2012","journal-title":"Magn. Reson. Imaging"},{"key":"B5","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.nbd.2007.09.006","article-title":"A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571 + 1G > A) leading to excision of exon 3","volume":"29","author":"Frugier","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1089\/hum.2020.301","article-title":"Intracerebroventricular administration of AAV9-PHP.B SYN1-EmGFP induces widespread transgene expression in the mouse and monkey central nervous system","volume":"32","author":"Galvan","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1089\/hum.2017.163","article-title":"Adeno-associated virus gene therapy in a sheep model of Tay-Sachs disease","volume":"29","author":"Gray-Edwards","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/mt.2015.187","article-title":"Production of recombinant adeno-associated virus vectors using suspension HEK293 cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector","volume":"24","author":"Grieger","year":"2016","journal-title":"Mol. Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1089\/hum.2018.206","article-title":"A single injection of an optimized adeno-associated viral vector into cerebrospinal fluid corrects neurological disease in a murine model of GM1 gangliosidosis","volume":"31","author":"Hinderer","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3079","DOI":"10.1093\/hmg\/ddy212","article-title":"AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease","volume":"27","author":"Hughes","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1093\/hmg\/11.8.885","article-title":"Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein","volume":"11","author":"Isosomppi","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1080\/00480169.2002.36311","article-title":"Neuronal ceroid-lipofuscinosis in Borderdale sheep","volume":"50","author":"Jolly","year":"2002","journal-title":"N. Z. Vet. J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/gt.2017.4","article-title":"Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression","volume":"24","author":"Katz","year":"2017","journal-title":"Gene Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"313ra180","DOI":"10.1126\/scitranslmed.aac6191","article-title":"AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease","volume":"7","author":"Katz","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B15","article-title":"Polioencephalomalacia in ruminants (Cerebrocortical necrosis)","author":"L\u00e9vy","year":"2020","journal-title":"Merck Sharpe Dohme Corp. MSD Vet. Man"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1089\/hum.2011.026","article-title":"Lentiviral-mediated gene transfer to the sheep brain: Implications for gene therapy in batten disease","volume":"22","author":"Linterman","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.molmed.2014.09.003","article-title":"A critical analysis of codon optimization in human therapeutics","volume":"20","author":"Mauro","year":"2014","journal-title":"Trends Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22918","article-title":"Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)","author":"Mitchell","year":"2023","journal-title":"Dev. Neurobiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1016\/j.ymthe.2018.07.015","article-title":"Longitudinal in\u00a0vivo monitoring of the CNS demonstrates the efficacy of gene therapy in a sheep model of CLN5 batten disease","volume":"26","author":"Mitchell","year":"2018","journal-title":"Mol. Ther."},{"key":"B20","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1186\/s13023-021-01813-5","article-title":"Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients","volume":"16","author":"Mole","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"B21","article-title":"Neuronal ceroid lipofuscinoses","author":"Mole","year":"2013","journal-title":"GeneReviews"},{"key":"B22","doi-asserted-by":"publisher","first-page":"108600","DOI":"10.1016\/j.exer.2021.108600","article-title":"Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease","volume":"207","author":"Murray","year":"2021","journal-title":"Exp. Eye Res."},{"key":"B23","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1212235","article-title":"Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease","author":"Murray","year":"2023","journal-title":"Front. Pharmacol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1016\/j.ymthe.2018.07.008","article-title":"Extensive transduction and enhanced spread of a modified AAV2 capsid in the non-human primate CNS","volume":"26","author":"Naidoo","year":"2018","journal-title":"Mol. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1684\/epd.2016.0844","article-title":"Neuronal ceroid lipofuscinoses","volume":"18","author":"Nita","year":"2016","journal-title":"Epileptic Disord."},{"key":"B26","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1186\/s12967-023-04208-1","article-title":"Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC","volume":"21","author":"O\u2019Leary","year":"2023","journal-title":"J. Transl. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.nbd.2005.01.025","article-title":"Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6)","volume":"20","author":"Oswald","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s00203-020-02007-6","article-title":"Comparative analysis of the gut microbiota composition in the Cln1 R151X and Cln2 R207X mouse models of Batten disease and in three wild-type mouse strains","volume":"203","author":"Parker","year":"2021","journal-title":"Arch. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e01096","DOI":"10.1002\/brb3.1096","article-title":"Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses","volume":"8","author":"Russell","year":"2018","journal-title":"Brain Behav."},{"key":"B30","doi-asserted-by":"publisher","first-page":"107188","DOI":"10.1016\/j.dib.2021.107188","article-title":"Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses","volume":"37","author":"Russell","year":"2021","journal-title":"Data Br."},{"key":"B31","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1002\/cpt.2531","article-title":"Translational approaches for brain delivery of biologics via cerebrospinal fluid","volume":"111","author":"Sadekar","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.ymthe.2006.01.006","article-title":"Gene therapy for lysosomal storage diseases","volume":"13","author":"Sands","year":"2006","journal-title":"Mol. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of intraventricular cerliponase alfa for CLN2 disease","volume":"378","author":"Schulz","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1111\/dmcn.13473","article-title":"Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5","volume":"59","author":"Simonati","year":"2017","journal-title":"Dev. Med. Child. Neurol."},{"key":"B35","article-title":"Enteric nervous system defects underlie bowel dysfunction in Cln1, Cln2 and Cln3 disease mice: A new therapeutic target?","author":"Wang","year":"2021"},{"key":"B36","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/mt.2010.279","article-title":"MicroRNA-regulated, systemically delivered rAAV9: A step closer to CNS-restricted transgene expression","volume":"19","author":"Xie","year":"2011","journal-title":"Mol. Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1212\/WNL.0b013e3181cff70d","article-title":"CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL","volume":"74","author":"Xin","year":"2010","journal-title":"Neurology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/mt.2008.76","article-title":"Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection","volume":"16","author":"Zincarelli","year":"2008","journal-title":"Mol. Ther."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1212228\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T16:56:27Z","timestamp":1702918587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1212228\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":38,"alternative-id":["10.3389\/fgene.2023.1212228"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1212228","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,8]]},"article-number":"1212228"}}