{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T22:08:06Z","timestamp":1783721286301,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022951","name":"Batten Disease Support and Research Association Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022951","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001530","name":"Canterbury Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"publisher","award":["1814"],"award-info":[{"award-number":["1814"]}],"id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of rare inherited neurodegenerative disorders caused by mutations in one of 13 ceroid lipofuscinosis neuronal (\n                      <jats:italic>CLN<\/jats:italic>\n                      ) genes. The diseases share a common set of symptoms, including motor and cognitive dysfunction, progressive loss of vision, and seizure activity. A naturally occurring model of CLN5 NCL exists in New Zealand Borderdale sheep, which exhibit similar clinical disease and post\u2010mortem pathology to the human disease. Recent trials of concurrent intracerebroventricular and intravitreal gene therapy in sheep with CLN5 disease confirmed the therapeutic efficacy of this approach. Given the documented natural history of brain volume changes, detected by MRI, in sheep with CLN5 disease, the current study sought to utilize MRI as both a longitudinal readout and cross\u2010sectional measure of therapeutic efficacy in treated sheep.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>Sheep treated at a pre\u2010symptomatic timepoint underwent five T1\u2010weighted structural MRI scans between 5 and 18 months of age. Sheep treated at early and advanced symptomatic disease stages underwent a single MRI at 18 months of age. All scans from treated sheep were compared to historical healthy control and affected untreated sheep at each age.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Finding<\/jats:title>\n                    <jats:p>Pre\u2010symptomatic treated sheep showed growth in intracranial volume at a comparable rate to healthy control sheep over the course of the study. Whilst grey matter volume decreased and cerebrospinal fluid volume increased in treated sheep, this was to a much smaller degree than in untreated affected sheep. The majority of the cortical regions assessed showed stable volumes over the course of the study, with the notable exception of the cerebellum.<\/jats:p>\n                    <jats:p>Both early and advanced symptomatic treated sheep showed intracranial volumes comparable to untreated affected sheep at 18 months of age. However, when individual tissue types were assessed, grey and white matter were significantly larger, and cerebrospinal fluid was significantly smaller in early symptomatic sheep compared to untreated affected sheep, while the same volumes in advanced symptomatic treated sheep were comparable to untreated affected sheep. Cortical regions assessed showed an age\u2010at\u2010treatment and dose effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study has demonstrated that MRI, a clinically relevant outcome measure, can be successfully utilized to assess therapeutic efficacy in a large animal model of CLN5 NCL, both in a longitudinal study and a cross\u2010sectional study when robust natural history data is available for comparison.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.70431","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T05:56:41Z","timestamp":1743832601000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Magnetic Resonance Imaging as a Readout of CLN5 Gene Therapy Efficacy in Sheep"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-2205","authenticated-orcid":false,"given":"Samantha J.","family":"Murray","sequence":"first","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Canterbury New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa M.","family":"Almuqbel","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group  Christchurch New Zealand"},{"name":"New Zealand Brain Research Institute  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A.","family":"Felton","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolas J.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley R.","family":"Deane","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Canterbury New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Myall","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Shoorangiz","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ars\u00e8ne","family":"Ella","sequence":"additional","affiliation":[{"name":"UMR Physiologie de la Reproduction &amp; des Comportements INRAE\/CNRS\/University of Tours  Nouzilly France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Keller","sequence":"additional","affiliation":[{"name":"UMR Physiologie de la Reproduction &amp; des Comportements INRAE\/CNRS\/University of Tours  Nouzilly France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9703-5351","authenticated-orcid":false,"given":"David N.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Canterbury New Zealand"},{"name":"Department of Radiology University of Otago  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy R.","family":"Melzer","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group  Christchurch New Zealand"},{"name":"New Zealand Brain Research Institute  Christchurch New Zealand"},{"name":"Department of Medicine University of Otago  Christchurch New Zealand"},{"name":"School of Psychology, Speech and Hearing University of Canterbury  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia L.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Canterbury New Zealand"},{"name":"Department of Radiology University of Otago  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v067.i01"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A6726"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A4669"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201045859\u20109"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24079"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mri.2015.09.001"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mri.2012.05.001"},{"key":"e_1_2_10_9_1","volume-title":"An R Companion to Applied Regression","author":"Fox J.","year":"2011"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.09.006"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2019.11.023"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.163"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.1.1"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2013.08.008"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/00480169.2002.36311"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165772"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A4816"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.536221"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22878"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1212228"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22918"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.015"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.05.011"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000334838"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac339"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1212235"},{"key":"e_1_2_10_27_1","unstructured":"R Core Team.2021. \u201cR: A Language and Environment for Statistical Computing.\u201dhttps:\/\/www.R\u2010project.org."},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1096"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132331"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712649"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(23)00384\u20108"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.14405\/kjvr.20220027"},{"key":"e_1_2_10_33_1","first-page":"163","article-title":"Features of Brain MRI in Dogs With Treated and Untreated Mucopolysaccharidosis Type I","volume":"63","author":"Vite C. 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