{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:36:25Z","timestamp":1792654585332,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"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\/501100001515","name":"Cure Kids","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001515","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005468","name":"Batten Disease Support and Research Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005468","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, astrogliosis, and lysosomal storage accumulation in CLN5 affected (CLN5\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) and CLN6 affected (CLN6\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) sheep eyes and age-matched controls at 3, 6, 12, and 18\u00a0months of age to determine the onset and progression of retinal pathology in NCL sheep. The retina of CLN5\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    sheep shows progressive atrophy of the outer retinal layers, widespread gliosis, and accumulation of lysosomal storage in retinal ganglion cells late in disease. In contrast, CLN6\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    retina shows significant atrophy of all retinal layers, progressive gliosis, and earlier accumulation of lysosomal storage. This study has highlighted the differential vulnerability of retinal layers and the time course of retinal atrophy in two distinct models of NCL disease. This data will be valuable in determining potential targets for ocular therapies and the optimal timing of these therapies for protection from retinal dysfunction and degeneration in NCL.\n                  <\/jats:p>","DOI":"10.1038\/s41598-022-07612-7","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T06:06:11Z","timestamp":1646633171000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Natural history of retinal degeneration in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses"],"prefix":"10.1038","volume":"12","author":[{"given":"S. J.","family":"Murray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. L.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,7]]},"reference":[{"key":"7612_CR1","first-page":"2262","volume":"1852","author":"J Radke","year":"2015","unstructured":"Radke, J., Stenzel, W. & Goebel, H. H. Human NCL neuropathology. Biochem. Biophys. Acta. 1852, 2262\u20132266 (2015).","journal-title":"Biochem. Biophys. Acta."},{"key":"7612_CR2","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.applanim.2015.11.012","volume":"175","author":"GM Cronin","year":"2016","unstructured":"Cronin, G. M. et al. Manifestation of neuronal ceroid lipofuscinosis in Australian Merino sheep: Observations on altered behaviour and growth. Appl. Anim. Behav. Sci. 175, 32\u201340 (2016).","journal-title":"Appl. Anim. Behav. Sci."},{"key":"7612_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2021.108686","author":"GR Kick","year":"2021","unstructured":"Kick, G. R. et al. Visual system pathology in a canine model of CLN5 neuronal ceroid lipofuscinosis. Exp. Eye Res. https:\/\/doi.org\/10.1016\/j.exer.2021.108686 (2021).","journal-title":"Exp. Eye Res."},{"key":"7612_CR4","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1016\/j.ymthe.2018.02.027","volume":"26","author":"S-M Kleine Holthaus","year":"2018","unstructured":"Kleine Holthaus, S.-M. et al. Prevention of photoreceptor cell loss in a Cln6 mouse model of batten disease requires CLN6 gene transfer to bipolar cells. Mol. Ther. 26, 1343\u20131353 (2018).","journal-title":"Mol. Ther."},{"key":"7612_CR5","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1167\/iovs.14-16045","volume":"56","author":"HO Leinonen","year":"2015","unstructured":"Leinonen, H. O. et al. Retinal dysfunction precedes motor symptoms by several months in a CLN5 mouse model of neuronal ceroid lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 56, 4257\u20134257 (2015).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"7612_CR6","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1006\/mcne.2001.1099","volume":"19","author":"GM Seigel","year":"2002","unstructured":"Seigel, G. M. et al. Retinal pathology and function in a Cln3 knockout mouse model of juvenile neuronal ceroid lipofuscinosis (Batten disease). Mol. Cell. Neurosci. 19, 515\u2013527 (2002).","journal-title":"Mol. Cell. Neurosci."},{"key":"7612_CR7","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.exer.2015.02.012","volume":"134","author":"REH Whiting","year":"2015","unstructured":"Whiting, R. E. H. et al. Multifocal retinopathy in Dachshunds with CLN2 neuronal ceroid lipofuscinosis. Exp. Eye Res. 134, 123\u2013132 (2015).","journal-title":"Exp. Eye Res."},{"key":"7612_CR8","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.nbd.2007.09.006","volume":"29","author":"T Frugier","year":"2008","unstructured":"Frugier, T. et al. 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. Neurobiol. Dis. 29, 306\u2013315 (2008).","journal-title":"Neurobiol. Dis."},{"key":"7612_CR9","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/j.bbadis.2006.09.004","volume":"1762","author":"I Tammen","year":"2006","unstructured":"Tammen, I. et al. A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA. Biochim. Biophys. Acta Mol. Basis Dis. 1762, 898\u2013905 (2006).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"7612_CR10","first-page":"294","volume":"25","author":"RJ Graydon","year":"1984","unstructured":"Graydon, R. J. & Jolly, R. D. Ceroid-lipofuscinosis (Batten\u2019s disease). Sequential electrophysiologic and pathologic changes in the retina of the ovine model. Invest. Ophthalmol. Vis. Sci. 25, 294\u2013301 (1984).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"7612_CR11","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1111\/j.1365-2990.1985.tb00025.x","volume":"11","author":"IG Mayhew","year":"1985","unstructured":"Mayhew, I. G., Jolly, R. D., Pickett, B. T. & Slack, P. M. Ceroid-lipofuscinosis (Batten\u2019s disease): Pathogenesis of blindness in the ovine model. Neuropathol. Appl. Neurobiol. 11, 273\u2013290 (1985).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"7612_CR12","doi-asserted-by":"publisher","first-page":"107188","DOI":"10.1016\/j.dib.2021.107188","volume":"37","author":"KN Russell","year":"2021","unstructured":"Russell, K. N., Mitchell, N. L., Wellby, M. P., Barrell, G. K. & Palmer, D. N. Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses. Data Brief 37, 107188 (2021).","journal-title":"Data Brief"},{"key":"7612_CR13","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1093\/hmg\/ddr022","volume":"20","author":"AV Cideciyan","year":"2011","unstructured":"Cideciyan, A. V. et al. Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: Generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum. Mol. Genet. 20, 1411\u20131423 (2011).","journal-title":"Hum. Mol. Genet."},{"key":"7612_CR14","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s40478-019-0768-5","volume":"7","author":"P Manogaran","year":"2019","unstructured":"Manogaran, P. et al. Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis. Acta Neuropathol. Commun. 7, 116 (2019).","journal-title":"Acta Neuropathol. Commun."},{"key":"7612_CR15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.2147\/OPTH.S13850","volume":"5","author":"L Reznicek","year":"2010","unstructured":"Reznicek, L. et al. In vivo characterization of ischemic retina in diabetic retinopathy. Clin. Ophthalmol. 5, 31\u201335 (2010).","journal-title":"Clin. Ophthalmol."},{"key":"7612_CR16","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1167\/iovs.12-11286","volume":"54","author":"S Sadigh","year":"2013","unstructured":"Sadigh, S. et al. Abnormal thickening as well as thinning of the photoreceptor layer in intermediate age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 1603\u20131612 (2013).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"7612_CR17","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/BF00237966","volume":"206","author":"H B\u00fcssow","year":"1980","unstructured":"B\u00fcssow, H. The astrocytes in the retina and optic nerve head of mammals: A special glia for the ganglion cell axons. Cell Tissue Res. 206, 367\u2013378 (1980).","journal-title":"Cell Tissue Res."},{"key":"7612_CR18","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1016\/0042-6989(94)90024-8","volume":"34","author":"JM Ramirez","year":"1994","unstructured":"Ramirez, J. M., Trivino, A., Ramirez, A. I., Salazar, J. J. & Garcia-Sanchez, J. Immunohistochemical study of human retinal astroglia. Vis. Res. 34, 1935\u20131946 (1994).","journal-title":"Vis. Res."},{"key":"7612_CR19","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.preteyeres.2006.05.003","volume":"25","author":"A Bringmann","year":"2006","unstructured":"Bringmann, A. et al. M\u00fcller cells in the healthy and diseased retina. Prog. Retin. Eye Res. 25, 397\u2013424 (2006).","journal-title":"Prog. Retin. Eye Res."},{"key":"7612_CR20","doi-asserted-by":"publisher","first-page":"14185","DOI":"10.1038\/s41598-019-50726-8","volume":"9","author":"Y Atiskova","year":"2019","unstructured":"Atiskova, Y. et al. Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype. Sci. Rep. 9, 14185 (2019).","journal-title":"Sci. Rep."},{"key":"7612_CR21","doi-asserted-by":"publisher","first-page":"696","DOI":"10.3390\/cells10030696","volume":"10","author":"M Bassal","year":"2021","unstructured":"Bassal, M., Liu, J., Jankowiak, W., Saftig, P. & Bartsch, U. Rapid and progressive loss of multiple retinal cell types in cathepsin D-deficient mice\u2014an animal model of CLN10 disease. Cells 10, 696 (2021).","journal-title":"Cells"},{"key":"7612_CR22","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1038\/s41598-017-01716-1","volume":"7","author":"H Leinonen","year":"2017","unstructured":"Leinonen, H. et al. Retinal degeneration in a mouse model of CLN5 disease is associated with compromised autophagy. Sci. Rep. 7, 1597 (2017).","journal-title":"Sci. Rep."},{"key":"7612_CR23","doi-asserted-by":"publisher","first-page":"e75963","DOI":"10.1371\/journal.pone.0075963","volume":"8","author":"M Mirza","year":"2013","unstructured":"Mirza, M. et al. Progressive retinal degeneration and glial activation in the CLN6nclf mouse model of neuronal ceroid lipofuscinosis: A beneficial effect of DHA and Curcumin supplementation. PLOS ONE 8, e75963 (2013).","journal-title":"PLOS ONE"},{"key":"7612_CR24","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1016\/j.ymthe.2018.07.015","volume":"26","author":"NL Mitchell","year":"2018","unstructured":"Mitchell, N. L. et al. Longitudinal in vivo monitoring of the CNS demonstrates the efficacy of gene therapy in a sheep model of CLN5 Batten disease. Mol. Ther. 26, 2366\u20132378 (2018).","journal-title":"Mol. Ther."},{"key":"7612_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jnen\/62.1.1","volume":"62","author":"M Haltia","year":"2003","unstructured":"Haltia, M. The neuronal ceroid-lipofuscinoses. J. Neuropathol. Exp. Neurol. 62, 1\u201313 (2003).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"7612_CR26","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1002\/humu.10227","volume":"22","author":"JD Sharp","year":"2003","unstructured":"Sharp, J. D. et al. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 22, 35\u201342 (2003).","journal-title":"Hum. Mutat."},{"key":"7612_CR27","volume-title":"The Neuronal Ceroid Lipofuscinoses (Batten Disease)","author":"S Mole","year":"2011","unstructured":"Mole, S., Williams, R. & Goebel, H. The Neuronal Ceroid Lipofuscinoses (Batten Disease) (Oxford University Press, Oxford, 2011)."},{"key":"7612_CR28","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/mt.2015.114","volume":"23","author":"E Banin","year":"2015","unstructured":"Banin, E. et al. Gene augmentation therapy restores retinal function and visual behavior in a sheep model of CNGA3 achromatopsia. Mol. Ther. 23, 1423\u20131433 (2015).","journal-title":"Mol. Ther."},{"key":"7612_CR29","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1002\/path.4641","volume":"238","author":"C Kostic","year":"2016","unstructured":"Kostic, C. & Arsenijevic, Y. Animal modelling for inherited central vision loss. J. Pathol. 238, 300\u2013310 (2016).","journal-title":"J. Pathol."},{"key":"7612_CR30","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1089\/hum.2020.023","volume":"31","author":"M Ross","year":"2020","unstructured":"Ross, M. et al. Evaluation of photoreceptor transduction efficacy of capsid-modified adeno-associated viral vectors following intravitreal and subretinal delivery in sheep. Hum. Gene Ther. 31, 719\u2013729 (2020).","journal-title":"Hum. Gene Ther."},{"key":"7612_CR31","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.tvjl.2009.05.029","volume":"185","author":"MH Shamir","year":"2010","unstructured":"Shamir, M. H. et al. A novel day blindness in sheep: Epidemiological, behavioural, electrophysiological and histopathological studies. Vet. J. 185, 130\u2013137 (2010).","journal-title":"Vet. J."},{"key":"7612_CR32","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.ymthe.2006.01.006","volume":"13","author":"MS Sands","year":"2006","unstructured":"Sands, M. S. & Davidson, B. L. Gene therapy for lysosomal storage diseases. Mol. Ther. 13, 839\u2013849 (2006).","journal-title":"Mol. Ther."},{"key":"7612_CR33","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/gt.2009.61","volume":"16","author":"TK Park","year":"2009","unstructured":"Park, T. K. et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther. 16, 916\u2013926 (2009).","journal-title":"Gene Ther."},{"key":"7612_CR34","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1136\/bjophthalmol-2014-306018","volume":"99","author":"JD Pitcher","year":"2015","unstructured":"Pitcher, J. D., Witkin, A. J., DeCroos, F. C. & Ho, A. C. A prospective pilot study of intravitreal aflibercept for the treatment of chronic central serous chorioretinopathy: The CONTAIN study. Br. J. Ophthalmol. 99, 848\u2013852 (2015).","journal-title":"Br. J. Ophthalmol."},{"key":"7612_CR35","doi-asserted-by":"crossref","unstructured":"Diabetic Retinopathy Clinical Research Network et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 372, 1193\u20131203 (2015).","DOI":"10.1056\/NEJMoa1414264"},{"key":"7612_CR36","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12886-019-1251-6","volume":"20","author":"G Staurenghi","year":"2020","unstructured":"Staurenghi, G. et al. Functional versus functional and anatomical criteria-guided ranibizumab treatment in patients with neovascular age-related macular degeneration\u2014results from the randomized, phase IIIb OCTAVE study. BMC Ophthalmol. 20, 18 (2020).","journal-title":"BMC Ophthalmol."},{"key":"7612_CR37","doi-asserted-by":"publisher","first-page":"108600","DOI":"10.1016\/j.exer.2021.108600","volume":"207","author":"SJ Murray","year":"2021","unstructured":"Murray, S. J. et al. Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease. Exp. Eye Res. 207, 108600 (2021).","journal-title":"Exp. Eye Res."},{"key":"7612_CR38","unstructured":"Neurogene Announces FDA Clearance of IND for NGN-101 Gene Therapy to Treat CLN5 Batten Disease. Neurogene https:\/\/www.neurogene.com\/press-releases\/neurogene-announces-fda-clearance-of-ind-for-ngn-101-gene-therapy-to-treat-cln5-batten-disease\/."},{"key":"7612_CR39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1006\/mcne.2002.1168","volume":"21","author":"AR Harvey","year":"2002","unstructured":"Harvey, A. R. et al. Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: A comparison with lentiviral vectors. Mol. Cell. Neurosci. 21, 141\u2013157 (2002).","journal-title":"Mol. Cell. Neurosci."},{"key":"7612_CR40","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/gt.2013.64","volume":"21","author":"FM Mowat","year":"2014","unstructured":"Mowat, F. M. et al. Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach. Gene Ther. 21, 96\u2013105 (2014).","journal-title":"Gene Ther."},{"key":"7612_CR41","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1016\/j.mri.2012.05.001","volume":"30","author":"A Fedorov","year":"2012","unstructured":"Fedorov, A. et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn. Resonon. Imaging 30, 1323\u20131341 (2012).","journal-title":"Magn. Resonon. Imaging"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-07612-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-07612-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-07612-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T18:47:17Z","timestamp":1669315637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-07612-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,7]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["7612"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-07612-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-1022407\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,7]]},"assertion":[{"value":"27 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3670"}}