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One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (<jats:italic>PPT1<\/jats:italic>) gene and severely reduces the child\u2019s lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR\/Cas9 gene editing technology. Three <jats:italic>PPT1<\/jats:italic> homozygote sheep were generated by insertion of a disease-causing <jats:italic>PPT1<\/jats:italic> (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17\u2009\u00b1\u20091 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR\/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and <jats:italic>in vivo<\/jats:italic> brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.<\/jats:p>","DOI":"10.1038\/s41598-019-45859-9","type":"journal-article","created":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T13:01:56Z","timestamp":1562677316000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["CRISPR\/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)"],"prefix":"10.1038","volume":"9","author":[{"given":"S. L.","family":"Eaton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Proudfoot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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D. & Sands, M. S. Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease). Biochimica et biophysica acta 1832, 1906\u20131909, https:\/\/doi.org\/10.1016\/j.bbadis.2013.05.026 (2013).","journal-title":"Biochimica et biophysica acta"},{"key":"45859_CR3","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1016\/j.bbadis.2015.05.011","volume":"1852","author":"SE Mole","year":"2015","unstructured":"Mole, S. E. & Cotman, S. L. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochimica et biophysica acta 1852, 2237\u20132241, https:\/\/doi.org\/10.1016\/j.bbadis.2015.05.011 (2015).","journal-title":"Biochimica et biophysica acta"},{"key":"45859_CR4","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1006\/mgme.1999.2809","volume":"66","author":"OP van Diggelen","year":"1999","unstructured":"van Diggelen, O. P. et al. A rapid fluorogenic palmitoyl-protein thioesterase assay: pre- and postnatal diagnosis of INCL. 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