CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)

Abstract The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutation...

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Autores principales:	S. L. Eaton, C. Proudfoot, S. G. Lillico, P. Skehel, R. A. Kline, K. Hamer, N. M. Rzechorzek, E. Clutton, R. Gregson, T. King, C. A. O’Neill, J. D. Cooper, G. Thompson, C. B. Whitelaw, T. M. Wishart
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7155c59c589e4aa29b872c1109c35b0c
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spelling	oai:doaj.org-article:7155c59c589e4aa29b872c1109c35b0c2021-12-02T15:09:38ZCRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)10.1038/s41598-019-45859-92045-2322https://doaj.org/article/7155c59c589e4aa29b872c1109c35b0c2019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-45859-9https://doaj.org/toc/2045-2322Abstract The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child’s 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 PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (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 ± 1 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 in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.S. L. EatonC. ProudfootS. G. LillicoP. SkehelR. A. KlineK. HamerN. M. RzechorzekE. CluttonR. GregsonT. KingC. A. O’NeillJ. D. CooperG. ThompsonC. B. WhitelawT. M. WishartNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-8 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q S. L. Eaton C. Proudfoot S. G. Lillico P. Skehel R. A. Kline K. Hamer N. M. Rzechorzek E. Clutton R. Gregson T. King C. A. O’Neill J. D. Cooper G. Thompson C. B. Whitelaw T. M. Wishart CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
description	Abstract The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child’s 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 PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (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 ± 1 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 in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.
format	article
author	S. L. Eaton C. Proudfoot S. G. Lillico P. Skehel R. A. Kline K. Hamer N. M. Rzechorzek E. Clutton R. Gregson T. King C. A. O’Neill J. D. Cooper G. Thompson C. B. Whitelaw T. M. Wishart
author_facet	S. L. Eaton C. Proudfoot S. G. Lillico P. Skehel R. A. Kline K. Hamer N. M. Rzechorzek E. Clutton R. Gregson T. King C. A. O’Neill J. D. Cooper G. Thompson C. B. Whitelaw T. M. Wishart
author_sort	S. L. Eaton
title	CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
title_short	CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
title_full	CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
title_fullStr	CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
title_full_unstemmed	CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)
title_sort	crispr/cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (cln1 disease)
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/7155c59c589e4aa29b872c1109c35b0c
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CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)

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