Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

Kim, Yong Baek; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Jae-Yong; Ahn, Jungoh; Heo, Soon Young; Kang, Jee Hyun; Choi, Yong‐Keel; Choi, Seong–Jun; Shim, Hosup

doi:10.1016/j.bbrc.2014.08.125

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…These advantages are superior to non-human primates, which normally produce single fetus and have long sexual maturity time with a long pregnancy period. Transgenic pig models for a variety of neurodegenerative diseases have been established, including Alzheimer’s diseases ( Kragh et al, 2009 ; Søndergaard et al, 2012 ; Jakobsen et al, 2013 ), Huntington’s disease ( Yang et al, 2010 ; Baxa et al, 2013 ; Yan et al, 2018 ), Parkinson’s disease ( Yao et al, 2014 ; Zhou et al, 2015 ), amyotrophic lateral sclerosis ( Chieppa et al, 2014 ; Yang et al, 2014 ), spinal muscular atrophy ( Lorson et al, 2011 ), and ataxia–telangiectasia ( Kim et al, 2014 ). Our previous studies have shown that pigs expressing full-length mutant HTT at endogenous levels exhibit neuropathologic and behavioral characteristics similar to the HD patients ( Yan et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig

Lin

Wang

et al. 2023

Front. Cell Dev. Biol.

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Animal models are important for understanding the pathogenesis of human diseases and for developing and testing new drugs. Pigs have been widely used in the research on the cardiovascular, skin barrier, gastrointestinal, and central nervous systems as well as organ transplantation. Recently, pigs also become an attractive large animal model for the study of neurodegenerative diseases because their brains are very similar to human brains in terms of mass, gully pattern, vascularization, and the proportions of the gray and white matters. Although adeno-associated virus type 9 (AAV9) has been widely used to deliver transgenes in the brain, its utilization in large animal models remains to be fully characterized. Here, we report that intravenous injection of AAV9-GFP can lead to widespread expression of transgene in various organs in the pig. Importantly, GFP was highly expressed in various brain regions, especially the striatum, cortex, cerebellum, hippocampus, without detectable inflammatory responses. These results suggest that intravenous AAV9 administration can be used to establish large animal models of neurodegenerative diseases caused by gene mutations and to treat these animal models as well.

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Section: Introductionmentioning

confidence: 99%

Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig

Lin

Wang

et al. 2023

Front. Cell Dev. Biol.

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“…Another ATM-targeted pig has recently been reported using similar strategy , however that model is still in early stages, and only the generation of heterozygote females was described without any neurological or behavioral characterization (66). The initial characterizations have shown several neuropathologic and motor features of AT patients (15,16,52,53) suggesting the suitability of the new model to study AT.…”

Section: Discussionmentioning

confidence: 99%

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

et al. 2015

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Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. † These authors contributed equally.

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“…The detailed characterization of pATM gene structure, transcription regulatory elements, and tissue‐specific expression provided useful insights for the generation of a pig model of A–T . At least one heterozygous pATM knockout pig model has been generated to date and is in Minnesota miniature pigs generated by SCNT using pATM targeted fibroblasts as nuclei donors. Disruption of the porcine ATM gene was achieved by traditional targeting (vector‐mediated homologous recombination), with a targeting frequency of 1.3% .…”

Section: Current Genetically Modified Pig Models For Human Ndsmentioning

confidence: 99%

“…At least one heterozygous pATM knockout pig model has been generated to date and is in Minnesota miniature pigs generated by SCNT using pATM targeted fibroblasts as nuclei donors. Disruption of the porcine ATM gene was achieved by traditional targeting (vector‐mediated homologous recombination), with a targeting frequency of 1.3% . Although no A–T‐associated phenotype was reported in the founder heterozygous pATM knockout pig, we look forward to the recapitulation of A–T pathogenesis in the homozygous pATM knockout pigs in the near future.…”

Section: Current Genetically Modified Pig Models For Human Ndsmentioning

confidence: 99%

Genetically modified pig models for neurodegenerative disorders

Holm

Alstrup

Luo

2015

The Journal of Pathology

100

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Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions.

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Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

Cited by 7 publications

References 24 publications

Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig

Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

Genetically modified pig models for neurodegenerative disorders

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