Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

Rozh Husain Al-Mashhadi; Charlotte Brandt Sørensen; Peter M. Kragh; Christina Christoffersen; Martin Bødtker Mortensen; Lars Poulsen Tolbod; Troels Thim; Yutao Du; Juan Li; Ying Liu; Brian Moldt; Mette Schmidt; Gabor Vajta; Torben Larsen; Stig Purup; Lars Bolund; Lars Bo Nielsen; Henrik Callesen; Erling Falk; Jacob Giehm Mikkelsen; Jacob Fog Bentzon

doi:10.1126/scitranslmed.3004853

Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

Rozh Husain Al-Mashhadi, Charlotte Brandt Sørensen, Peter M. Kragh, Christina Christoffersen, Martin Bødtker Mortensen, Lars Poulsen Tolbod, Troels Thim, Yutao Du, Juan Li, Ying Liu, Brian Moldt, Mette Schmidt, Gabor Vajta, Torben Larsen, Stig Purup, Lars Bolund, Lars Bo Nielsen, Henrik Callesen, Erling Falk, Jacob Giehm MikkelsenJacob Fog Bentzon

129 Citations (Scopus)

Abstract

Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

Original language	English
Article number	166ra1
Journal	Science Translational Medicine
Volume	5
Issue number	166
Number of pages	11
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3004853
Publication status	Published - 2 Jan 2013

Keywords

Animals
Animals, Genetically Modified
Atherosclerosis
Cloning, Organism
DNA
Disease Models, Animal
Female
Humans
Hypercholesterolemia
Hyperlipoproteinemia Type II
Liver
Male
Mutation
Phenotype
Proprotein Convertases
RNA, Messenger
Receptors, LDL
Serine Endopeptidases
Swine
Swine, Miniature
Transgenes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/scitranslmed.3004853

Cite this

Al-Mashhadi, R. H., Sørensen, C. B., Kragh, P. M., Christoffersen, C., Mortensen, M. B., Tolbod, L. P., Thim, T., Du, Y., Li, J., Liu, Y., Moldt, B., Schmidt, M., Vajta, G., Larsen, T., Purup, S., Bolund, L., Nielsen, L. B., Callesen, H., Falk, E., ... Bentzon, J. F. (2013). Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Science Translational Medicine, 5(166), Article 166ra1. https://doi.org/10.1126/scitranslmed.3004853

Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. / Al-Mashhadi, Rozh Husain; Sørensen, Charlotte Brandt; Kragh, Peter M. et al.
In: Science Translational Medicine, Vol. 5, No. 166, 166ra1, 02.01.2013.

Research output: Contribution to journal › Journal article › Research › peer-review

Al-Mashhadi, RH, Sørensen, CB, Kragh, PM, Christoffersen, C, Mortensen, MB, Tolbod, LP, Thim, T, Du, Y, Li, J, Liu, Y, Moldt, B, Schmidt, M, Vajta, G, Larsen, T, Purup, S, Bolund, L, Nielsen, LB, Callesen, H, Falk, E, Mikkelsen, JG & Bentzon, JF 2013, 'Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant', Science Translational Medicine, vol. 5, no. 166, 166ra1. https://doi.org/10.1126/scitranslmed.3004853

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abstract = "Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.",

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AU - Kragh, Peter M.

AU - Christoffersen, Christina

AU - Mortensen, Martin Bødtker

AU - Tolbod, Lars Poulsen

AU - Thim, Troels

AU - Du, Yutao

AU - Li, Juan

AU - Liu, Ying

AU - Moldt, Brian

AU - Schmidt, Mette

AU - Vajta, Gabor

AU - Larsen, Torben

AU - Purup, Stig

AU - Bolund, Lars

AU - Nielsen, Lars Bo

AU - Callesen, Henrik

AU - Falk, Erling

AU - Mikkelsen, Jacob Giehm

AU - Bentzon, Jacob Fog

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N2 - Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

AB - Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

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KW - Hypercholesterolemia

KW - Hyperlipoproteinemia Type II

KW - Liver

KW - Male

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KW - Phenotype

KW - Proprotein Convertases

KW - RNA, Messenger

KW - Receptors, LDL

KW - Serine Endopeptidases

KW - Swine

KW - Swine, Miniature

KW - Transgenes

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DO - 10.1126/scitranslmed.3004853

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