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

Rozh H Al-Mashhadi; Charlotte B Sørensen; Peter M Kragh; Christina Christoffersen; Martin B Mortensen; Lars P Tolbod; Troels Thim; Yutao Du; Juan Li; Ying Liu; Brian Moldt; Mette Schmidt; Gabor Vajta; Torben Larsen; Stig Purup; Lars Bolund; Lars B Nielsen; Henrik Callesen; Erling Falk; Jacob Giehm Mikkelsen; Jacob F 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 H Al-Mashhadi, Charlotte B Sørensen, Peter M Kragh, Christina Christoffersen, Martin B Mortensen, Lars P Tolbod, Troels Thim, Yutao Du, Juan Li, Ying Liu, Brian Moldt, Mette Schmidt, Gabor Vajta, Torben Larsen, Stig Purup, Lars Bolund, Lars B Nielsen, Henrik Callesen, Erling Falk, Jacob Giehm MikkelsenJacob F Bentzon

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

174 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
Journal	Science Translational Medicine
Volume	5
Issue	166
Pages (from-to)	166ra1
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3004853
Publication status	Published - 2013

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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), 166ra1. https://doi.org/10.1126/scitranslmed.3004853

@article{2f185926017c443ba91076c0809855af,

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

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.",

author = "Al-Mashhadi, {Rozh H} and S{\o}rensen, {Charlotte B} and Kragh, {Peter M} and Christina Christoffersen and Mortensen, {Martin B} and Tolbod, {Lars P} and Troels Thim and Yutao Du and Juan Li and Ying Liu and Brian Moldt and Mette Schmidt and Gabor Vajta and Torben Larsen and Stig Purup and Lars Bolund and Nielsen, {Lars B} and Henrik Callesen and Erling Falk and Mikkelsen, {Jacob Giehm} and Bentzon, {Jacob F}",

year = "2013",

doi = "10.1126/scitranslmed.3004853",

language = "English",

volume = "5",

pages = "166ra1",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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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, pp. 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 H ; Sørensen, Charlotte B; Kragh, Peter M et al.
In: Science Translational Medicine, Vol. 5, No. 166, 2013, p. 166ra1.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

AU - Al-Mashhadi, Rozh H

AU - Sørensen, Charlotte B

AU - Kragh, Peter M

AU - Christoffersen, Christina

AU - Mortensen, Martin B

AU - Tolbod, Lars P

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 B

AU - Callesen, Henrik

AU - Falk, Erling

AU - Mikkelsen, Jacob Giehm

AU - Bentzon, Jacob F

PY - 2013

Y1 - 2013

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.

U2 - 10.1126/scitranslmed.3004853

DO - 10.1126/scitranslmed.3004853

M3 - Journal article

C2 - 23283366

SN - 1946-6234

VL - 5

SP - 166ra1

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 166

ER -

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

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