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Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mut...

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Autores principales: Dorado, Beatriz, Pløen, Gro Grunnet, Barettino, Ana, Macías, Alvaro, Gonzalo, Pilar, Andrés-Manzano, María Jesús, González-Gómez, Cristina, Galán-Arriola, Carlos, Alfonso, José Manuel, Lobo, Manuel, López-Martín, Gonzalo J., Molina, Antonio, Sánchez-Sánchez, Raúl, Gadea, Joaquín, Sánchez-González, Javier, Liu, Ying, Callesen, Henrik, Filgueiras-Rama, David, Ibáñez, Borja, Sørensen, Charlotte Brandt, Andrés, Vicente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423020/
https://www.ncbi.nlm.nih.gov/pubmed/30911407
http://dx.doi.org/10.1038/s41421-019-0084-z
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author Dorado, Beatriz
Pløen, Gro Grunnet
Barettino, Ana
Macías, Alvaro
Gonzalo, Pilar
Andrés-Manzano, María Jesús
González-Gómez, Cristina
Galán-Arriola, Carlos
Alfonso, José Manuel
Lobo, Manuel
López-Martín, Gonzalo J.
Molina, Antonio
Sánchez-Sánchez, Raúl
Gadea, Joaquín
Sánchez-González, Javier
Liu, Ying
Callesen, Henrik
Filgueiras-Rama, David
Ibáñez, Borja
Sørensen, Charlotte Brandt
Andrés, Vicente
author_facet Dorado, Beatriz
Pløen, Gro Grunnet
Barettino, Ana
Macías, Alvaro
Gonzalo, Pilar
Andrés-Manzano, María Jesús
González-Gómez, Cristina
Galán-Arriola, Carlos
Alfonso, José Manuel
Lobo, Manuel
López-Martín, Gonzalo J.
Molina, Antonio
Sánchez-Sánchez, Raúl
Gadea, Joaquín
Sánchez-González, Javier
Liu, Ying
Callesen, Henrik
Filgueiras-Rama, David
Ibáñez, Borja
Sørensen, Charlotte Brandt
Andrés, Vicente
author_sort Dorado, Beatriz
collection PubMed
description Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.
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spelling pubmed-64230202019-03-25 Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome Dorado, Beatriz Pløen, Gro Grunnet Barettino, Ana Macías, Alvaro Gonzalo, Pilar Andrés-Manzano, María Jesús González-Gómez, Cristina Galán-Arriola, Carlos Alfonso, José Manuel Lobo, Manuel López-Martín, Gonzalo J. Molina, Antonio Sánchez-Sánchez, Raúl Gadea, Joaquín Sánchez-González, Javier Liu, Ying Callesen, Henrik Filgueiras-Rama, David Ibáñez, Borja Sørensen, Charlotte Brandt Andrés, Vicente Cell Discov Article Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients. Nature Publishing Group UK 2019-03-19 /pmc/articles/PMC6423020/ /pubmed/30911407 http://dx.doi.org/10.1038/s41421-019-0084-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dorado, Beatriz
Pløen, Gro Grunnet
Barettino, Ana
Macías, Alvaro
Gonzalo, Pilar
Andrés-Manzano, María Jesús
González-Gómez, Cristina
Galán-Arriola, Carlos
Alfonso, José Manuel
Lobo, Manuel
López-Martín, Gonzalo J.
Molina, Antonio
Sánchez-Sánchez, Raúl
Gadea, Joaquín
Sánchez-González, Javier
Liu, Ying
Callesen, Henrik
Filgueiras-Rama, David
Ibáñez, Borja
Sørensen, Charlotte Brandt
Andrés, Vicente
Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title_full Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title_fullStr Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title_full_unstemmed Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title_short Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
title_sort generation and characterization of a novel knockin minipig model of hutchinson-gilford progeria syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423020/
https://www.ncbi.nlm.nih.gov/pubmed/30911407
http://dx.doi.org/10.1038/s41421-019-0084-z
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