2026-06-14T03:30:12Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/75132024-09-27T07:57:55Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607
Repisalud
author
Dorado, Beatriz
author
Pløen, Gro Grunnet
author
Barettino, Ana
author
Macias, Alvaro
author
Gonzalo, Pilar
author
Andres-Manzano, Maria J.
author
Gonzalez-Gomez, Cristina
author
Galan-Arriola, Carlos
author
Alfonso-Almazan, Jose M.
author
Lobo-Gonzalez, Manuel
author
Lopez-Martin, Gonzalo J.
author
Molina-Iracheta, Antonio
author
Sánchez-Sánchez, Raúl
author
Gadea, Joaquín
author
Sanchez-Gonzalez, Javier
author
Liu, Ying
author
Callesen, Henrik
author
Filgueiras-Rama, David
author
Ibáñez, Borja
author
Sørensen, Charlotte Brandt
author
Andres, Vicente
funder
Fundación ProCNIC
funder
Progeria Research Foundation
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
University of Murcia (España)
funder
Gobierno de la Región de Murcia (España)
2019-04-25T13:32:45Z
2019-04-25T13:32:45Z
2019
Cell Discov. 2019; 5:16
10.1038/s41421-019-0084-z
2056-5968
Cell discovery
30911407
http://hdl.handle.net/20.500.12105/7513
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.
eng
Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
journal article
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