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dc.contributor.authorDorado, Beatriz 
dc.contributor.authorPløen, Gro Grunnet
dc.contributor.authorBarettino, Ana 
dc.contributor.authorMacías, Álvaro 
dc.contributor.authorGonzalo, Pilar 
dc.contributor.authorAndres-Manzano, Maria J. 
dc.contributor.authorGonzalez-Gomez, Cristina 
dc.contributor.authorGalan-Arriola, Carlos 
dc.contributor.authorAlfonso, Jose Manuel 
dc.contributor.authorLobo-Gonzalez, Manuel 
dc.contributor.authorLopez-Martin, Gonzalo J. 
dc.contributor.authorMolina-Iracheta, Antonio 
dc.contributor.authorSánchez-Sánchez, Raúl
dc.contributor.authorGadea, Joaquín
dc.contributor.authorSanchez-Gonzalez, Javier 
dc.contributor.authorLiu, Ying
dc.contributor.authorCallesen, Henrik
dc.contributor.authorFilgueiras-Rama, David 
dc.contributor.authorIbanez, Borja 
dc.contributor.authorSørensen, Charlotte Brandt
dc.contributor.authorAndres, Vicente
dc.identifier.citationCell Discov. 2019; 5:16es_ES
dc.description.abstractHutchinson-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.es_ES
dc.description.sponsorshipThis project was mainly supported by an Established Investigator Award from the Progeria Research Foundation (2014-52), and from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU), and the European Regional Development Fund (FEDER, “A way to build Europe”) (SAF2016-79490-R, CB16/11/00405). Ana Barettino has a predoctoral contract from MCIU (BES-2017-079705). Work at Universidad de Murcia is supported by Fundación Seneca-Agencia de Ciencia y Tecnología de la Región de Murcia (20040/GERM/16). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).es_ES
dc.publisherSpringer Naturees_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleGeneration and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndromees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderFundación ProCNICes_ES
dc.contributor.funderProgeria Research Foundationes_ES
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)es_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderUniversidad de Murciaes_ES
dc.contributor.funderRegion de Murciaes_ES
dc.identifier.journalCell discoveryes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Laboratorio Traslacional para la Imagen y Terapia Cardiovasculares_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Desarrollo Avanzado sobre Mecanismos y Terapias de las Arritmiases_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Medicina Comparativaes_ES

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