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

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  • Beatriz Dorado, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • Gro Grunnet Pløen
  • Ana Barettino, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • Alvaro Macías, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
  • ,
  • Pilar Gonzalo, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • María Jesús Andrés-Manzano, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • Cristina González-Gómez, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • Carlos Galán-Arriola, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • José Manuel Alfonso, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
  • ,
  • Manuel Lobo, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)
  • ,
  • Gonzalo J. López-Martín, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
  • ,
  • Antonio Molina, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
  • ,
  • Raúl Sánchez-Sánchez, INIA (Spanish National Institute for Agricultural and Food Research and Technology)
  • ,
  • Joaquín Gadea, Universidad de Murcia
  • ,
  • Javier Sánchez-González, Philips HealthCare Iberia
  • ,
  • Ying Liu
  • ,
  • Henrik Callesen
  • David Filgueiras-Rama, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV), Hospital Clínico de San Carlos
  • ,
  • Borja Ibáñez, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV), Instituto de Investigación Sanitaria 12 de Octubre (i+12)
  • ,
  • Charlotte Brandt Sørensen
  • Vicente Andrés, Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBER en Enfermedades Cardiovasculares (CIBER-CV)

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.

Original languageEnglish
Article number16
JournalCell Discovery
Volume5
ISSN2056-5968
DOIs
Publication statusPublished - Mar 2019

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