Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Dorado B

PROVIDER: S-EPMC6423020 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Dorado Beatriz B Pløen Gro Grunnet GG Barettino Ana A Macías Alvaro A Gonzalo Pilar P Andrés-Manzano María Jesús MJ González-Gómez Cristina C Galán-Arriola Carlos C Alfonso José Manuel JM Lobo Manuel M López-Martín Gonzalo J GJ Molina Antonio A Sánchez-Sánchez Raúl R Gadea Joaquín J Sánchez-González Javier J Liu Ying Y Callesen Henrik H Filgueiras-Rama David D Ibáñez Borja B Sørensen Charlotte Brandt CB Andrés Vicente V

Cell discovery 20190319

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 <i>LMNA</i> 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 t ...[more]

PMID: 30911407

Similar Datasets

Project description:PurposeChildren with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development.MethodsChildren from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction.ResultsExtraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03).ConclusionsExtraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Project description:Importance:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare disorder associated with premature death due to cardiovascular events during the second decade of life. However, because of its rarity (107 identified living patients), the natural history of cardiac disease remains uncharacterized. Therefore, meaningful cardiac end points for clinical trials have been difficult to establish. Objective:To examine the course of appearance of cardiac abnormalities in patients with HGPS to identify meaningful cardiac end points for use in future clinical trials. Design, Setting, and Participants:In this prospective, cross-sectional, observational study, 27 consecutive patients with clinically and genetically confirmed classic HGPS were evaluated at a single center for 1 visit from July 1, 2014, through February 29, 2016, before initiation of treatment. Exposure:Classic HGPS. Main Outcomes and Measures:Echocardiography was used to assess ventricular and valve function using standard techniques. Diastolic left ventricular (LV) function was assessed using tissue Doppler imaging. Previously published normative data were used to adjust findings to age and body size. Results:This study included 27 patients (median age, 5.6 years; age range, 2-17 years; 15 [56%] male). Among echocardiographic indicators, LV diastolic dysfunction, defined as a tissue Doppler septal or lateral early velocity z score less than -2, was the most prevalent abnormality, seen in 16 patients (59%). Diastolic dysfunction was seen in all age groups, and its prevalence increased with age, mirroring findings seen during normal aging. Indicators of LV diastolic function were more abnormal in older patients. The z scores for lateral and septal early velocities were lower (r = -0.77, P < .001; and r = -0.66, P < .001, respectively), whereas those for the ratio of early mitral inflow velocity to early diastolic tissue Doppler myocardial velocity were higher (r = 0.80, P < .001; and r = 0.72, P < .001, respectively) in older patients. Other echocardiographic findings, including LV hypertrophy, LV systolic dysfunction, and valve disease, were less prevalent in the first decade and were seen more frequently in the second decade. Conclusions and Relevance:In this largest-to-date cohort of patients with HGPS, LV diastolic dysfunction was the most prevalent echocardiographic abnormality and its prevalence increased with aging. Echocardiographic indicators of LV diastolic function may be useful end points in future clinical trials in this patient population.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets