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.
Highlights
Introduction HutchinsonGilford progeria syndrome (HGPS) is an extremely rare disorder characterized by premature aging and death during adolescence1,2
Hutchinson-Gilford progeria syndrome (HGPS) patients appear normal at birth and typically do not manifest signs of disease until around 1–2 years of age, when they begin to exhibit failure to thrive and develop symptoms reminiscent of physiological aging, including alopecia, lipodystrophy, pigmented spots and skin wrinkling with sclerodermia, and bone-skeletal dysplasia
Skin primary fibroblasts from a newborn male Yucatan minipig were co-transfected with sgRNA1, a Cas[9] plasmid construct, an enhanced green fluorescent protein (EGFP) reporter plasmid, and a donor DNA construct including the c.1824C > T mutation flanked by a left and a right homology arm
Summary
Introduction HutchinsonGilford progeria syndrome (HGPS) is an extremely rare disorder (prevalence of 1 in 20 million; https://www.progeriaresearch.org/) characterized by premature aging and death during adolescence. HGPS is caused by a de novo heterozygous mutation in the LMNA gene (encoding A-type lamins), with more than 90% of patients carrying a c.1824C > T (pG608G) point mutation[3,4]. This mutation activates usage of an alternative 5′ splice donor site in exon 11 that results in deletion of 150 nucleotides from LMNA mRNA and the synthesis of a truncated protein called progerin. There is no effective therapy or cure for HGPS, and patients die at an average age of 14.6 years predominantly due to CVD complications[10]
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