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.

Hutchinson-Gilford早衰综合症（HGPS）是一种极为罕见的遗传性疾病，尚无治愈方法。该疾病的特征是过早衰老和由于心血管并发症导致的青春期不可避免的死亡。大多数HGPS患者携带新杂合的LMNA c.1824C> T突变，该突变会激起称为progerin的显性负突变蛋白的表达。在类似HGPS的小鼠模型中证明有效的疗法在HGPS临床试验中仅产生了适度的益处。为了克服HGPS小鼠模型与患者之间的鸿沟，我们通过CRISPR-Cas9基因编辑了第一个大型动物模型HGPS（一种敲入杂合的LMNA）来生成c.1824C> T尤卡坦微型猪。像HGPS患者一样，HGPS小型猪内源性地共表达早老蛋白和正常的层粘液A / C，并表现出严重的生长迟缓，脂肪营养不良，皮肤和骨骼改变，心血管疾病，并在青春期前后死亡。值得注意的是，HGPS小型猪概括了患者所见的重要心血管改变，例如左心室舒张功能障碍，心脏电活动改变和血管平滑肌细胞丢失。我们的分析还显示由于微血管损伤和心肌间质纤维化而导致的心肌灌注减少，以前未描述的读数可能对监测患者的疾病进展有用。