Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, Lmna^G609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease.

Hutchinson–Gilford早衰综合症（HGPS）是一种罕见的遗传病，可导致儿童系统性加速衰老。该综合征是由于LMNA基因中的突变导致突变的lamin A的截短且有毒的形式而产生的，称为progerin。由于A型lamin之间的平衡是由RNA结合蛋白SRSF1控制的，因此我们假设其抑制作用可能对HGPS具有治疗作用。为此，我们评估了抗糖尿病药物二甲双胍，并证明了用5 mmol / l二甲双胍治疗48小时可降低源自HGPS诱导的多能干细胞（HGPS MSC）的间充质干细胞中的SRSF1和progerin表达。然后在几个体外实验中证实了二甲双胍对早老素的作用HGPS的模型，即人原代HGPS成纤维细胞，Lmna ^{G609G / G609G}小鼠成纤维细胞和健康的MSC，之前用诱导早^老蛋白的PMO（磷酸二氨基吗啉代寡核苷酸）处理过。这伴随着与该疾病有关的两种体外表型的改善：核形状异常和HGPS MSCs的过早成骨细胞分化。总体而言，这些结果表明了一种针对HGPS疗法的新颖方法，可以将其添加到针对与疾病相关的其他分子缺陷的当前分析的治疗方法中。