Exploring new therapeutic strategies in Hutchinson-Gilford progeria syndrome preclinical models

Hutchinson-Gilford早衰综合征（HGPS）是一种极其罕见的遗传性疾病（患病率：1 / 2000万），其特征是多器官缺陷，衰老加速，平均年龄14.6岁，主要死于心肌梗死或中风。它是由LMNA基因的杂合从头突变引起的，导致progerin的合成，progerin是一种永久法酰化的prelamin a突变蛋白。HGPS无法治愈，针对孕蛋白法尼化的临床试验显示，接受治疗的患者平均生存期仅增加了约1.6年。因此，迫切需要制定新的策略来治疗或治愈HGPS。treatment -HGPS是一个跨国项目，为期3年，涉及来自4个欧洲国家的科学家，他们将利用现有的HGPS细胞和小鼠模型：a)发现对抗HGPS的治疗药物的新组合，b)提供有关proger蛋白诱导损伤可逆性的重要新知识。特定目的：1)评估已知靶向早衰蛋白（雷帕霉素、全反式维甲酸、萝卜硫素、曲古霉素A）或早衰蛋白诱导效应（抗il6r抗体）的现有药物组合是否可以协同改善HGPS细胞和小鼠模型中的疾病症状。RNA干扰策略也将被测试。2)评估在不同时间点的系统性抑制progerin是否能逆转HGPS的进展，以确定未来针对progerin表达的方法的潜在益处。3)评估限制于血管平滑肌细胞（早衰蛋白的主要靶点）的早衰蛋白抑制是否能在类早衰小鼠中产生总体有益效果，作为更具挑战性的系统性早衰蛋白抑制的替代方法。

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease (prevalence: 1 in 20 million) characterized by multiorgan defects, accelerated aging, and death at an average age of 14.6 years mainly from myocardial infarction or stroke. It is caused by a heterozygous de novo point mutation in the LMNA gene leading to the synthesis of progerin, a permanently farnesylated prelamin A mutant protein. HGPS has no cure and clinical trials targeting progerin farnesylation showed increased mean survival of only ~1.6 years in treated patients. It is therefore urgent to develop new strategies to treat or cure HGPS.TREAT-HGPS is a transnational 3-year program involving scientists from 4 European nations who will exploit existing HGPS cell and mouse models to: a) discover novel combinations of therapeutic drugs to fight HGPS, and b) provide essential new knowledge about reversibility of progerin-induced damage.SPECIFIC OBJECTIVES:1) Evaluate whether combinations of available drugs known to target either progerin (rapamycin, all-trans-retinoic acid, sulforaphane, trichostatin A) or progerin-induced effects (anti-IL6r antibodies) can synergize to ameliorate disease symptoms in cell and mouse models of HGPS. RNA interference strategies will be also tested.2) Assess whether systemic progerin suppression at different time-points in the lifespan of progeroid mice reverses HGPS progression to ascertain the potential benefit of future approaches targeting progerin expression.3) Evaluate whether progerin suppression restricted to vascular smooth muscle cells, main target of progerin, provokes overall beneficial effects in progeroid mice as an alternative approach to more challenging systemic progerin suppression.