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

Hutchinson-Gilford早衰综合征（HGPS）是一种极为罕见的遗传性疾病（患病率：2000万分之一），其特征是多器官缺陷、加速衰老和平均年龄14.6岁的死亡，主要死于心肌梗死或中风。它是由LMNA基因中的杂合从头点突变引起的，导致早老蛋白（一种永久性法尼基化的核纤层蛋白A前体突变蛋白）的合成。HGPS无法治愈，针对早老蛋白法尼基化的临床试验显示，治疗患者的平均生存期仅增加约1.6年。因此，迫切需要开发新的策略来治疗或治愈HGPS。HGPS是一项为期3年的跨国计划，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）发现新的治疗药物组合来对抗HGPS，以及B）提供关于早老素诱导的损伤可逆性的基本新知识。1）评估已知靶向早老蛋白或早老蛋白的可用药物的组合是否（雷帕霉素，全反式视黄酸，萝卜硫素，抑制素A）或早老蛋白诱导的作用（抗IL 6 r抗体）可以协同作用以改善HGPS的细胞和小鼠模型中的疾病症状。还将测试RNA干扰策略。2）评估在早老性小鼠寿命中的不同时间点的系统性早老蛋白抑制是否逆转HGPS进展，以确定靶向早老蛋白表达的未来方法的潜在益处。3）评估早老蛋白抑制是否限于血管平滑肌细胞，早老蛋白的主要靶点，在早老性小鼠中引起总体有益效果，作为更具挑战性的全身性早老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.