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

探索 Hutchinson-Gilford 早衰综合征临床前模型的新治疗策略

• 批准号: 398640205
• 负责人: Professorin Dr. Karima Djabali
• 金额: --
• 依托单位: Munich School of BioEngineering
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398640205?language=en
• 关键词: Exploring; new; therapeutic; strategies; Hutchinson

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.

Hutchinson-Gilford早衰症(HGPS)是一种极其罕见的遗传性疾病(患病率：2000万人中有1人)，其特征是多器官缺陷，加速衰老，平均年龄14.6岁，主要死于心肌梗死或中风。这是由于LMNA基因中的杂合点突变导致了孕激素的合成，孕蛋白是一种永久法尼化的前层蛋白A突变蛋白。HGPS没有治愈方法，针对孕激素法尼化的临床试验显示，接受治疗的患者的平均生存期仅增加了约1.6年。因此，迫切需要开发新的策略来治疗或治愈HGPS。TREAT-HGPS是一个跨国三年计划，涉及来自4个欧洲国家的科学家，他们将利用现有的HGPS细胞和小鼠模型来：a)发现对抗HGPS的治疗药物的新组合，以及b)提供关于孕激素诱导的损伤的可逆性的基本新知识。特殊目标：1)评估现有药物的组合是否可以针对孕激素(雷帕霉素、全反式维甲酸、萝卜素、曲曲菌素A)或孕激素诱导的效应(抗IL6R抗体)协同改善HGPS细胞和小鼠模型中的疾病症状。还将测试RNA干扰策略。2)评估在孕激素小鼠生命周期的不同时间点的全身孕激素抑制是否逆转HGPS进展，以确定未来针对孕激素表达的方法的潜在益处。3)评估孕激素抑制仅限于血管平滑肌细胞(孕激素的主要靶点)是否会在孕激素小鼠中引发整体有益影响，作为更具挑战性的全身孕激素抑制的替代方法。