Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.
Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.
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基于异戊二烯半胱氨酸羧甲基转移酶的哈钦森-吉尔福德早衰综合症疗法。
DOI：
10.1021/acscentsci.0c01698
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发表时间：
2021-08-25
影响因子：
18.2
通讯作者：
Ortega-Gutiérrez S
中科院分区：
文献类型：
--
作者：
Marcos-Ramiro B;Gil-Ordóñez A;Marín-Ramos NI;Ortega-Nogales FJ;Balabasquer M;Gonzalo P;Khiar-Fernández N;Rolas L;Barkaway A;Nourshargh S;Andrés V;Martín-Fontecha M;López-Rodríguez ML;Ortega-Gutiérrez S
哈钦森-吉尔福德早衰综合征（HGPS, progeria）是一种罕见的遗传性疾病，其特征是过早衰老和儿童死亡，直到去年11月，lonafarnib获得了长期寻求的FDA批准，才获得批准用于治疗这种疾病的药物。然而，洛那法尼对患者的益处是有限的，这突出了对新的治疗策略的需求。在这里，我们验证了酶异戊酰半胱氨酸羧甲基转移酶（ICMT）作为早衰症的新治疗靶点，并开发了一系列新的有效抑制剂，这些抑制剂具有良好的抗早衰性。其中，复方UCM-13207显著改善了早衰症的主要标志。具体来说，用UCM-13207处理类早衰小鼠的成纤维细胞，使核膜上的早衰蛋白脱位，降低了其总蛋白水平，导致DNA损伤减少，细胞活力增加。重要的是，这些效应也在患者来源的细胞中观察到。在LmnaG609G/G609G类早衰小鼠模型中，UCM-13207表现出良好的体内作用，增加体重，增强握力，延长寿命20%，减少多器官组织衰老。此外，UCM-13207治疗导致关键心血管标志的改善，如主动脉和心内膜组织中早衰蛋白水平降低，血管平滑肌细胞（VSMCs）数量增加。其有益效果远远超过该领域先前报道的其他治疗策略所引起的效果，因此支持将UCM-13207作为早衰症的新治疗方法。异戊酰半胱氨酸羧甲基转移酶（ICMT）抑制剂诱导核边缘的早衰蛋白脱位并降低其水平，显著改善早衰的主要标志。
Hutchinson–Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the LmnaG609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria. Isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor induces progerin delocalization from the nuclear rim and decreases its levels, significantly improving the main hallmarks of progeria.
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影响因子：
16.6
作者：
Balmus G;Larrieu D;Barros AC;Collins C;Abrudan M;Demir M;Geisler NJ;Lelliott CJ;White JK;Karp NA;Atkinson J;Kirton A;Jacobsen M;Clift D;Rodriguez R;Sanger Mouse Genetics Project;Adams DJ;Jackson SP
通讯作者：
Jackson SP
影响因子：
82.9
作者：
Beyret, Ergin;Liao, Hsin-Kai;Belmonte, Juan Carlos Izpisua
通讯作者：
Belmonte, Juan Carlos Izpisua
影响因子：
82.9
作者：
Barcena, Clea;Valdes-Mas, Rafael;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
7.8
作者：
del Campo, Lara;Sanchez-Lopez, Amanda;Andres, Vicente
通讯作者：
Andres, Vicente
影响因子：
11.1
作者：
Hamczyk, Magda R.;Villa-Bellosta, Ricardo;Andres, Vicente
通讯作者：
Andres, Vicente