Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging
Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging
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DOI：
10.1126/scitranslmed.3002847
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发表时间：
2011-10-26
影响因子：
17.1
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Osorio, Fernando G.;Navarro, Claire L.;Lopez-Otin, Carlos
哈钦森-吉尔福德早衰综合征（HGPS）是由LMNA基因的一个点突变引起的，该突变激活了一个隐秘的供体剪接位点，产生了一种被称为早衰蛋白的截断形式的前纤层蛋白a。在正常衰老过程中也会产生少量的progerin。用小鼠HGPS模型进行的研究使这种疾病的第一个治疗方法得以发展。然而，由于缺乏合适的小鼠模型，这些早期的工作都没有解决在HGPS患者中观察到的异常和致病性LMNA剪接。在这里，我们报道了一种携带HGPS突变的转基因小鼠品系。这些小鼠积累了早衰蛋白，呈现出类早衰模型的组织学和转录改变特征，并表现出人类HGPS的主要临床表现，包括寿命缩短、骨骼和心血管畸变。利用这种动物模型，我们开发了一种基于反义morpholino的治疗方法，可以阻止致病性Lmna剪接，显著减少progerin的积累及其相关的核缺陷。用这些morpholinos治疗突变小鼠可显著改善其类早衰表型，并显著延长其寿命，从而支持基于反义寡核苷酸的疗法治疗人类加速衰老疾病的有效性。
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino-based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide-based therapies for treating human diseases of accelerated aging.