PABPN1 gene therapy for oculopharyngeal muscular dystrophy.
PABPN1 gene therapy for oculopharyngeal muscular dystrophy.
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DOI：
10.1038/ncomms14848
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发表时间：
2017-03-31
影响因子：
16.6
通讯作者：
Dickson G
中科院分区：
文献类型：
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作者：
Malerba A;Klein P;Bachtarzi H;Jarmin SA;Cordova G;Ferry A;Strings V;Espinoza MP;Mamchaoui K;Blumen SC;St Guily JL;Mouly V;Graham M;Butler-Browne G;Suhy DA;Trollet C;Dickson G
眼咽肌营养不良症（OPMD）是一种常染色体显性遗传的迟发性肌肉疾病，其特征是上睑下垂、吞咽困难、近端肢体无力和骨骼肌核聚集。OPMD是由PABPN 1基因中的三核苷酸重复扩增引起的，其导致多聚A结合蛋白核1（PABPN 1）中的N-末端扩增的多聚丙氨酸束。在这里，我们表明，用基于腺相关病毒的基因疗法治疗OPMD小鼠模型，结合内源性PABPN 1的完全敲除及其被野生型PABPN 1的替代，大大减少了不溶性聚集体的量，减少了肌肉纤维化，恢复了肌肉力量到健康肌肉的水平，并使肌肉转录组正常化。在源自OPMD患者的细胞中进一步证实了组合治疗的功效。这些结果为OPMD治疗的基因替代方法铺平了道路。眼咽肌营养不良症是由PABPN 1基因中的三核苷酸重复扩增引起的。在这里，作者使用基于AAV的基因疗法来敲低突变基因并用野生型等位基因取代它，并在小鼠和患者细胞中显示出有效性。
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment. Oculopharyngeal muscular dystrophy is caused by trinucleotide repeat expansions in the PABPN1 gene. Here the authors use AAV-based gene therapy to knockdown the mutant gene and replace it with a wild-type allele, and show effectiveness in mice and in patient cells.