Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide
Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide
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DOI：
10.1016/j.ymthe.2017.03.036
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发表时间：
2017-06-07
影响因子：
12.4
通讯作者：
Singh, Ravindra N.
中科院分区：
文献类型：
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作者：
Howell, Matthew D.;Ottesen, Eric W.;Singh, Ravindra N.
脊髓性肌萎缩症（SMA）是由运动神经元存活蛋白（SMN）水平低下引起的儿童主要遗传性疾病。在这里，我们采用A15/283，一种靶向深层内含子序列/结构的反义寡核苷酸，来研究轻度SMA小鼠模型中SMN恢复的影响。我们发现，在出生后第1天和第3天，SMA小鼠皮下注射A15/283后，尾部坏死的改善具有性别特异性。我们还证明，由于早期给予A15/283，SMN适度增加，可显著改善睾丸发育和精子发生。我们的研究结果揭示了近总修正成年睾丸中的几个基因的表达后，暂时增加SMN在出生后早期的发展。这是靶向深度内含子序列/结构的反义寡核苷酸的体内功效的首次证明。这也是SMN适度外周增加后SMA病理学性别特异性改善的首次报告。
Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.