A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse
A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse
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DOI：
10.1093/hmg/ddr600
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Burghes, Arthur H. M.
中科院分区：
文献类型：
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作者：
Porensky, Paul N.;Mitrpant, Chalermchai;Burghes, Arthur H. M.
脊髓性肌萎缩症（SMA）是一种以脊髓前角运动神经元缺失为特征的常染色体隐性遗传疾病。SMA由运动神经元生存基因1（SMN 1）缺失或突变和SMN 2保留引起。SMN 1和SMN 2之间的单核苷酸差异导致大多数SMN 2转录物排除外显子7，导致SMN蛋白水平降低和SMA发生。一系列剪接增强子和沉默子调节SMN 2外显子7的掺入;这些剪接基序可以用反义寡聚体（ASO）阻断，以改变SMN 2转录物剪接。我们评价了吗啉代（MO）寡聚体对ISS-N1 [HSMN 2 Ex 7 D（10，29）]的作用，并通过脑室内（ICV）注射将该MO递送至出生后第0天（P0）SMA幼仔（Smn/、SMN 2/、SMN 7/）。存活率从15天显著增加到100天。延迟CNS MO注射具有中度疗效，延迟外周注射具有轻度生存优势，表明早期CNS阿索给药对于SMA治疗考虑至关重要。ICV处理增加了神经组织中的全长SMN 2转录物以及SMN蛋白，但在外周组织中仅最低限度地增加。区间分析显示，随着时间的推移，选择性剪接修饰减少。我们认为，中枢神经系统SMN的增加将对SMA产生重大影响，SMN水平的早期增加导致运动表型的纠正。最后，通过鞘内递送MO寡聚体的早期引入是SMA患者的潜在治疗。
Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by -motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino (MO) oligomer against ISS-N1 [HSMN2Ex7D(10,29)], and delivered this MO to postnatal day 0 (P0) SMA pups (Smn/, SMN2/, SMN7/) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to 100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.