SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy
SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy
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DOI：
10.1093/hmg/ddq023
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发表时间：
2010-04-15
影响因子：
3.5
通讯作者：
Wirth, Brunhilde
中科院分区：
文献类型：
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作者：
Riessland, Markus;Ackermann, Bastian;Wirth, Brunhilde
近端脊髓性肌萎缩症（SMA）是一种常见的常染色体隐性遗传性神经肌肉疾病，由脊髓内α运动神经元的功能损伤决定。 SMA 是由运动神经元存活基因 1 (SMN1) 的功能丧失引起的，而疾病的严重程度主要受 SMN2 拷贝数的影响。 SMN2仅产生低水平的全长mRNA/蛋白质，可以通过小分子和药物进行调节，从而为SMA治疗提供了独特的可能性。在这里，我们分析了辛二酰苯胺异羟肟酸 (SAHA)（一种 FDA 批准的组蛋白脱乙酰酶抑制剂）作为两种严重 SMA 小鼠模型的潜在药物，每种小鼠模型均携带两个 SMN2 转基因：每个等位基因有一个 SMN2 的 US-SMA 小鼠 (Smn(-/-)；SMN2(tg/tg)) 和每个等位基因有两个 SMN2 的台湾-SMA 小鼠 (Smn(-/-)；SMN2(tg/tg))。 SMN2(tg/wt))，均在纯 FVB/N 背景下。 US-SMA 小鼠胚胎致死，杂合雄性小鼠的生育能力显着降低。对怀孕母亲进行 SAHA 治疗挽救了导致 SMA 后代胚胎死亡的情况。通过对台湾模型（Smn(-/-)；SMN2(tg/tg) x Smn(-/+) 小鼠）使用一种新颖的育种策略，我们在每窝中获得了 50% 的 SMA 后代，其存活时间与 10 天相似，并且有 50% 的对照携带者。与媒介物处理的 SMA 小鼠相比，每天两次 25 mg/kg SAHA 的治疗使 SMA 小鼠的寿命延长了 30%，显着改善了运动功能能力，减少了脊髓内运动神经元的变性，并增加了神经肌肉接头和肌纤维的大小。 SMN RNA 和蛋白质水平在包括脊髓和肌肉在内的各种组织中显着升高。因此，SAHA 可减缓 SMA 的进展，可能适合 SMA 治疗。
Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder determined by functional impairment of alpha-motor neurons within the spinal cord. SMA is caused by functional loss of the survival motor neuron gene 1 (SMN1), whereas disease severity is mainly influenced by the number of SMN2 copies. SMN2, which produces only low levels of full-length mRNA/protein, can be modulated by small molecules and drugs, thus offering a unique possibility for SMA therapy. Here, we analysed suberoylanilide hydroxamic acid (SAHA), a FDA-approved histone deacetylase inhibitor, as potential drug in two severe SMA mouse models each carrying two SMN2 transgenes: US-SMA mice with one SMN2 per allele (Smn(-/-); SMN2(tg/tg)) and Taiwanese-SMA mice with two SMN2 per allele (Smn(-/-); SMN2(tg/wt)), both on pure FVB/N background. The US-SMA mice were embryonically lethal with heterozygous males showing significantly reduced fertility. SAHA treatment of pregnant mothers rescued the embryonic lethality giving rise to SMA offspring. By using a novel breeding strategy for the Taiwanese model (Smn(-/-); SMN2(tg/tg) x Smn(-/+) mice), we obtained 50% SMA offspring that survive similar to 10 days and 50% control carriers in each litter. Treatment with 25 mg/kg twice daily SAHA increased lifespan of SMA mice by 30%, significantly improved motor function abilities, reduced degeneration of motor neurons within the spinal cord and increased the size of neuromuscular junctions and muscle fibers compared with vehicle-treated SMA mice. SMN RNA and protein levels were significantly elevated in various tissues including spinal cord and muscle. Hence, SAHA, which lessens the progression of SMA, might be suitable for SMA therapy.