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沙丁胺醇可提高脊髓性肌萎缩症(SMA)患者白细胞中存活运动神经元(SMN)转录本水平:对临床试验设计的意义。

Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design.

机构信息

Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1 00168 Roma, Italy.

出版信息

J Med Genet. 2010 Dec;47(12):856-8. doi: 10.1136/jmg.2010.080366. Epub 2010 Sep 12.

Abstract

BACKGROUND

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognised (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2) which produces insufficient levels of functional survival motor neuron (SMN) protein. Recently, evidence has been provided that SMN2 expression can be enhanced in vitro by salbutamol, a β2-adrenergic agonist. This compound has also been shown to improve motor function of SMA patients in two different pilot trials.

AIM

To evaluate the in vivo molecular efficacy of salbutamol in SMA patients.

METHODS

Twelve type II-III patients took salbutamol orally for 6 months. SMN2 full length transcript levels were determined in peripheral blood leucocytes by absolute real-time PCR, at baseline and after 3 and 6 months of treatment.

RESULTS

A significant and constant increase in SMN2 full length transcript levels was detected; the response was directly proportional to SMN2 gene copy number.

CONCLUSIONS

The data strongly support salbutamol as a candidate for treating SMA, and suggest that SMN2 copy number may predict the molecular response to treatment and may be a useful randomisation parameter in a double blind placebo controlled clinical trial design.

摘要

背景

脊髓性肌萎缩症(SMA)是一种由 SMN1 基因突变引起的神经肌肉疾病。根据严重程度,可识别出三种形式的 SMA(I-III 型)。所有患者通常有 2-4 个高度同源的基因(SMN2)拷贝,这些拷贝产生的生存运动神经元(SMN)蛋白功能不足。最近有证据表明,β2-肾上腺素能激动剂沙丁胺醇可在体外增强 SMN2 的表达。该化合物还在两项不同的试点试验中显示出改善 SMA 患者的运动功能。

目的

评估沙丁胺醇在 SMA 患者体内的分子疗效。

方法

12 名 II-III 型患者口服沙丁胺醇 6 个月。通过绝对实时 PCR 在基线和治疗 3 个月和 6 个月后测定外周血白细胞中的 SMN2 全长转录本水平。

结果

检测到 SMN2 全长转录本水平的显著和持续增加;该反应与 SMN2 基因拷贝数成正比。

结论

这些数据强烈支持沙丁胺醇作为治疗 SMA 的候选药物,并表明 SMN2 拷贝数可能预测治疗的分子反应,并且可能是双盲安慰剂对照临床试验设计中的有用随机化参数。

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