Institute of Genomic Medicine, Catholic University, Roma, Italy.
Muscle Pathology and Neuroimmunology Unit, Neurological Institute Carlo Besta, Milano, Italy.
J Med Genet. 2019 May;56(5):293-300. doi: 10.1136/jmedgenet-2018-105482. Epub 2018 Dec 28.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron () gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating levels.
We have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4 mg of salbutamol or placebo/three times a day. Molecular tests were copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design.
Thirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients.
Our data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying levels.
EudraCT no. 2007-001088-32.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，由于生存运动神经元（SMN）基因功能丧失所致。最近批准的第一种治疗方法是基于对高度同源基因（）mRNA 中外显子 7 跳跃的减少。本研究的主要目的是评估血液中 SMN 基因产物的剂量作为 SMA 生物标志物的适用性，以及口服沙丁胺醇（一种调节水平的β2-肾上腺素能激动剂）的安全性。
我们对 45 名成年 SMA 患者进行了为期 1 年的多中心、双盲、安慰剂对照研究，给予沙丁胺醇或安慰剂，每日 3 次，每次 4mg。分子检测包括 SMN 基因拷贝数、SMN 转录本和蛋白水平。我们还根据研究设计时的可用结果指标，探索了临床效果。
36 名患者完成了研究。沙丁胺醇安全且耐受良好。我们观察到沙丁胺醇治疗患者外周血中全长水平显著且持续增加（p<0.00001）。对运动功能的探索性分析显示大多数患者有所改善。
我们的数据证明了沙丁胺醇的安全性和分子疗效。我们首次对调节基因表达的化合物（外周血中的 SMN 转录本和蛋白）进行了纵向评估：外周血中的转录本剂量可靠，可作为系统化合物调节水平的临床试验中的药效标志物。
EudraCT 编号 2007-001088-32。
