PT  - JOURNAL ARTICLE
AU  - Tiziano, Francesco Danilo
AU  - Lomastro, Rosa
AU  - Abiusi, Emanuela
AU  - Pasanisi, Maria Barbara
AU  - Di Pietro, Lorena
AU  - Fiori, Stefania
AU  - Baranello, Giovanni
AU  - Angelini, Corrado
AU  - Sorarù, Gianni
AU  - Gaiani, Alessandra
AU  - Mongini, Tiziana
AU  - Vercelli, Liliana
AU  - Mercuri, Eugenio
AU  - Vasco, Gessica
AU  - Pane, Marika
AU  - Vita, Giuseppe
AU  - Vita, Gianluca
AU  - Messina, Sonia
AU  - Petillo, Roberta
AU  - Passamano, Luigia
AU  - Politano, Luisa
AU  - Campanella, Angela
AU  - Mantegazza, Renato
AU  - Morandi, Lucia
TI  - Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol
AID  - 10.1136/jmedgenet-2018-105482
DP  - 2019 May 01
TA  - Journal of Medical Genetics
PG  - 293--300
VI  - 56
IP  - 5
4099  - http://jmg.bmj.com/content/56/5/293.short
4100  - http://jmg.bmj.com/content/56/5/293.full
SO  - J Med Genet2019 May 01; 56
AB  - Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) 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 (SMN2). 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 SMN2 levels.Methods 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 SMN2 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.Results Thirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in SMN2 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.Conclusions 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: SMN transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying SMN2levels.Trial registration number EudraCT no. 2007-001088-32.