RT Journal Article
SR Electronic
T1 Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 293
OP 300
DO 10.1136/jmedgenet-2018-105482
VO 56
IS 5
A1 Francesco Danilo Tiziano
A1 Rosa Lomastro
A1 Emanuela Abiusi
A1 Maria Barbara Pasanisi
A1 Lorena Di Pietro
A1 Stefania Fiori
A1 Giovanni Baranello
A1 Corrado Angelini
A1 Gianni Sorarù
A1 Alessandra Gaiani
A1 Tiziana Mongini
A1 Liliana Vercelli
A1 Eugenio Mercuri
A1 Gessica Vasco
A1 Marika Pane
A1 Giuseppe Vita
A1 Gianluca Vita
A1 Sonia Messina
A1 Roberta Petillo
A1 Luigia Passamano
A1 Luisa Politano
A1 Angela Campanella
A1 Renato Mantegazza
A1 Lucia Morandi
YR 2019
UL http://jmg.bmj.com/content/56/5/293.abstract
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.