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.
- spinal muscular atrophy
- real-time PCR
- double-blind clinical trial
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Contributors FDT and LM conceived the study, performed statistical analysis and wrote down the manuscript. RL, LDP, EA and SF performed molecular analyses. MBP performed clinical evaluation of patients and contributed to write down the manuscript. GB, CA, GS, AG, TM, LV, EM, GeVa, MP, GiVi, GiaVi, SM, RP, LuPa, LuPo GDG, AC and RM performed the enrolment and clinical evaluation of patients. All authors revised the manuscript before submission.
Funding The present study has been granted by Agenzia Italiana del Farmaco (AIFA, grant number FARM79AJ8P). LDP was granted by Telethon Italia (grant number GGP12116).
Competing interests None declared.
Ethics approval Ethics committee of the National Neurologic Institute Carlo Besta, Milano.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Obtained.