Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design
- Francesco Danilo Tiziano1,
- Rosa Lomastro1,
- Anna Maria Pinto1,
- Sonia Messina2,
- Adele D'Amico3,
- Stefania Fiori1,
- Carla Angelozzi1,
- Marika Pane4,
- Eugenio Mercuri4,
- Enrico Bertini3,
- Giovanni Neri1,
- Christina Brahe1
- 1Institute of Medical Genetics, Catholic University, Rome, Italy
- 2Institute of Neurology, University of Messina, Messina
- 3Molecular Medicine Unit, Bambino Gesù Hospital, Rome, Italy
- 4Institute of Neurology, Catholic University, Rome
- Correspondence to Dr Francesco D Tiziano, Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1 00168 Roma, Italy;
- Received 21 April 2010
- Revised 8 June 2010
- Accepted 9 June 2010
- Published Online First 12 September 2010
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.
- Spinal muscular atrophy
- pilot trial
- molecular genetics
- motor neurone disease
- neuromuscular disease
Funding Other funders: Telethon Italia Grant GGP07035.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Catholic University Rome Italy.
Provenance and peer review Not commissioned; externally peer reviewed.