title: Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1 00168 Roma, Italy. fdtiziano@rm.unicatt.it
authors.forename: Francesco Danilo
authors.initials: FD
authors.lastname: Tiziano
authors.forename: Rosa
authors.initials: R
authors.lastname: Lomastro
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pinto
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiori
authors.forename: Carla
authors.initials: C
authors.lastname: Angelozzi
authors.forename: Marika
authors.initials: M
authors.lastname: Pane
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Christina
authors.initials: C
authors.lastname: Brahe
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D012333:RNA, Messenger; D055540:Survival of Motor Neuron 2 Protein; D000420:Albuterol