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. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 856-858 |
| Number of pages | 3 |
| Journal | Journal of Medical Genetics |
| Volume | 47 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2010 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients : Relevance for clinical trial design. / Tiziano, Francesco Danilo; Lomastro, Rosa; Pinto, Anna Maria; Messina, Sonia; D'Amico, Adele; Fiori, Stefania; Angelozzi, Carla; Pane, Marika; Mercuri, Eugenio; Bertini, Enrico; Neri, Giovanni; Brahe, Christina.
In: Journal of Medical Genetics, Vol. 47, No. 12, 12.2010, p. 856-858.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients
T2 - Relevance for clinical trial design
AU - Tiziano, Francesco Danilo
AU - Lomastro, Rosa
AU - Pinto, Anna Maria
AU - Messina, Sonia
AU - D'Amico, Adele
AU - Fiori, Stefania
AU - Angelozzi, Carla
AU - Pane, Marika
AU - Mercuri, Eugenio
AU - Bertini, Enrico
AU - Neri, Giovanni
AU - Brahe, Christina
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
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U2 - 10.1136/jmg.2010.080366
DO - 10.1136/jmg.2010.080366
M3 - Article
VL - 47
SP - 856
EP - 858
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 12
ER -