Salbutamol increases SMN transcript levels in leukocytes of spinal muscular atrophy patients: relevance for clinical trial design
Résumé
Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (type I-III). All patients have usually 2-4 copies of a highly homologous gene (SMN2) which produces insufficient levels of functional SMN protein. Recently, we have provided evidence that SMN2 expression can be enhanced in vitro by salbutamol, a beta2-adrenergic agonist. This compound has also been shown to improve motor function of SMA patients in two different pilot trials. Aim: In the present study, we have evaluated the in vivo molecular efficacy of salbutamol in SMA patients. Methods: 12 type II-III patients took the compound orally for six months. SMN2 full length transcript levels have been determined in peripheral blood leukocytes 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: Our data strongly support salbutamol as candidate for SMA treatment, suggest that SMN2 copy number may predict the molecular response to treatment and may be a useful randomization parameter in double blind placebo-controlled clinical trial design.
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