Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability

Eduardo Tizzano (1) , Eva Also-Rallo (1) , Laura Alias (1) , Rebeca Martínez-Hernández (1) , Lidia Caselles (1) , Maria J Barceló (1) , Montserrat Baiget (1) , Sara Bernal (1)

1 Genetics

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by mutations in the SMN1 gene. The homologous copy (SMN2) is always present in SMA patients. SMN1 gene transcripts are usually full-length but exon 7 is spliced out in a high proportion of SMN2 transcripts (delta7). Advances in drug therapy for SMA have shown that an increase in SMN mRNA and protein levels can be achieved in vitro. We performed a systematic analysis of SMN expression in primary fibroblasts and EBV-transformed lymphoblasts from 7 SMA patients with varying clinical severity and different SMN1 genotypes to determine expression differences in two accessible tissues (skin and blood). The basal expression of SMN mRNA full-length (FL) and delta7 (Δ7) in fibroblasts and lymphoblasts was analyzed by quantitative real time PCR. The FL-SMN and FL/Δ7 SMN ratios were significantly higher in control cells than in patients. Furthermore, we investigated the response of these cell lines to hydroxyurea, valproate and phenylbutyrate, drugs previously reported to upregulate SMN2. The response to treatments with these compounds was heterogeneous. We found both intra-patient and inter-patient variability even within haploidentical siblings, suggesting that tissue and individual factors may affect the response to these compounds. To optimise the stratification of patients in clinical trials, in vitro studies should be performed prior to enrolment so as to define each patient as a responder or non-responder to the compound under investigation.

Mots clés: Spinal muscualr atrophy; survival motor neuron gene; upregulation

Eduardo Tizzano, Eva Also-Rallo, Laura Alias, Rebeca Martínez-Hernández, Lidia Caselles, et al.. Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.89⟩. ⟨hal-00644704⟩