Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability.
- Authors
- Also-Rallo, Eva; Alías, Laura; Martínez-Hernández, Rebeca; Caselles, Lidia; Barceló, María J; Baiget, Montserrat; Bernal, Sara; Tizzano, Eduardo F
- Year
- 2011
- Journal
- European journal of human genetics : EJHG
- PMID
- 21610752
- DOI
- 10.1038/ejhg.2011.89
- PMCID
- PMC3190259
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 (FL), but exon 7 is spliced out in a high proportion of SMN2 transcripts (delta7) (Δ7). 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 seven 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 FL and Δ7 in fibroblasts and lymphoblasts was analyzed by quantitative real-time PCR. The FL-SMN and FL/Δ7 SMN ratios were 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 optimize the stratification of patients in clinical trials, in vitro studies should be performed before enrolment so as to define each patient as a responder or non-responder to the compound under investigation.
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Full-Length SMN Transcript in Extracellular Vesicles as Biomarker in Individuals with Spinal Muscular Atrophy Type 2 Treated with Nusinersen. | Trifunov S et al. | — | 2023 | → |
| Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment. | Nishio H et al. | — | 2023 | → |
| Biological networks and complexity in early-onset motor neuron diseases. | Butchbach MER et al. | — | 2022 | → |
| The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap. | Brown SJ et al. | — | 2022 | → |
| Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons. | Sansa A et al. | — | 2021 | → |
| Spinal muscular atrophy: from rags to riches. | Mercuri E | — | 2021 | → |
| Drug treatment for spinal muscular atrophy types II and III. | Wadman RI et al. | — | 2020 | → |
| Spinal muscular atrophy - insights and challenges in the treatment era. | Mercuri E et al. | — | 2020 | → |
| Drug treatment for spinal muscular atrophy type I. | Wadman RI et al. | — | 2019 | → |
| Overexpression of SMN2 Gene in Motoneuron-Like Cells Differentiated from Adipose-Derived Mesenchymal Stem Cells by Ponasterone A. | Mohseni R et al. | — | 2019 | → |
| Investigating transcription factor synergism in humans. | Cumbo F et al. | — | 2018 | → |
| Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy. | Groen EJN et al. | — | 2018 | → |
| A Comparative Study of SMN Protein and mRNA in Blood and Fibroblasts in Patients with Spinal Muscular Atrophy and Healthy Controls. | Wadman RI et al. | — | 2016 | → |
| Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients. | Mohseni J et al. | — | 2016 | → |
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| Shift from extracellular signal-regulated kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells. | Branchu J et al. | — | 2013 | → |
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| Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron. | Locatelli D et al. | — | 2012 | → |
| Therapy development for spinal muscular atrophy in SMN independent targets. | Tsai LK | — | 2012 | → |