Hydroxyurea enhances <i>SMN2</i> gene expression in spinal muscular atrophy cells

Grzeschik, Susanna; Ganta, Madhuri; Prior, Thomas W.; Heavlin, William D.; Wang, Ching H.

doi:10.1002/ana.20548

Cited by 103 publications

(65 citation statements)

References 49 publications

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“…Previous reports have also shown a lack of correlation of FL/D7 ratios in blood cells, 20,28,32 fibroblasts 16 and lymphoblasts. 18 In the four haploidentical sisters, we found no differences in the FL/D7 ratios, either in fibroblasts or in lymphoblasts. In fibroblasts from eight discordant families, Helmken et al 33 found no differences in FL/D7 ratios between affected and unaffected siblings, although they did find ratio differences in lymphoblasts in one family.…”

Section: Discussionmentioning

confidence: 59%

“…In vitro experiments with phenylbutyrate (PBA) and valproic acid (VPA) -two well-known HDACi -have shown an increase in SMN mRNA and protein levels in SMA fibroblasts. [15][16][17] Similar studies with hydroxyurea (HU) in EBV-immortalized SMA lymphoblasts 18 have shown an increase in the FL-SMN/D7-SMN (FL/D7 ratio). Pilot trials with these drugs have been performed in SMA patients and results were promising, [19][20][21] leading to the development of placebo-controlled clinical trials.…”

Section: Introductionmentioning

confidence: 73%

“…Grzeschik et al 18 proposed that this mechanism could explain the increase in FL/D7 ratios observed in SMA lymphoblasts. It has recently been suggested that HU enhances SMN2 expression in lymphoblasts through the release of nitric oxide but its mechanism of action on SMN2 genes is as yet unknown.…”

Section: Discussionmentioning

confidence: 99%

“…15,16,18 All compounds were freshly prepared immediately before each use. Cells were treated for 24 and 48 h (with daily addition) for HU and VPA and for 8 and 24 h for PBA.…”

Section: Drugsmentioning

confidence: 99%

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

et al. 2011

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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) (D7). 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 D7 in fibroblasts and lymphoblasts was analyzed by quantitative real-time PCR. The FL-SMN and FL/D7 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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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

“…15,16,18 All compounds were freshly prepared immediately before each use. Cells were treated for 24 and 48 h (with daily addition) for HU and VPA and for 8 and 24 h for PBA.…”

Section: Drugsmentioning

confidence: 99%

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

et al. 2011

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“…Recently, evidence has been provided that SMN2 gene expression can be enhanced by pharmacological treatment in vivo and/or in vitro, using different compounds. [9][10][11][12][13][14][15][16][17] The clinical efficacy of some of these compounds has been tested also in clinical trials. [18][19][20][21] The advances in SMA clinical research highlight the need of reliable biomarkers to monitor the efficacy at the molecular level of treatments during trials, the dosage of SMN transcripts or protein in peripheral blood samples being the only one potentially available.…”

Section: Introductionmentioning

confidence: 99%

SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR

Tiziano¹,

Pinto²,

Fiori³

et al. 2009

Eur J Hum Genet

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Three forms of SMA are recognized (type I-III) on the basis of clinical severity. All patients have at least one or more (usually 2-4) copies of a highly homologous gene (SMN2), which produces insufficient levels of functional SMN protein, because of alternative splicing of exon 7. Recently, evidence has been provided that SMN2 expression can be enhanced by pharmacological treatment. However, no reliable biomarkers are available to test the molecular efficacy of the treatments. At present, the only potential biomarker is the dosage of SMN products in peripheral blood. However, the demonstration that SMN full-length (SMN-fl) transcript levels are reduced in leukocytes of patients compared with controls remains elusive (except for type I). We have developed a novel assay based on absolute real-time PCR, which allows the quantification of SMN1-fl/SMN2-fl transcripts. For the first time, we have shown that SMN-fl levels are reduced in leukocytes of type II-III patients compared with controls. We also found that transcript levels are related to clinical severity as in type III patients SMN2-fl levels are significantly higher compared with type II and directly correlated with functional ability in type II patients and with age of onset in type III patients. Moreover, in haploidentical siblings with discordant phenotype, the less severely affected individuals showed significantly higher transcript levels. Our study shows that SMN2-fl dosage in leukocytes can be considered a reliable biomarker and can provide the rationale for SMN dosage in clinical trials.

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Drug treatment for spinal muscular atrophy types II and III

Bosboom

Vrancken

Berg

et al. 2009

Cochrane Database of Systematic Reviews

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BackgroundSpinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. ObjectivesTo evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. Search methodsWe searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. Selection criteriaWe sought all randomised or quasi-randomised trials that examined the e icacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year a er the onset of treatment. Secondary outcome measures within one year a er the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period.Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.

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Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells

Cited by 103 publications

References 49 publications

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

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

SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR

Drug treatment for spinal muscular atrophy types II and III

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