Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy

Brichta, Lars; Hofmann, Yvonne; Hahnen, Eric; Siebzehnrubl, Florian A.; Raschke, Heidrun; Blümcke, Ingmar; Eyüpoglu, Ilker Y.; Wirth, Brunhilde

doi:10.1093/hmg/ddg256

Cited by 344 publications

(267 citation statements)

References 38 publications

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“…The FL/D7 ratio in the SMA cells under study was similar, even though our patients had diverse genotypes and phenotypes. 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.…”

Section: Discussionmentioning

confidence: 76%

“…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: 76%

“…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: 76%

Section: Introductionmentioning

confidence: 76%

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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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“…Some therapeutic approaches aim to increase the amount of SMN protein produced by SMN2 through promoter activation, reduction of exon 7 alternative splicing, or both. [13][14][15][16][17][18][19][20][21][22] Some of these approaches are being investigated in ongoing or planned clinical trials, and great efforts have been done to identify the most appropriate clinical outcome measures for patients affected from various severities. 23 In this view, it would be very useful to have reliable biomarkers of disease severity and response to treatment.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Tiziano¹,

Lomastro²,

Pietro³

et al. 2012

Eur J Hum Genet

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Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (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 due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including the availability of biomarkers. This study was aimed at evaluating whether the quantification of SMN2 products in peripheral blood is a suitable biomarker for SMA. Forty-five adult type III patients were evaluated by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-min walk test, myometry, forced vital capacity, and dual X-ray absorptiometry. Molecular assessments included SMN2 copy number, levels of full-length SMN2 (SMN2-fl) transcripts and those lacking exon 7 and SMN protein. Clinical outcome measures strongly correlated to each other. Lean body mass correlated inversely with years from diagnosis and with several aspects of motor performance. SMN2 copy number and SMN protein levels were not associated with motor performance or transcript levels. SMN2-fl levels correlated with motor performance in ambulant patients. Our results indicate that SMN2-fl levels correlate with motor performance only in patients preserving higher levels of motor function, whereas motor performance was strongly influenced by disease duration and lean body mass. If not taken into account, the confounding effect of disease duration may impair the identification of potential SMA biomarkers.

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“…HDAC-inhs have been tested in vitro and in vivo: hydroxybutyric acid was the first compound shown to increase SMN2 levels in lymphoblastoid cell lines from SMA patients and to also increase the lifespan of a SMA mice [Chang et al, 2001]. Since then, valproic acid, phenylbutyrate, trycostatin A, and SAHA have also been shown to increase SMN levels in vitro and/or to improve the survival of SMA models in pre-clinical studies [Brichta et al, 2003;Sumner et al, 2003;Andreassi et al, 2004;Hahnen et al, 2006;Avila et al, 2007;Narvel et al, 2008;Riessland et al, 2010]. Valproic acid and phenylbutyrate have been tested in patients with SMA but with discordant outcomes.…”

mentioning

confidence: 99%

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy

Cited by 344 publications

References 38 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

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

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