Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

Brahe, Christina; Vitali, Tiziana; Tiziano, Francesco Danilo; Angelozzi, Carla; Pinto, Anna Maria; Borgo, Federica; Moscato, Umberto; Bertini, Enrico; Mercuri, Eugenio; Neri, Giovanni

doi:10.1038/sj.ejhg.5201320

Cited by 146 publications

(88 citation statements)

References 11 publications

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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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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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“…[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. PBA has been investigated in a double-blind placebocontrolled trial in 107 children with type II SMA.…”

Section: Introductionmentioning

confidence: 99%

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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“…Recent investigations into the pathogenesis of spinal muscular atrophy (SMA) have led to hope that a specific therapy might soon be possible [1,2]. This prospect raises important concerns about the best manner for testing a putative therapy [3].…”

Section: Introductionmentioning

confidence: 99%

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

Krosschell

Maczulski²,

Crawford

et al. 2006

Neuromuscular Disorders

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The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra-and interrater reliability and the test-retest stability of a modified version of the scale. Both intra-and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20°. These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

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Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

Cited by 146 publications

References 11 publications

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

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

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

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

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