Pilot trial of albuterol in spinal muscular atrophy

Kinali, Maria; Mercuri, Eugenio; Main, Marion; Biasia, F. De; Karatza, Ageliki; Higgins, Rosemary D.; Banks, L. M.; Manzur, Adnan; Muntoni, Francesco

doi:10.1212/wnl.59.4.609

Cited by 112 publications

(60 citation statements)

References 8 publications

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“…It has been previously reported that SMN is phosphorylated at serines 28 and (8,12,14). ␤-Adrenergic agonists have been shown to improve muscle strength in human subjects with healthy and diseased muscle (29)(30)(31), and daily albuterol treatment had beneficial effects in an open-label pilot study in SMA type II and III patients (16). Salbutamol has been also been shown to increase SMN protein levels in patient-derived fibroblasts (1).…”

Section: Discussionmentioning

confidence: 99%

Regulation of SMN Protein Stability

Burnett

Muñoz

Tandon

et al. 2009

Molecular and Cellular Biology

246

261

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Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMN⌬7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMN⌬7 proteins have been largely unexplored. Using pulsechase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMN⌬7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.

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Section: Discussionmentioning

confidence: 99%

Regulation of SMN Protein Stability

Burnett

Muñoz

Tandon

et al. 2009

Molecular and Cellular Biology

246

261

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“…Gabapentin, a likely neuroprotective agent, did not lead to differences in the outcome measure, 12 whereas, in pilot trials using thyrotropin-releasing hormone and albuterol, improvement of muscle strength in a small number of type II and III patients has been reported. 13,14 None of these drugs appears to act on the molecular defect. Essentially two strategies to increase SMN2 fl transcripts can be envisaged: one leading to the upregulation of the SMN2 genes and the other resulting in the modification of the SMN2 mRNA splicing pattern.…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

et al. 2003

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, characterized by degeneration of the anterior horn cells of the spinal cord. SMA presents with a highly variable phenotype ranging from very severe to mild (type I-III). No cure for SMA is available at present. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene. However, all patients have one or more copies of the SMN2 gene, nearly identical to SMN1. Both genes encode the SMN protein but the level produced by SMN2 is insufficient to protect from disease. Increasing SMN2 gene expression could be of considerable therapeutic importance. The aim of this study was to assess whether SMN2 gene expression can be increased by 4-phenylbutyrate (PBA). Fibroblast cell cultures from 16 SMA patients affected by different clinical severities were treated with PBA, and full-length SMN2 transcripts were measured by real-time PCR. In all cell cultures, except one, PBA treatment caused an increase in full-length SMN2 transcripts, ranging from 50 to 160% in type I and from 80 to 400% in type II and III cultures. PBA was found also effective in enhancing SMN protein levels and the number of SMN-containing nuclear structures (gems). These data show that SMN expression is considerably increased by PBA, and suggest that the compound, owing also to its favorable pharmacological properties, could be a good candidate for the treatment of SMA.

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“…In an open label pilot trial with thirteen SMA type II and III patients, there was a significant increase in muscle strength measured by myometry and forced vital capacity (FVC) after six months of salbutamol treatment. The therapy was well tolerated, but in several patients an increase in contractures was seen that may have been due to a stronger effect of salbutamol on agonist muscles [115]. In another open trial on 23 SMA type II patients, the functional scores were significantly higher after 6 and 12 months of treatment with salbutamol and there were no major side effects [116].…”

Section: Thyrotropin Releasing Hormone (Trh) Hasmentioning

confidence: 96%

Treatment strategies for spinal muscular atrophy

Fuller¹,

Barišić

Šešo-Šimić³

et al. 2010

Translational Neuroscience

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Progress in understanding the genetic basis and pathophysiology of spinal muscular atrophy (SMA), along with continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels have resulted in several strategies that have been proposed as potential directions for efficient drug development. Here we provide an overview on the current status of the following approaches: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the very near future. Unfortunately, studies indicate that the short half-life of sodium butyrate in human serum does not recommend its use in clinical trials [30]. KeywordsA derivative of sodium butyrate -sodium-4-phenyl-butyrate, also known as phenylbutyrate (PB), was also shown to increase SMN transcript expression, SMN protein and gem counts in fibroblast cells derived from SMA patients [31,32]. It has a well-known pharmacokinetic and safety profile and good penetration into the central nervous system, and so appeared to be a promising candidate for the treatment of SMA. In a small uncontrolled trial an improvement of motor function in 10 SMA type II patients was found after nine weeks of treatment with oral PB, with no apparent major side effects [33]. However, a placebo-controlled trial of intermittent treatment over 13 weeks suggested that there was no improvement in functional scores under the conditions used [34,35]. A phase I/II study initiated by the US Other approachesThe base of treatment in SMA is still supportive care, which requires multidisciplinary medical care [21]. Due to intensive supportive care, such as ventilation, the use of mechanical insufflation-exsufflation device and tube feeding, the survival of patients with SMA type I has significantly increased in recent years [22]. Since forced exercise was found to be of benefit in ALS mouse models [147,148] it was recently studied in SMA mice. Type II SMA mice developed by were used in the interesting study of Grondard et al. [68].The mice were subjected to a training protocol of forced run on a wheel or no training. [1] Botta A., Tacconelli A., Bagni I., Giardina E., Bonifazi E., Pietropolli A., Neurology, 2007Neurology, , 69, 1931Neurology, -1936 [23] Wang C. H., Finkel R. S., Bertini E. S., Schroth M., Simonds A., Wong B.,

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Pilot trial of albuterol in spinal muscular atrophy

Cited by 112 publications

References 8 publications

Regulation of SMN Protein Stability

Regulation of SMN Protein Stability

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

Treatment strategies for spinal muscular atrophy

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