P.6.4 Salbutamol tolerability and efficacy in adult type III SMA patients: Results of a multicentric, molecular and clinical, double-blind, placebo-controlled study

Morandi, Lucia; Abiusi, Emanuela; Pasanisi, Maria Barbara; Lomastro, Rosa; Fiori, Stefania; Pietro, Lorena Di; Angelini, Corrado; Sorarù, Gianni; Gaiani, Alessandra; Mongini, Tiziana; Vercelli, Liliana; Vasco, Gessica; Vita, Giuseppe; Politano, Luisa; Passamano, Luigia; Gregorio, G. Di; Tiziano, Francesco Danilo

doi:10.1016/j.nmd.2013.06.475

Cited by 5 publications

(7 citation statements)

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“…Salbutamol alleviates the symptoms in SMA patients [13] , [14] , [15] . The beneficial effects of salbutamol can be explained partly by prevention of SMN protein degradation.…”

Section: Discussionmentioning

confidence: 96%

“…However, the β2-adrenergic receptor agonist, salbutamol, which is widely used as a bronchodilator in asthma patients, has recently been reported to alleviate symptoms in SMA patients [13] , [14] , [15] , and Angelozzi et al reported that salbutamol increased SMN protein levels in SMA fibroblast cells [16] . However, the mechanism whereby salbutamol increases SMN protein levels remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

Harahap

Nurputra

Rochmah

et al. 2015

Biochemistry and Biophysics Reports

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Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1. Although the SMN1 homolog SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of SMN1. Salbutamol, a β2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels in a dose-dependent manner in SMA fibroblast cells lacking SMN1, though no significant changes in SMN2 mRNA levels were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and deubiquitinase inhibitor, respectively. Co-immunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating β2-adrenergic receptor-PKA pathways.

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“…Salbutamol alleviates the symptoms in SMA patients [13] , [14] , [15] . The beneficial effects of salbutamol can be explained partly by prevention of SMN protein degradation.…”

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

Harahap

Nurputra

Rochmah

et al. 2015

Biochemistry and Biophysics Reports

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“…on patients with SMA types 3 and 4; preliminary results confirmed that SMN ‐fl increased only in the salbutamol‐treated group. Their study also confirmed that salbutamol is well‐tolerated, and it may produce clinical improvement . After this trial, adult patients with SMA types 2, 3, and 4 followed at our institute were treated with salbutamol.…”

mentioning

confidence: 58%

“…As reported by Montes et al ., innovative research strategies and clinically feasible outcome measures are needed to test the effects of new drugs on patients with SMA . In addition, the discrepancy between clinical outcomes and patients' opinions about salbutamol effects was observed . A first step toward better investigation of patient perception of treatment efficacy with valid and reliable self‐reported instruments able to capture patient experiences has already been made by our group .…”

mentioning

confidence: 99%

Perceived efficacy of salbutamol by persons with spinal muscular atrophy: A mixed methods study

Giovannetti¹,

Pasanisi²,

Černiauskaitė³

et al. 2016

Muscle Nerve

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“…We identified and assessed 59 studies (36 new) for possible inclusion in the review. 2007), and a trial with salbutamol (Morandi 2013), were only published in conference abstracts which did not include enough data for analysis (Merlini 2010;Morandi 2013). We also could not obtain the results of three completed randomised, placebocontrolled trials with hydroxyurea (NCT00568802), with riluzole in SMA types II and III (ASIRI 2008), and with 4AP in adults with SMA type III (NCT01645787).…”

Section: Excluded Studiesmentioning

confidence: 99%

Drug treatment for spinal muscular atrophy types II and III

Wadman

Bosboom

Pol

et al. 2012

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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P.6.4 Salbutamol tolerability and efficacy in adult type III SMA patients: Results of a multicentric, molecular and clinical, double-blind, placebo-controlled study

Cited by 5 publications

References 0 publications

Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

Perceived efficacy of salbutamol by persons with spinal muscular atrophy: A mixed methods study

Drug treatment for spinal muscular atrophy types II and III

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