Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design

Tiziano, Francesco Danilo; Lomastro, Rosa; Pinto, Anna Maria; Messina, Sonia; D’Amico, Adele; Fiori, Stefania; Angelozzi, Carla; Pane, Marika; Mercuri, Eugenio; Bertini, Enrico; Neri, Giovanni; Brahe, Cristina Beate

doi:10.1136/jmg.2010.080366

Cited by 65 publications

(49 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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“…The different technical approaches utilized are analyzed in detail throughout this section. [121][122][123][124][125][126][127] A greater number of studies belong to the second category, as the majority of therapeutic approaches have aimed to increase SMN protein levels by increasing the level of SMN transcripts. An exception to this transcript ''rule'' is the modification of SMN protein stability, 117 where a change in SMN transcript levels is not expected.…”

Section: Smn Transcript Assaysmentioning

confidence: 99%

Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

Cherry

Kobayashi

Lynes

et al. 2014

ASSAY and Drug Development Technologies

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“…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]. Tiziano et al [117] reported that oral administration of salbutamol (albuterol) for 6 months, [7]. Some interesting and promising data show that these stem cell-derived motor neurons can grow axons and form neuromuscular junctions in preclinical experiments [123,124].…”

Section: Thyrotropin Releasing Hormone (Trh) Hasmentioning

confidence: 99%

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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Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design

Abstract: The data strongly support salbutamol as a candidate for treating SMA, and suggest that SMN2 copy number may predict the molecular response to treatment and may be a useful randomisation parameter in a double blind placebo controlled clinical trial design.

Cited by 65 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

Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

Treatment strategies for spinal muscular atrophy

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