SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy

Rießland, Markus; Ackermann, Bastian; Förster, Anja; Jakubik, Miriam; Hauke, Jan; Garbes, Lutz; Fritzsche, Ina; Mende, Ylva; Blümcke, Ingmar; Hahnen, Eric; Wirth, Brunhilde

doi:10.1093/hmg/ddq023

Cited by 194 publications

(170 citation statements)

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“…Breeding of Smn À/ À ; SMN2 tg/tg with Smn þ / À resulted in 50% SMA (Smn À/ À ; SMN2 tg/0 ) and 50% control carriers (Smn À/ þ ; SMN2 tg/0 ) in each litter. 30 We found that doses of 10 mg/kg daily and 5 mg/kg daily of JNJ-26481585 (dissolved in DMSO) were toxic leading to death before P5 and P8, respectively, irrespective of the genotype. Doses as low as 1.25 mg/kg every 5th day starting at P0 led to a mild improvement of the phenotype as seen by significantly better motor test results at P8 (Po0.001) (Figure 2b) and significantly higher weight at P8, P9 (Po0.001) and P10 (P ¼ 0.01) compared with untreated animals (Figure 2a).…”

Section: Discussionmentioning

confidence: 85%

“…SMA mice are described in detail and were bred as previously reported with 50% of the offspring being SMA mice (Smn À/ À ;SMN2 tg/0 ) and 50% control carriers (Smn À/ þ ;SMN2 tg/0 ). 30 Mice carrying homozygously the SMN2 transgene on exon 7 disrupted murine Smn background (Smn À/ À ; SMN2 tg/tg ) 40 fail to develop any motor SMA phenotype, are fertile and live for 41 year, but develop a short and thickened necrotic tail and necrotic ears. Mice heterozygous for the SMN2 transgene on exon 7 disrupted murine Smn background (Smn À/ À ;SMN2 tg/0 ) developed a severe SMA phenotype with a mean age of survival of B10 days.…”

Section: Micementioning

confidence: 99%

“…Moreover, HDACi treatment has previously been shown to increase SMN2 transcription and to ameliorate the phenotype in SMA mouse models. 27,[29][30][31] However, the clinical benefit of the substances tested to date remains uncertain. 21,[32][33][34][35] A complete rescue of the phenotype by HDACi application is unlikely to be achieved for patients most severely affected and only possessing a low number of SMN2 copies, and thereby restricted potential for increase in FL protein expression.…”

Section: Introductionmentioning

confidence: 99%

“…The remaining 50% are healthy SMA carriers (Smn þ / À ; SMN2 tg/0 ) and used as controls. 30 Recent reports suggest that abnormal heart development in mice and human [41][42][43][44] as well as defects in skeletal muscle 45 and skeletal muscle vasculature 46 of mice are part of the phenotype and that SMA may be not a pure motoneuron disease. In addition, decreased levels of hepatic insulin-like growth factor binding protein acid labile subunit 18 possibly account for some of the dwarfism observed consistently across different SMA mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by a-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of -primary or secondary -non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

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Section: Discussionmentioning

confidence: 85%

Section: Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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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.…”

Section: Sma Treatment: How When and Where?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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