Sustained Improvement of Spinal Muscular Atrophy Mice Treated with Trichostatin A Plus Nutrition

Animal Care Division, National Institute of Neurological Disorders and Stroke, National Institute of Health, Johns Hopkins University, Baltimore, MD 21287, USA.
Annals of Neurology (Impact Factor: 11.91). 10/2008; 64(4):465-70. DOI: 10.1002/ana.21449
Source: PubMed

ABSTRACT Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients.

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    • "The delivery of SMN using scAAV9 at different postnatal stages in SMND7 mice demonstrated that, while P10 administration was not effective and P5 administration showed marginal survival extension, P1 administration significantly extended the lifespan of the transgenic mice to over 250 days (Fig. 4) (Foust et al., 2010). Another study showed that, by delivering compounds at different developmental stages (Narver et al., 2008; Butchbach et al., 2010), early but not late embryonic restoration of SMN by two inducible SMN alleles rescued lethality (Hammond et al., 2010; Sleigh et al., 2011). In addition, mouse models of differing severities show similar degrees of motor neuron loss, which indicates that the developmental stage at which degeneration occurs is a key determinant of disease progression (Sleigh et al., 2011). "
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    ABSTRACT: Spinal Muscular Atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade and gene delivery to the central nervous system by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) being amongst the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favourable and have been at the fore of this evolution of potential gene therapies and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialisation of the first gene therapies for diseases, such as pancreatitis in the form of Glybera®, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors which can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavour to highlight both the promising results which may be applicable to various associated diseases and also discuss the potential to overcome present limitations.
    Human gene therapy 05/2014; 25(7). DOI:10.1089/hum.2013.186 · 3.62 Impact Factor
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    • "Compounds that have been shown to increase SMN2 expression include various histone deacetylase (HDAC) inhibitors, aclarubicin , indoprofen, splicing modifiers, a DcpS inhibitor, anti‐ terminators, proteasome inhibitors and inhibitors of multiple signalling pathways (Andreassi et al, 2001; Avila et al, 2007; Bowerman et al, 2010, 2012; Burnett et al, 2009; Chen et al, 2012; Farooq et al, 2009; Garbes et al, 2009; Hahnen et al, 2006; Hastings et al, 2009; Heier & DiDonato, 2009; Jarecki et al, 2005; Kernochan et al, 2005; Kwon et al, 2011; Lunn et al, 2004; Makhortova et al, 2011; Narver et al, 2008; Singh et al, 2008; Wolstencroft et al, 2005; Zhang et al, 2001, 2011). Because many of these activators are non‐specific and can have off‐target effects, their long‐term safety remains to be determined. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.
    EMBO Molecular Medicine 07/2013; 5(7). DOI:10.1002/emmm.201202305 · 8.25 Impact Factor
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    • "Phenotypic end-points in severe SMA mouse models closely mirror SMA pathology in patients, particularly Type1 SMA. However, the progressive nature of these phenotypes, increased fetal expression of SMN and the general observation that SMA phenotypes can be most effectively rescued by adding back full length SMN perinatally, suggest that defining events in SMA pathology might occur at very early stages of development (Baumer et al., 2009; Burlet et al., 1998; Butchbach et al., 2010; Foust et al., 2010; Gabanella et al., 2005; Hammond et al., 2010; Murray et al., 2010; Narver et al., 2008). Thus, obvious target tissues in SMA such as motor neurons and muscle might be exquisitely susceptible to a reduction in SMN function such that subtle defects in neuromuscular development or physiology are the first to appear at these loci – consistent with the threshold hypothesis for SMA (Sleigh et al., 2011). "
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    ABSTRACT: Severe reduction in Survival Motor Neuron 1 (SMN1) protein in humans causes Spinal Muscular Atrophy (SMA), a debilitating childhood disease that leads to progressive impairment of the neuro-muscular system. Although previous studies have attempted to identify the tissue(s) in which SMN1 loss most critically leads to disease, tissue-specific functions for this widely expressed protein still remain unclear. Here, we have leveraged RNA interference methods to manipulate SMN function selectively in Drosophila neurons or muscles followed by behavioral and electrophysiological analysis. High resolution measurement of motor performance shows profound alterations in locomotor patterns following pan-neuronal knockdown of SMN. Further, locomotor phenotypes can be elicited by SMN knockdown in motor neurons, supporting previous demonstrations of motor neuron-specific SMN function in mice. Electrophysiologically, SMN modulation in muscles reveals largely normal synaptic transmission, quantal release and trans-synaptic homeostatic compensation at the larval neuro-muscular junction. Neuronal SMN knockdown does not alter baseline synaptic transmission, the dynamics of synaptic depletion or acute homeostatic compensation. However, chronic glutamate receptor-dependent developmental homeostasis at the neuro-muscular junction is strongly attenuated following reduction of SMN in neurons. Together, these results support a distributed model of SMN function with distinct neuron-specific roles that are likely to be compromised following global loss of SMN in patients. While complementary to, and in broad agreement with, recent mouse studies that suggest a strong necessity for SMN in neurons, our results uncover a hitherto under-appreciated role for SMN in homeostatic regulatory mechanisms at motor synapses.
    Brain research 10/2012; 1489. DOI:10.1016/j.brainres.2012.10.035 · 2.83 Impact Factor
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