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: 9.98).
10/2008; 64(4):465-70. DOI: 10.1002/ana.21449
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.
Available from: Hong Liu
- "Soft bedding, water-soaked food cubes and transgel were provided to the pups in TSA- and vehicle-treated groups after weaning at P21. Warm pads were also provided to Smn2B/- pups under the cages from P21 to P25. In order to eliminate the synergistic effects of diet and TSA , mice received a regular diet without any caloric or dietary enhancement. During TSA or vehicle treatment at P12-P25, mice were kept in the surgical surveillance area. "
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ABSTRACT: Spinal muscular atrophy is an autosomal recessive neuromuscular disease characterized by the progressive loss of alpha motor neurons in the spinal cord. Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. It is currently unclear whether TSA specifically targets the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-SMN mediated pathway. TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/- mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Of interest, TSA treatment did not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. In addition, no change in the level of Smn transcripts or protein in the brain or spinal cord of TSA-treated SMA model mice was observed. Furthermore, TSA did not increase Smn protein levels in the hind limb muscle, heart, or liver of Smn2B/- mice. We therefore conclude that TSA likely exerts its effects independent of the endogenous mouse Smn gene. As such, identification of the pathways regulated by TSA in the Smn2B/- mice could lead to the development of novel therapeutics for treating SMA.
Available from: Janice Stricker-Shaver
- "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.
Available from: Matthew D Howell
- "Treatment Process Models used References Histone deacetylase inhibitors Trichostatin A Transcription Δ7 SMA mice   "
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ABSTRACT: Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
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