Human Molecular Genetics Advance Access originally published online on January 22, 2010
Human Molecular Genetics 2010 19(8):1492-1506; doi:10.1093/hmg/ddq023
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy
1 Institute of Human Genetics, 2 Institute of Genetics, 3 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany and 4 Department of Neuropathology, University of Erlangen, Erlangen, Germany
* To whom correspondence should be addressed at: Institute of Human Genetics, University of Cologne, Kerpener Str. 34 50931 Cologne, Germany. Tel: +49 22147886464; Fax: +49 22147886465; Email: brunhilde.wirth{at}uk-koeln.de
Received November 18, 2009; Revised December 21, 2009; Accepted January 19, 2010
Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder determined by functional impairment of 
-motor neurons within the spinal cord. SMA is caused by functional loss of the survival motor neuron gene 1 (SMN1), whereas disease severity is mainly influenced by the number of SMN2 copies. SMN2, which produces only low levels of full-length mRNA/protein, can be modulated by small molecules and drugs, thus offering a unique possibility for SMA therapy. Here, we analysed suberoylanilide hydroxamic acid (SAHA), a FDA-approved histone deacetylase inhibitor, as potential drug in two severe SMA mouse models each carrying two SMN2 transgenes: US-SMA mice with one SMN2 per allele (Smn–/–;SMN2tg/tg) and Taiwanese-SMA mice with two SMN2 per allele (Smn–/–;SMN2tg/wt), both on pure FVB/N background. The US-SMA mice were embryonically lethal with heterozygous males showing significantly reduced fertility. SAHA treatment of pregnant mothers rescued the embryonic lethality giving rise to SMA offspring. By using a novel breeding strategy for the Taiwanese model (Smn–/–;SMN2tg/tg x Smn–/+ mice), we obtained 50% SMA offspring that survive 
10 days and 50% control carriers in each litter. Treatment with 25 mg/kg twice daily SAHA increased lifespan of SMA mice by 30%, significantly improved motor function abilities, reduced degeneration of motor neurons within the spinal cord and increased the size of neuromuscular junctions and muscle fibers compared with vehicle-treated SMA mice. SMN RNA and protein levels were significantly elevated in various tissues including spinal cord and muscle. Hence, SAHA, which lessens the progression of SMA, might be suitable for SMA therapy.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. T. Gladman, T. W. Bebee, C. Edwards, X. Wang, Z. Sahenk, M. M. Rich, and D. S. Chandler A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype Hum. Mol. Genet., August 27, 2010; (2010) ddq343v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Heier, R. Satta, C. Lutz, and C. J. DiDonato Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice Hum. Mol. Genet., August 18, 2010; (2010) ddq330v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hua, K. Sahashi, G. Hung, F. Rigo, M. A. Passini, C. F. Bennett, and A. R. Krainer Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model Genes & Dev., August 1, 2010; 24(15): 1634 - 1644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Lorson, H. Rindt, and M. Shababi Spinal muscular atrophy: mechanisms and therapeutic strategies Hum. Mol. Genet., April 28, 2010; (2010) ddq147v2. [Abstract] [Full Text] [PDF]
|
|