SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy.
Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder determined by functional impairment of alpha-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(-/-);SMN2(tg/tg)) and Taiwanese-SMA mice with two SMN2 per allele (Smn(-/-);SMN2(tg/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(-/-);SMN2(tg/tg) x Smn(-/+) mice), we obtained 50% SMA offspring that survive approximately 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.
Riessland
Markus
M
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Ackermann
Bastian
B
Förster
Anja
A
Jakubik
Miriam
M
Hauke
Jan
J
Garbes
Lutz
L
Fritzsche
Ina
I
Mende
Ylva
Y
Blumcke
Ingmar
I
Hahnen
Eric
E
Wirth
Brunhilde
B
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007558:Italy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D010641:Phenotype; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism; D000077337:Vorinostat
D006877:Hydroxamic Acids; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000077337:Vorinostat