Spinal amyotrophy (SMA) is characterized by the loss of anterior horn motor neurons of the spinal cord causing paralysis. SMA is caused by functional loss of the survival motor neuron gene 1 (SMN1) due to homozygous deletion, gene conversion or subtle mutations. The number of SMN2 copy genes mainly influences the severity of SMA. SMN2 carries a translationally silent mutation that affects splicing of exon 7 and produces only about 10% full-length SMN2 transcript and protein that is identical to the protein encoded by SMN1. The majority of SMN2 transcripts lack exon 7 (SMN2Δ7) and encode a truncated and unstable protein. One therapeutic strategy thus aims to enhance the expression of the SMN2 gene to increase the level of the SMN protein. A study published in July 2006 by German researchers showed that suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, increases the expression of the SMN2 gene and the level of SMN protein in cell cultures of fibroblasts from patients with SMA or rat neurons. In addition, SAHA, which has already been used in clinical trials for cancer, is well tolerated in humans and has good bioavailability when administered orally. It has also been verified that SAHA crosses the blood-brain barrier, which is essential for prospective SMA therapy. In an article published in January 2010, the same researchers have demonstrated the significance of SAHA for the treatment of SMA, this time in two mouse models of SMA. In both models, SAHA prolonged the average life span and improved weight and motor function in treated mice. A decrease in the loss of motoneurons as well as an increase in the size of neuromuscular junctions and muscle fibres was also observed. Last but not least, the treatment allowed an increased expression of SMN in the spinal cord and muscles.

Références : SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy.
Hum Mol Genet. 2010 Feb 8. [Epub ahead of print]