Spinal muscular atrophy: state-of-the-art and therapeutic perspectives.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans caused by degeneration of alpha motor neurons in the anterior horns of the spinal cord. This affects voluntary movements, leading to muscle weakness and atrophy. SMA is caused by homozygous deletions/mutations in the survival motor neuron gene 1 (SMN1). The severity of the phenotype is modulated by the copy number of SMN2 and by other yet unknown factors. SMN2 is affected by a critical non-translational nucleotide exchange in exon 7 that disrupts an exonic splicing enhancer. In consequence SMN2 produces mainly alternatively spliced mRNA that lacks exon 7. Trans-activating factors such as Htra2-beta1, as well as various drugs like sodium butyrate or aclarubicin, are able to restore the full-length SMN2 RNA to large amounts. Since each SMA patient carries at least one SMN2 copy, reconstitution of full-length SMN2 protein is an exciting strategy for somatic gene therapy in SMA patients.