Therapeutics that directly increase SMN expression to treat spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease and is a leading cause of infantile death. This disease has a carrier frequency of 1:35, affecting 1/6,000 live births and is the result of a homozygous loss of the survival of motor neuron 1 gene (SMN1). Humans carry a nearly identical copy gene, SMN2, that codes for very low levels of the full-length protein, ∼10% when compared to SMN1. This is due to one silent nucleotide transition at the 5' end of exon 7 that disrupts a critical splicing regulatory domain. The underlying protein coding region, however, is unaffected by this and other nucleotide differences between SMN1 and SMN2. SMN2 has, therefore, been envisioned as an outstanding target for therapeutic strategies that 1) increases SMN2 expression, 2) alters the pre-messenger RNA splicing of exon 7 or 3) stabilizes the SMN2-derived protein products. In this review, we summarize numerous therapeutic approaches including nucleic acid-based and drug-oriented therapies that have progressed toward treating SMA.