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riluzole), creatine to improve energy metabolism, and albuterol for its anabolic properties and the molecular effect on SMN2 gene expression [58]. Preliminary therapeutic efforts have been dominated by drugs targeting to the modulation of SMN2 pre-mRNA splicing, aimed at increasing SMN-fl levels, or to the enhancement of SMN2 promoter activity. An alternative therapeutic strategy is based on the use of antisense oligonucleotides (ASOs) targeting the 3’ splice site (ss) of exon 8 [59] and inhibiting the function of a negative splicing regulator (E1) within intron 6. The antisense strategy has further evolved by the development of alternative chemistries and through the incorporation of an untethered binding platform for positively acting splicing factors to the SMN2 exon 7 region. This has been accomplished by combining the antisense region with either a covalently bound synthetic peptide or with a non-complementary ESE (exon splicing enhancer) sequence acting as a binding platform for SR proteins (bifunctional RNAs) [60]. Similar to the synthetic RNAs, bifunctional RNAs may be expressed from AAV vectors, leading to increased SMN protein levels in cell-based models [61]. Following extensive high throughput screening of SMN promoter-activating compounds, novel quinazoline derivatives were recently developed, which not only increased SMN in vitro, but also improved the SMA phenotype in the SMNΔ7 mouse model [62,63].
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