Therapeutic targets for spinal muscular atrophy : Inhibiting the inhibitors

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is a leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1: 6,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). A human-specific copy gene is present on the same region of chromosome 5q called SMN2. SMN2 is nearly identical to SMN1; however, mutations in SMN2 have no clinical consequence if SMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated and unstable protein. The presence of SMN2 in all SMA patients is fundamental to the biology of the disease; however, from a translational perspective, targeting SMN2 may prove to be the most important therapeutic opportunity for all patients. The presence of SMN2 opens the door to a number of exciting therapeutic strategies, including anti-sense oligonucleotides (ASOs) that prevent the pathogenic SMN2 splicing event. Our efforts are focused on several repressor regions upstream and downstream of SMN2 exon 7. Importantly, when manipulating these repressor regions, hallmarks of the disease at the cellular level such as neuromuscular junction pathology in various SMA animal models are corrected. Currently, there are no approved SMA-specific compounds, and developing a broad array of therapeutic strategies to address this complex disease is essential. The development and design of highly-potent ASOs provide novel molecular targets for SMA therapeutics that can dramatically improve disease phenotype and extend patients' life span.