Figure 1. Therapeutic strategies in spinal muscular atrophy.

The predominant therapeutic approach in spinal muscular atrophy (SMA) is to increase the amount of full-length survival motor neuron (SMN) protein, by promoting greater inclusion of exon seven in transcripts from Smn2 or by over-expressing full-length SMN complementary DNA. Both approaches have been shown to provide striking rescue of neuromuscular phenotype and survival when applied early in preclinical mouse models. To prepare for the possibility that SMN-targeted therapies may not prove fully effective in all patients, other strategies are being evaluated in parallel. One involves correcting the downstream effects of SMN deficiency, such as splicing defects in specific transcripts required for neuromuscular integrity. Another, which was recently reported to show benefit in SMA patients, is to identify neuroprotective agents that can prevent or slow motor neuron death in an SMN-independent manner or stimulate the regeneration of motor circuits. It is likely that a combination of such approaches will be required to completely address the needs of all SMA patients.

Abbreviations: AAV, adeno-associated virus; ANT, adenine nucleotide translocator; ASO, antisense oligonucleotide; CypD, cyclophilin D; SMN, survival motor neuron; SMN2, survival motor neuron 2; SNARE, soluble NSF-attachment protein (SNAP) receptors; VDAC, voltage-gated anion channel.