Spinal muscular atrophy: from tissue specificity to therapeutic strategies

Abstract

Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value.

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.

Figure 2.. Cell type diversity of requirement for survival motor neuron

Although spinal muscular atrophy (SMA) has long been considered a disease affecting primarily motor neurons, studies in animal models have demonstrated that multiple cell types are affected and may contribute to SMA pathogenesis. Selective restoration of survival motor neuron (SMN) in specific cell types in SMA mouse models has been a powerful tool used to determine the cell type-specific effects of low SMN. Restoring SMN expression selectively in motor neurons provides a relatively modest benefit, while restoring SMN in all neurons provides a dramatic phenotypic rescue. Additionally, it has been demonstrated that loss of proprioceptive afferents precedes motor neuron loss and may induce electrophysiological deficits in motor neurons. These experiments suggest that non-cell autonomous disease mechanisms within the motor circuit contribute substantially to SMA pathogenesis. In addition to synaptic deficits, altered myelination and reactive astrocytes may contribute to motor neuron loss in SMA. An important consideration in the development of potential therapies for SMA is to design treatments that target the cell types most relevant to disease progression. Abbreviations: GFAP, glial fibrillary acidic protein.