Mechanisms and SMN-independent therapies for spinal muscular atrophy

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Project Summary Mutations in the Survival of Motor Neuron 1 (SMN1) gene and low levels of its translated product, the SMN protein, provoke the frequently fatal, infantile-onset neuromuscular disorder, spinal muscular atrophy (SMA). Afflicted individuals invariably carry a copy gene, SMN2. However, SMN2 produces only residual protein owing to a splicing defect. Still, given the cause of SMA and the invariable presence of SMN2 in patients, it is not surprising that the copy gene has served as the most common target for the treatment of the disease. The strategy of targeting SMN2 is embodied in one FDA-approved agent, Spinraza®, which restores the SMN protein by correcting the splicing defect in the gene. Small molecule modulators of SMN2 and therapies that exploit viral vectors to directly restore SMN add to the choice of therapeutic agents that replenish the protein to treat patients. While these developments and SMN repletion in general, raise considerable optimism for the treatment of SMA, they have done little to shed light on precisely how SMN paucity preferentially disables the neuromuscular system. Besides, it is still quite uncertain if restoring SMN as currently practiced will be curative or merely delay the onset of disease. Already it is clear that the most effective outcomes require early treatment; symptomatic patients derive considerably less benefit, and it would not be surprising if even pre- symptomatic treatment merely converts a fatal disease into a chronic one. Here we propose experiments that address gaps in our understanding of the basic biology of SMA as a means to better and more assured clinical outcomes. Accordingly, in Aim 1, we wish to identify a novel determinant of the SMA phenotype by exploiting strain-specific differences in model mice that turn a severe form of the disease into a remarkably mild one. We hypothesize that the gene/factor in question is related to a chaperone modifier we have identified and thus likely shares functions with the chaperone in what could imply a novel pathway, synaptic proteostasis, in SMA. In Aim 2, we will focus on the original chaperone modifier with experiments designed to explore its potential as a novel therapeutic target for the treatment of motor neuron disease. We propose that the chaperone, via its effects on proteostasis, potentiates neurotransmission at the neuromuscular synapses of individuals afflicted with SMA. Finally, in Aim 3, we will investigate how reduced SMN in skeletal muscle contributes to the neuromuscular SMA phenotype. We posit that low SMN affects muscle, at least in part, through its effects on resident progenitor cells, disrupting the ability of these cells to self-renew and thus impairing muscle repair and regeneration. If successful, the project will a) identify a novel suppressor of the SMA phenotype, b) reveal a distinct neuromuscular disease-relevant pathway that impacts disorders like SMA and, c) explain how SMN maintains skeletal muscle – the underlying rationale for targeting this tissue to optimally treat the human disease.