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Review
. 2017 Aug 1;10(8):943-954.
doi: 10.1242/dmm.030148.

Therapeutic Strategies for Spinal Muscular Atrophy: SMN and Beyond

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Free PMC article
Review

Therapeutic Strategies for Spinal Muscular Atrophy: SMN and Beyond

Melissa Bowerman et al. Dis Model Mech. .
Free PMC article

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

Keywords: Animal models; Cellular models; Combinatorial therapies; Skeletal muscle; Spinal muscular atrophy; Survival motor neuron.

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
SMN1 and SMN2 contribute to spinal muscular atrophy (SMA). In healthy individuals, the survival motor neuron 1 (SMN1) gene produces 100% full length (FL) SMN protein while the SMN2 gene produces ∼10% FL SMN and ∼90% of a non-functional product that lacks exon 7 (SMNΔ7) due to aberrant alternative splicing. In SMA patients, the SMN1 gene is lost due to mutations or deletions. SMN2 remains and the small amount of FL SMN is sufficient for survival. The number of SMN2 copies correlates with disease severity, with a lower copy number being linked to more severe types of SMA.
Fig. 2.
Fig. 2.
Localization of the survival motor neuron (SMN) protein in neuronal cells and associated general cellular functions. SMN regulates small nuclear ribonucleoprotein (snRNP) biogenesis, maturation and recycling in Gemini of coiled bodies (Gems) and Cajal bodies; ribosome biogenesis in nucleolus; snRNP biogenesis and actin dynamics in the cytoplasm; mRNA transport in axons; actin dynamics and vesicle release in the synpase.
Fig. 3.
Fig. 3.
A model experimental plan to determine the therapeutic potential of a candidate non-survival motor neuron (SMN) molecular target or drug, alone and as a combinatorial therapy. Various in vitro and in vivo models such as an in vitro blood-brain barrier (BBB) model, Smn mutant zebrafish, hypomorphic SMA mouse models and induced pluripotent stem cell (iPSC)-dervied cells (e.g. motor neurons) could be used to evaluate different activity and efficiency parameters of the candidate target or drug. Each model system has a particular informative value depending on the candidate target or drug. Finally, the same experimental paradigm should be followed to assess the synergistic or additive value of combining the non-SMN treatment strategy with an SMN-dependent therapy.
Fig. 4.
Fig. 4.
Overview of the natural history of spinal muscular atrophy (SMA), major developmental milestones and treatment strategies. Although the precise details of SMN expression in the developing human nervous system are difficult to study, evidence from animal models suggests that SMN levels peak in the period of maximum neuromuscular development and then decline to a stable low level. This means that there are different windows of opportunity for the various types of proposed therapies to be effectively employed. Whether combinatorial therapies might be particularly applicable in the more chronic phase of SMA or from the outset is a priority area for research. ASO therapy in utero will be dependent on an optimal route of delivery, which at present remains unclear.

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