The Need for SMN-Independent Treatments of Spinal Muscular Atrophy (SMA) to Complement SMN-Enhancing Drugs

Abstract

Spinal Muscular Atrophy (SMA) is monogenic motoneuron disease caused by low levels of the Survival of Motoneuron protein (SMN). Recently, two different drugs were approved for the treatment of the disease. The antisense oligonucleotide Nusinersen/Spinraza® and the gene replacement therapy Onasemnogene Abeparvovec/Zolgensma® both enhance SMN levels. These treatments result in impressive benefits for the patients. However, there is a significant number of non-responders and an intervention delay has a strong negative impact on the efficacy. Obviously, later stages of motoneuron degeneration cannot be reversed by SMN-restoration. Therefore, complementary, SMN-independent strategies are needed which are able to address such SMN-irreversible degenerative processes. Those are defined as pathological alterations which are not reversed by SMN-restoration for a given dose and intervention delay. It is crucial to tailor SMN-independent approaches to the novel clinical situation with SMN-restoring treatments. On the molecular level, such SMN-irreversible changes become manifest in altered signaling modules as described by molecular systems biology. Based on our current knowledge about altered signaling, we introduce a network approach for an informed decision for the most potent SMN-independent treatment targets. Finally, we present recommendations for the identification of novel treatments which can be combined with SMN-restoring drugs.

Keywords: SMN-independency; SMN-irreversibility; network biology; neurodegeneration; spinal muscular atrophy; survival of motoneuron (SMN); systems biology; therapy.

Figure 1

Model for motoneuron degeneration and the underlying signaling network in SMA. Motoneuron loss observed in post mortem analyses is preceded by a functional degeneration of central synapses and the neuromuscular junction. The subsequent axonal damage induces a chromatolytic phenotype of the motoneurons. During disease progression those processes become less reversible indicated by a reduced regenerative capacity. This is reflected by a growing network of dysregulated signaling nodes with an increased fraction of SMN-irreversible (black) vs. SMN-reversible (blue) signaling mediators. SMN-restoration restores blue nodes only. The relative number of SMN-restorable nodes becomes reduced over time as illustrated in this hypothetical scheme. Highly connected SMN-irreversible (black) nodes may be potent treatment targets (arrow). Those nodes may be critical regulators for a module involved in a specific degenerative process.