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.
Highlights
Spinal Muscular Atrophy (SMA) is a monogenic, autosomal recessive neurodegenerative disease
This leads to an altered splicing of the vast majority of the SMN2 pre-mRNA resulting
An elevation of Survival of Motoneuron protein (SMN) levels in the spinal cord has been a successful strategy for novel therapeutics approved recently. In this state-of-the-art review, we focus on the approved compounds Nusinersen/Spinraza R and Onasemnogene Abeparvovec/Zolgensma R which both enhance SMN levels in the central nervous system (CNS)
Summary
Spinal Muscular Atrophy (SMA) is a monogenic, autosomal recessive neurodegenerative disease. In experimental SMA models, such as SMA mice, it is possible to perform an organ or cell-specific rescue approach which selectively restores SMN protein levels in single cell types.
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