Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.
Highlights
To determine whether the effect of muscle-specific kinase (MuSK) antibody #13 on vulnerable muscles is primarily due to increased innervation, we examined muscle morphometry in the resistant muscles, such as the extensor digitorum longus (EDL) muscle, which is fully innervated at end stage of delta7 mice [15,18]
The Spinal muscular atrophy (SMA) community has witnessed three recent breakthrough gene-targeted treatments for SMA patients: Spinraza, a SMN2-splicing antisense oligonucleotide approved by the US Food and Drug Administration (FDA) in 2016; Zolgensma, an AAV9-mediated gene replacement therapy in 2019; and Evrysdi, a SMN2 splicing modifier small molecule in 2020
All of these three drugs significantly enhance the production of survival motor neuron (SMN) protein levels and show remarkable efficacy in treating SMA patients
Summary
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality when untreated, is a motor neuron disorder caused by deletions or mutations of the survival motor neuron 1 (SMN1) gene [1,2]. The human genome contains one or more copies of a nearly identical SMN2 gene, which differs from SMN1 in a C to T transition at position. 6 of exon 7, altering splicing and leading to exclusion of sequences encoded by exon 7. The. SMN2 protein is less stable and expressed at ~10-fold lower levels than SMN1 protein [3,4]. The copy number of SMN2 is negatively correlated with disease severity and responsible for different SMA subtypes [5], consistent with the idea that SMA is caused by insufficient levels of SMN protein
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