Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug-drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.
Highlights
Spinal muscular atrophy (SMA) afflicts ~1 in 6,000–10,000 live births, and half succumb within 2 yr (Verhaart et al, 2017)
We hypothesize that the human survival motor neuron (SMN) proteins expressed in the Het control mice are increased by mouse SMN proteins because of the oligomerization properties of SMN (Lorson et al, 1998) and/or through increased SMN exon 7 incorporation due to higher SMN protein levels (Jodelka et al, 2010; Ruggiu et al, 2012)
We show that a 30-times lower dose of NVS-SM2 administered daily s.c. for five consecutive days, increased brain SMN protein by 4.5-fold in severe SMA and Het mice
Summary
Spinal muscular atrophy (SMA) afflicts ~1 in 6,000–10,000 live births, and half succumb within 2 yr (Verhaart et al, 2017). The SMN1 gene, located on human chromosome 5q13.2, is duplicated, resulting in the nearly identical SMN2 gene possessing a nucleotide transition (C → T) in exon 7, causing exon skipping and loss of the terminal 17 amino acids of the SMN protein (Lefebvre et al, 1995; Lorson et al, 1999; Monani et al, 1999). Some patients did not respond to treatment, and there is a strong inverse correlation between the age at which treatment began and efficacy (Dangouloff & Servais, 2019) This highlights the need for co-therapy investigation, as one SMN-modifying agent may not be sufficient to completely improve motor skills and disease severity
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