Abstract
Introduction and ObjectiveSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers.MethodsSMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90.ResultsOf the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO.ConclusionThis study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers.
Highlights
Introduction and ObjectiveSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder
The SMN1 and SMN2 genes differ by a single nucleotide in exon 7 a C to T change which results in alteration of a splice modulator resulting in the exclusion of SMN exon 7 from the majority of the transcript produced by SMN2 [6,7,8,9,10]
SMN levels were increased in all tissues at P12, including peripheral tissues such as liver and muscles, in antisense oligonucleotides (ASO)-SMA in response to P0 ICV administration of ISS-N1 when compared to SMA mice (Fig 1)
Summary
Introduction and ObjectiveSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. Copy number of SMN2 correlates with phenotypic severity, but there are exceptions to the copy number correlation [16,17,18,19,20,21] One reason this can occur is due to the c.859G>C variant in exon 7 of SMN2 which results in increased incorporation of SMN2 exon 7 and increased amount of full length SMN mRNA produced [22,23,24]. This variant has been shown to not occur in type 1 cases, to be present in the heterozygote state with one additional SMN2 copy (2 copy individual) in type 2 cases, and when this variant is present in 2 copies the individual has mild Type 3b SMA This would indicate that approximately a 25% increase in full length SMN from a 2 copy SMN2 SMA individual if given at the required time will result in a normal motor neuron function [25, 26]
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