Dataset Information

Normalization of Patient-Identified Plasma Biomarkers in SMN?7 Mice following Postnatal SMN Restoration.

ABSTRACT:

Introduction and objective

Spinal 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 SMN?7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers.

Methods

SMN?7 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.

Results

Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMN?7 mice compared to control mice and were normalized in SMN?7 mice treated with ASO.

Conclusion

This 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.

SUBMITTER: Arnold WD

PROVIDER: S-EPMC5132001 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration.

Arnold W David WD Duque Sandra S Iyer Chitra C CC Zaworski Phillip P McGovern Vicki L VL Taylor Shannon J SJ von Herrmann Katharine M KM Kobayashi Dione T DT Chen Karen S KS Kolb Stephen J SJ Paushkin Sergey V SV Burghes Arthur H M AH

PloS one 20161201 12

<h4>Introduction and objective</h4>Spinal 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 plas ...[more]

PMID: 27907033

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