Cargando…
Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration
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...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132001/ https://www.ncbi.nlm.nih.gov/pubmed/27907033 http://dx.doi.org/10.1371/journal.pone.0167077 |
_version_ | 1782470982335725568 |
---|---|
author | Arnold, W. David Duque, Sandra Iyer, Chitra C. Zaworski, Phillip McGovern, Vicki L. Taylor, Shannon J. von Herrmann, Katharine M. Kobayashi, Dione T. Chen, Karen S. Kolb, Stephen J. Paushkin, Sergey V. Burghes, Arthur H. M. |
author_facet | Arnold, W. David Duque, Sandra Iyer, Chitra C. Zaworski, Phillip McGovern, Vicki L. Taylor, Shannon J. von Herrmann, Katharine M. Kobayashi, Dione T. Chen, Karen S. Kolb, Stephen J. Paushkin, Sergey V. Burghes, Arthur H. M. |
author_sort | Arnold, W. David |
collection | PubMed |
description | 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 SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers. METHODS: SMNΔ7 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 SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 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. |
format | Online Article Text |
id | pubmed-5132001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-51320012016-12-21 Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration Arnold, W. David Duque, Sandra Iyer, Chitra C. Zaworski, Phillip McGovern, Vicki L. Taylor, Shannon J. von Herrmann, Katharine M. Kobayashi, Dione T. Chen, Karen S. Kolb, Stephen J. Paushkin, Sergey V. Burghes, Arthur H. M. PLoS One Research Article 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 SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers. METHODS: SMNΔ7 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 SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 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. Public Library of Science 2016-12-01 /pmc/articles/PMC5132001/ /pubmed/27907033 http://dx.doi.org/10.1371/journal.pone.0167077 Text en © 2016 Arnold et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Arnold, W. David Duque, Sandra Iyer, Chitra C. Zaworski, Phillip McGovern, Vicki L. Taylor, Shannon J. von Herrmann, Katharine M. Kobayashi, Dione T. Chen, Karen S. Kolb, Stephen J. Paushkin, Sergey V. Burghes, Arthur H. M. Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title | Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title_full | Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title_fullStr | Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title_full_unstemmed | Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title_short | Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration |
title_sort | normalization of patient-identified plasma biomarkers in smnδ7 mice following postnatal smn restoration |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132001/ https://www.ncbi.nlm.nih.gov/pubmed/27907033 http://dx.doi.org/10.1371/journal.pone.0167077 |
work_keys_str_mv | AT arnoldwdavid normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT duquesandra normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT iyerchitrac normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT zaworskiphillip normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT mcgovernvickil normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT taylorshannonj normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT vonherrmannkatharinem normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT kobayashidionet normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT chenkarens normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT kolbstephenj normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT paushkinsergeyv normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration AT burghesarthurhm normalizationofpatientidentifiedplasmabiomarkersinsmnd7micefollowingpostnatalsmnrestoration |