SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that l...

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Veröffentlicht in:Journal of neuromuscular diseases 2017, Vol.4 (1), p.59-66
Hauptverfasser: Iyer, Chitra, Wang, Xueqian, Renusch, Samantha R., Duque, Sandra I., Wehr, Allison M., Mo, Xiaokui-Molly, McGovern, Vicki L., Arnold, W. David, Burghes, Arthur H.M., Kolb, Stephen J.
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container_issue 1
container_start_page 59
container_title Journal of neuromuscular diseases
container_volume 4
creator Iyer, Chitra
Wang, Xueqian
Renusch, Samantha R.
Duque, Sandra I.
Wehr, Allison M.
Mo, Xiaokui-Molly
McGovern, Vicki L.
Arnold, W. David
Burghes, Arthur H.M.
Kolb, Stephen J.
description Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN). Objective: To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. Methods: We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). Results: We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Conclusions: Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies.
doi_str_mv 10.3233/JND-170209
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David ; Burghes, Arthur H.M. ; Kolb, Stephen J.</creator><creatorcontrib>Iyer, Chitra ; Wang, Xueqian ; Renusch, Samantha R. ; Duque, Sandra I. ; Wehr, Allison M. ; Mo, Xiaokui-Molly ; McGovern, Vicki L. ; Arnold, W. David ; Burghes, Arthur H.M. ; Kolb, Stephen J.</creatorcontrib><description>Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN). Objective: To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. Methods: We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). Results: We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Conclusions: Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies.</description><identifier>ISSN: 2214-3599</identifier><identifier>EISSN: 2214-3602</identifier><identifier>DOI: 10.3233/JND-170209</identifier><identifier>PMID: 28269795</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Animals ; Blood levels ; Clinical trials ; Denervation ; Disease Models, Animal ; Female ; Gene deletion ; Gene Knockdown Techniques ; Gene therapy ; Genetic Therapy ; Genetic Vectors ; Humans ; Infants ; Motor neuron diseases ; mRNA ; Muscular Atrophy, Spinal - blood ; Muscular Atrophy, Spinal - genetics ; Peripheral blood ; Pharmacodynamics ; Phenotypes ; Respiration ; RNA, Messenger - blood ; RNA, Small Interfering ; SMN protein ; Spinal muscular atrophy ; Survival of Motor Neuron 1 Protein - blood ; Survival of Motor Neuron 1 Protein - genetics ; Sus scrofa ; Swine</subject><ispartof>Journal of neuromuscular diseases, 2017, Vol.4 (1), p.59-66</ispartof><rights>IOS Press and the authors. 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David</creatorcontrib><creatorcontrib>Burghes, Arthur H.M.</creatorcontrib><creatorcontrib>Kolb, Stephen J.</creatorcontrib><title>SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy</title><title>Journal of neuromuscular diseases</title><addtitle>J Neuromuscul Dis</addtitle><description>Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN). Objective: To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. Methods: We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). Results: We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. 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David</creator><creator>Burghes, Arthur H.M.</creator><creator>Kolb, Stephen J.</creator><general>SAGE Publications</general><general>IOS Press BV</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>2017</creationdate><title>SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy</title><author>Iyer, Chitra ; Wang, Xueqian ; Renusch, Samantha R. ; Duque, Sandra I. ; Wehr, Allison M. ; Mo, Xiaokui-Molly ; McGovern, Vicki L. ; Arnold, W. David ; Burghes, Arthur H.M. ; Kolb, Stephen J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-7dcea70d7df228a2208ded5570f77b4d1fbc11fc51349b35d1c9531b330c48a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Blood levels</topic><topic>Clinical trials</topic><topic>Denervation</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gene deletion</topic><topic>Gene Knockdown Techniques</topic><topic>Gene therapy</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Infants</topic><topic>Motor neuron diseases</topic><topic>mRNA</topic><topic>Muscular Atrophy, Spinal - blood</topic><topic>Muscular Atrophy, Spinal - genetics</topic><topic>Peripheral blood</topic><topic>Pharmacodynamics</topic><topic>Phenotypes</topic><topic>Respiration</topic><topic>RNA, Messenger - blood</topic><topic>RNA, Small Interfering</topic><topic>SMN protein</topic><topic>Spinal muscular atrophy</topic><topic>Survival of Motor Neuron 1 Protein - blood</topic><topic>Survival of Motor Neuron 1 Protein - genetics</topic><topic>Sus scrofa</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iyer, Chitra</creatorcontrib><creatorcontrib>Wang, Xueqian</creatorcontrib><creatorcontrib>Renusch, Samantha R.</creatorcontrib><creatorcontrib>Duque, Sandra I.</creatorcontrib><creatorcontrib>Wehr, Allison M.</creatorcontrib><creatorcontrib>Mo, Xiaokui-Molly</creatorcontrib><creatorcontrib>McGovern, Vicki L.</creatorcontrib><creatorcontrib>Arnold, W. 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David</au><au>Burghes, Arthur H.M.</au><au>Kolb, Stephen J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy</atitle><jtitle>Journal of neuromuscular diseases</jtitle><addtitle>J Neuromuscul Dis</addtitle><date>2017</date><risdate>2017</risdate><volume>4</volume><issue>1</issue><spage>59</spage><epage>66</epage><pages>59-66</pages><issn>2214-3599</issn><eissn>2214-3602</eissn><abstract>Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN). Objective: To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. Methods: We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). Results: We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Conclusions: Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>28269795</pmid><doi>10.3233/JND-170209</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source Sage Journals GOLD Open Access 2024
subjects Animals
Blood levels
Clinical trials
Denervation
Disease Models, Animal
Female
Gene deletion
Gene Knockdown Techniques
Gene therapy
Genetic Therapy
Genetic Vectors
Humans
Infants
Motor neuron diseases
mRNA
Muscular Atrophy, Spinal - blood
Muscular Atrophy, Spinal - genetics
Peripheral blood
Pharmacodynamics
Phenotypes
Respiration
RNA, Messenger - blood
RNA, Small Interfering
SMN protein
Spinal muscular atrophy
Survival of Motor Neuron 1 Protein - blood
Survival of Motor Neuron 1 Protein - genetics
Sus scrofa
Swine
title SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy
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