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 |
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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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fullrecord | <record><control><sourceid>proquest_AFRWT</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5531281</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.3233_JND-170209</sage_id><sourcerecordid>1875400892</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3539-7dcea70d7df228a2208ded5570f77b4d1fbc11fc51349b35d1c9531b330c48a53</originalsourceid><addsrcrecordid>eNplkdtKAzEQhoMoVqo3PoAEvFCE1Rw2zeZG8HygrUL1OmSTrK6km5p0C317Iz3g4WoG5uObGX4A9jE6pYTSs8fhdYY5IkhsgB1CcJ7RHiKbq54J0QF7MX4ghDAvKENiG3RIQXqCC7YDzkeDIbx03hvYtzPrIqwbqOCzD7puLBx4Yx30FRxN6kY5OGijbp0K8GIa_OR9vgu2KuWi3VvWLni9vXm5us_6T3cPVxf9TFNGRcaNtoojw01FSKEIQYWxhjGOKs7L3OCq1BhXmmGai5Iyg7VgFJeUIp0XitEuOF94J205tsnWTINychLqsQpz6VUtf0-a-l2--ZlkSUMKnATHS0Hwn62NUzmuo7bOqcb6NkpccJYjVAiS0MM_6IdvQ_o-UUIkCBFBE3WyoHTwMQZbrY_BSH4nI1MycpFMgg9-nr9GVzkk4GgBRPVmf-z7r_oCH3ySpg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1994000293</pqid></control><display><type>article</type><title>SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy</title><source>Sage Journals GOLD Open Access 2024</source><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.</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. All rights reserved</rights><rights>Copyright IOS Press BV 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-7dcea70d7df228a2208ded5570f77b4d1fbc11fc51349b35d1c9531b330c48a53</citedby><cites>FETCH-LOGICAL-c3539-7dcea70d7df228a2208ded5570f77b4d1fbc11fc51349b35d1c9531b330c48a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.3233/JND-170209$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.3233/JND-170209$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>230,314,780,784,885,4024,21966,27853,27923,27924,27925,44945,45333</link.rule.ids><linktorsrc>$$Uhttps://journals.sagepub.com/doi/full/10.3233/JND-170209?utm_source=summon&utm_medium=discovery-provider$$EView_record_in_SAGE_Publications$$FView_record_in_$$GSAGE_Publications</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28269795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><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. 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.
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><subject>Animals</subject><subject>Blood levels</subject><subject>Clinical trials</subject><subject>Denervation</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene deletion</subject><subject>Gene Knockdown Techniques</subject><subject>Gene therapy</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Infants</subject><subject>Motor neuron diseases</subject><subject>mRNA</subject><subject>Muscular Atrophy, Spinal - blood</subject><subject>Muscular Atrophy, Spinal - genetics</subject><subject>Peripheral blood</subject><subject>Pharmacodynamics</subject><subject>Phenotypes</subject><subject>Respiration</subject><subject>RNA, Messenger - blood</subject><subject>RNA, Small Interfering</subject><subject>SMN protein</subject><subject>Spinal muscular atrophy</subject><subject>Survival of Motor Neuron 1 Protein - blood</subject><subject>Survival of Motor Neuron 1 Protein - genetics</subject><subject>Sus scrofa</subject><subject>Swine</subject><issn>2214-3599</issn><issn>2214-3602</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNplkdtKAzEQhoMoVqo3PoAEvFCE1Rw2zeZG8HygrUL1OmSTrK6km5p0C317Iz3g4WoG5uObGX4A9jE6pYTSs8fhdYY5IkhsgB1CcJ7RHiKbq54J0QF7MX4ghDAvKENiG3RIQXqCC7YDzkeDIbx03hvYtzPrIqwbqOCzD7puLBx4Yx30FRxN6kY5OGijbp0K8GIa_OR9vgu2KuWi3VvWLni9vXm5us_6T3cPVxf9TFNGRcaNtoojw01FSKEIQYWxhjGOKs7L3OCq1BhXmmGai5Iyg7VgFJeUIp0XitEuOF94J205tsnWTINychLqsQpz6VUtf0-a-l2--ZlkSUMKnATHS0Hwn62NUzmuo7bOqcb6NkpccJYjVAiS0MM_6IdvQ_o-UUIkCBFBE3WyoHTwMQZbrY_BSH4nI1MycpFMgg9-nr9GVzkk4GgBRPVmf-z7r_oCH3ySpg</recordid><startdate>2017</startdate><enddate>2017</enddate><creator>Iyer, Chitra</creator><creator>Wang, Xueqian</creator><creator>Renusch, Samantha R.</creator><creator>Duque, Sandra I.</creator><creator>Wehr, Allison M.</creator><creator>Mo, Xiaokui-Molly</creator><creator>McGovern, Vicki L.</creator><creator>Arnold, W. 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. David</creatorcontrib><creatorcontrib>Burghes, Arthur H.M.</creatorcontrib><creatorcontrib>Kolb, Stephen J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neuromuscular diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Iyer, Chitra</au><au>Wang, Xueqian</au><au>Renusch, Samantha R.</au><au>Duque, Sandra I.</au><au>Wehr, Allison M.</au><au>Mo, Xiaokui-Molly</au><au>McGovern, Vicki L.</au><au>Arnold, W. 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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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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