In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele
Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wi...
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| Veröffentlicht in: | Human gene therapy 2011, Vol.22 (1), p.27-34 |
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| creator | KUBODERA, Takayuki YAMADA, Hiromi YOKOTA, Takanori ANZAI, Masayuki OHIRA, Shinga YOKOTA, Shigefumi HIRAI, Yukihiko MOCHIZUKI, Hideki SHIMADA, Takashi MITANI, Tasuku MIZUSAWA, Hidehiro |
| description | Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our method may prove useful for siRNA-based gene therapy for dominantly inherited diseases. |
| doi_str_mv | 10.1089/hum.2010.054 |
| format | Article |
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We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our method may prove useful for siRNA-based gene therapy for dominantly inherited diseases.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2010.054</identifier><identifier>PMID: 20649474</identifier><identifier>CODEN: HGTHE3</identifier><language>eng</language><publisher>Larchmont, NY: Liebert</publisher><subject>Alleles ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - metabolism ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Applied cell therapy and gene therapy ; Biological and medical sciences ; Biotechnology ; Disease Models, Animal ; Fundamental and applied biological sciences. Psychology ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors - genetics ; Health. Pharmaceutical industry ; Humans ; Industrial applications and implications. Economical aspects ; Liver - physiopathology ; Medical sciences ; Mice ; Mice, Transgenic ; Mutation ; RNA Interference ; RNA, Messenger - genetics ; RNA, Small Interfering - metabolism ; Superoxide Dismutase - genetics ; Superoxide Dismutase-1 ; Transfection ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><ispartof>Human gene therapy, 2011, Vol.22 (1), p.27-34</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-b02caf6608dc0d8fc2e3be3a042387e199d7d316a7c297ceebcea87085d7f0b63</citedby><cites>FETCH-LOGICAL-c418t-b02caf6608dc0d8fc2e3be3a042387e199d7d316a7c297ceebcea87085d7f0b63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4009,27902,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23919071$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20649474$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KUBODERA, Takayuki</creatorcontrib><creatorcontrib>YAMADA, Hiromi</creatorcontrib><creatorcontrib>YOKOTA, Takanori</creatorcontrib><creatorcontrib>ANZAI, Masayuki</creatorcontrib><creatorcontrib>OHIRA, Shinga</creatorcontrib><creatorcontrib>YOKOTA, Shigefumi</creatorcontrib><creatorcontrib>HIRAI, Yukihiko</creatorcontrib><creatorcontrib>MOCHIZUKI, Hideki</creatorcontrib><creatorcontrib>SHIMADA, Takashi</creatorcontrib><creatorcontrib>MITANI, Tasuku</creatorcontrib><creatorcontrib>MIZUSAWA, Hidehiro</creatorcontrib><title>In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our method may prove useful for siRNA-based gene therapy for dominantly inherited diseases.</description><subject>Alleles</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Applied cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Disease Models, Animal</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - genetics</subject><subject>Health. Pharmaceutical industry</subject><subject>Humans</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Liver - physiopathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>RNA Interference</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase-1</subject><subject>Transfection</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0ElLxTAQwPEgivvNs-QiXqxOljbJ8SFu4AJueCtpOtVKX1uTVPDbG_GpR0-ZwC8D-ROyw-CQgTZHL9P8kEO6QS6XyDrLc5UpyflymkGKDITka2QjhFcAJvJCrZI1DoU0Usl18nTR08f2faCzcexaZ2M79HRoqO3p7fWspXfR24jPH7QZPI0vSO-wQxfb9zRN4-gxhJ8X9GqKto901nXJbJGVxnYBtxfnJnk4Pbk_Ps8ub84ujmeXmZNMx6wC7mxTFKBrB7VuHEdRobAgudAKmTG1qgUrrHLcKIdYObRagc5r1UBViE2y_7139MPbhCGW8zY47Drb4zCFUqcf69yA_l_KwgA3RiR58C2dH0Lw2JSjb-fWf5QMyq_oZYpefkUvU_TEdxeLp2qO9S_-qZzA3gLY4GzXeNu7Nvw5YZgBxcQnHsGJdQ</recordid><startdate>2011</startdate><enddate>2011</enddate><creator>KUBODERA, Takayuki</creator><creator>YAMADA, Hiromi</creator><creator>YOKOTA, Takanori</creator><creator>ANZAI, Masayuki</creator><creator>OHIRA, Shinga</creator><creator>YOKOTA, Shigefumi</creator><creator>HIRAI, Yukihiko</creator><creator>MOCHIZUKI, Hideki</creator><creator>SHIMADA, Takashi</creator><creator>MITANI, Tasuku</creator><creator>MIZUSAWA, Hidehiro</creator><general>Liebert</general><scope>IQODW</scope><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>7X8</scope><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>2011</creationdate><title>In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele</title><author>KUBODERA, Takayuki ; YAMADA, Hiromi ; YOKOTA, Takanori ; ANZAI, Masayuki ; OHIRA, Shinga ; YOKOTA, Shigefumi ; HIRAI, Yukihiko ; MOCHIZUKI, Hideki ; SHIMADA, Takashi ; MITANI, Tasuku ; MIZUSAWA, Hidehiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-b02caf6608dc0d8fc2e3be3a042387e199d7d316a7c297ceebcea87085d7f0b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alleles</topic><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Applied cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Disease Models, Animal</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - genetics</topic><topic>Health. Pharmaceutical industry</topic><topic>Humans</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>Liver - physiopathology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>RNA Interference</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase-1</topic><topic>Transfection</topic><topic>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KUBODERA, Takayuki</creatorcontrib><creatorcontrib>YAMADA, Hiromi</creatorcontrib><creatorcontrib>YOKOTA, Takanori</creatorcontrib><creatorcontrib>ANZAI, Masayuki</creatorcontrib><creatorcontrib>OHIRA, Shinga</creatorcontrib><creatorcontrib>YOKOTA, Shigefumi</creatorcontrib><creatorcontrib>HIRAI, Yukihiko</creatorcontrib><creatorcontrib>MOCHIZUKI, Hideki</creatorcontrib><creatorcontrib>SHIMADA, Takashi</creatorcontrib><creatorcontrib>MITANI, Tasuku</creatorcontrib><creatorcontrib>MIZUSAWA, Hidehiro</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KUBODERA, Takayuki</au><au>YAMADA, Hiromi</au><au>YOKOTA, Takanori</au><au>ANZAI, Masayuki</au><au>OHIRA, Shinga</au><au>YOKOTA, Shigefumi</au><au>HIRAI, Yukihiko</au><au>MOCHIZUKI, Hideki</au><au>SHIMADA, Takashi</au><au>MITANI, Tasuku</au><au>MIZUSAWA, Hidehiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2011</date><risdate>2011</risdate><volume>22</volume><issue>1</issue><spage>27</spage><epage>34</epage><pages>27-34</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><coden>HGTHE3</coden><abstract>Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our method may prove useful for siRNA-based gene therapy for dominantly inherited diseases.</abstract><cop>Larchmont, NY</cop><pub>Liebert</pub><pmid>20649474</pmid><doi>10.1089/hum.2010.054</doi><tpages>8</tpages></addata></record> |
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| subjects | Alleles Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Applied cell therapy and gene therapy Biological and medical sciences Biotechnology Disease Models, Animal Fundamental and applied biological sciences. Psychology Gene therapy Genetic Therapy - methods Genetic Vectors - genetics Health. Pharmaceutical industry Humans Industrial applications and implications. Economical aspects Liver - physiopathology Medical sciences Mice Mice, Transgenic Mutation RNA Interference RNA, Messenger - genetics RNA, Small Interfering - metabolism Superoxide Dismutase - genetics Superoxide Dismutase-1 Transfection Transfusions. Complications. Transfusion reactions. Cell and gene therapy |
| title | In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele |
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