Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo
Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate in...
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| Veröffentlicht in: | Molecular therapy 2006-03, Vol.13 (3), p.494-505 |
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| creator | Judge, Adam D Bola, Gurneet Lee, Amy C H MacLachlan, Ian |
| description | Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas. |
| doi_str_mv | 10.1016/j.ymthe.2005.11.002 |
| format | Article |
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However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2005.11.002</identifier><identifier>PMID: 16343994</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Animals ; Apolipoproteins ; Cells, Cultured ; Cytokines ; DNA Methylation ; Drug dosages ; Gene Silencing - immunology ; Gene therapy ; Humans ; Immune system ; Immunosuppressive Agents - administration & dosage ; Immunosuppressive Agents - chemical synthesis ; Inflammation Mediators - administration & dosage ; Inflammation Mediators - chemical synthesis ; Inflammation Mediators - physiology ; Interferon ; Kinases ; Leukocytes, Mononuclear - metabolism ; Leukocytes, Mononuclear - pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred ICR ; Molecular Sequence Data ; RNA Interference - immunology ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - chemical synthesis ; RNA, Small Interfering - physiology ; Toxicity ; Tumor necrosis factor-TNF ; Vehicles</subject><ispartof>Molecular therapy, 2006-03, Vol.13 (3), p.494-505</ispartof><rights>Copyright Nature Publishing Group Mar 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c407t-7e401aa083f23a687c48a9bb24a79a1af246a8ceaef140c12e322c19fb0e214d3</citedby><cites>FETCH-LOGICAL-c407t-7e401aa083f23a687c48a9bb24a79a1af246a8ceaef140c12e322c19fb0e214d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1792806692?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,782,786,27933,27934,64394,64396,64398,72478</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16343994$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Judge, Adam D</creatorcontrib><creatorcontrib>Bola, Gurneet</creatorcontrib><creatorcontrib>Lee, Amy C H</creatorcontrib><creatorcontrib>MacLachlan, Ian</creatorcontrib><title>Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.</description><subject>Animals</subject><subject>Apolipoproteins</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>DNA Methylation</subject><subject>Drug dosages</subject><subject>Gene Silencing - immunology</subject><subject>Gene therapy</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunosuppressive Agents - administration & dosage</subject><subject>Immunosuppressive Agents - chemical synthesis</subject><subject>Inflammation Mediators - administration & dosage</subject><subject>Inflammation Mediators - chemical synthesis</subject><subject>Inflammation Mediators - physiology</subject><subject>Interferon</subject><subject>Kinases</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Leukocytes, Mononuclear - pathology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred ICR</subject><subject>Molecular Sequence Data</subject><subject>RNA Interference - immunology</subject><subject>RNA, Small Interfering - administration & dosage</subject><subject>RNA, Small Interfering - chemical synthesis</subject><subject>RNA, Small Interfering - physiology</subject><subject>Toxicity</subject><subject>Tumor necrosis factor-TNF</subject><subject>Vehicles</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkF1LAzEQRYMotlZ_gSALgm9dM0n2I4-lfoIoij6HNJ2tKbtJ3ewW-u9NbVHwaS6TM5dwCDkHmgKF_HqZbpruE1NGaZYCpJSyAzKEjGXjGMXhb4Z8QE5CWMYEmcyPyQByLriUYkhebzDYhUt8lTjvrKtq3TS68-0mCRsX6ztrkmDfnidJg3OrO-sWycp36LpkgQ7jW43ObLfWJWu79qfkqNJ1wLP9HJGPu9v36cP46eX-cTp5GhtBi25coKCgNS15xbjOy8KIUsvZjAldSA26YiLXpUGNFQhqgCFnzICsZhQZiDkfkatd76r1Xz2GTjU2GKxr7dD3QUEBGS24jODlP3Dp-9bFv0VGspLmuWSR4jvKtD6EFiu1am2j240Cqra-1VL9-FZb3wpARcnx6mLf3c-in7-bvWD-DU-ofWw</recordid><startdate>200603</startdate><enddate>200603</enddate><creator>Judge, Adam D</creator><creator>Bola, Gurneet</creator><creator>Lee, Amy C H</creator><creator>MacLachlan, Ian</creator><general>Elsevier Limited</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>200603</creationdate><title>Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo</title><author>Judge, Adam D ; Bola, Gurneet ; Lee, Amy C H ; MacLachlan, Ian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c407t-7e401aa083f23a687c48a9bb24a79a1af246a8ceaef140c12e322c19fb0e214d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Apolipoproteins</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>DNA Methylation</topic><topic>Drug dosages</topic><topic>Gene Silencing - immunology</topic><topic>Gene therapy</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunosuppressive Agents - administration & dosage</topic><topic>Immunosuppressive Agents - chemical synthesis</topic><topic>Inflammation Mediators - administration & dosage</topic><topic>Inflammation Mediators - chemical synthesis</topic><topic>Inflammation Mediators - physiology</topic><topic>Interferon</topic><topic>Kinases</topic><topic>Leukocytes, Mononuclear - metabolism</topic><topic>Leukocytes, Mononuclear - pathology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred ICR</topic><topic>Molecular Sequence Data</topic><topic>RNA Interference - immunology</topic><topic>RNA, Small Interfering - administration & dosage</topic><topic>RNA, Small Interfering - chemical synthesis</topic><topic>RNA, Small Interfering - physiology</topic><topic>Toxicity</topic><topic>Tumor necrosis factor-TNF</topic><topic>Vehicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Judge, Adam D</creatorcontrib><creatorcontrib>Bola, Gurneet</creatorcontrib><creatorcontrib>Lee, Amy C H</creatorcontrib><creatorcontrib>MacLachlan, Ian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</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>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Judge, Adam D</au><au>Bola, Gurneet</au><au>Lee, Amy C H</au><au>MacLachlan, Ian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2006-03</date><risdate>2006</risdate><volume>13</volume><issue>3</issue><spage>494</spage><epage>505</epage><pages>494-505</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>16343994</pmid><doi>10.1016/j.ymthe.2005.11.002</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apolipoproteins Cells, Cultured Cytokines DNA Methylation Drug dosages Gene Silencing - immunology Gene therapy Humans Immune system Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - chemical synthesis Inflammation Mediators - administration & dosage Inflammation Mediators - chemical synthesis Inflammation Mediators - physiology Interferon Kinases Leukocytes, Mononuclear - metabolism Leukocytes, Mononuclear - pathology Mice Mice, Inbred BALB C Mice, Inbred ICR Molecular Sequence Data RNA Interference - immunology RNA, Small Interfering - administration & dosage RNA, Small Interfering - chemical synthesis RNA, Small Interfering - physiology Toxicity Tumor necrosis factor-TNF Vehicles |
| title | Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo |
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