RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice
Repair of β-globin pre-mRNA rendered defective by a thalassemia-causing splicing mutation, IVS2-654, in intron 2 of the human β-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morph...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2009-01, Vol.106 (4), p.1205-1210 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 106 |
| creator | Svasti, Saovaros Suwanmanee, Thipparat Fucharoen, Suthat Moulton, Hong M Nelson, Michelle H Maeda, Nobuyo Smithies, Oliver Kole, Ryszard |
| description | Repair of β-globin pre-mRNA rendered defective by a thalassemia-causing splicing mutation, IVS2-654, in intron 2 of the human β-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired β-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells. |
| doi_str_mv | 10.1073/pnas.0812436106 |
| format | Article |
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This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired β-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0812436106</identifier><identifier>PMID: 19164558</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; beta-Globins - genetics ; Biological Sciences ; Blood ; Cell Shape - drug effects ; Cells ; DNA repair ; Erythrocytes - drug effects ; Erythrocytes - pathology ; Erythroid cells ; Hemoglobin ; Hemoglobins ; Hemoglobins - genetics ; Hemoglobins - metabolism ; Humans ; Injections, Intravenous ; Interleukin-12 - blood ; Messenger RNA ; Mice ; Mutation ; Mutation - genetics ; Oligomers ; Oligonucleotides ; Oligonucleotides - administration & dosage ; Oligonucleotides - adverse effects ; Oligonucleotides - pharmacology ; Peptides ; Reverse transcriptase polymerase chain reaction ; Ribonucleic acid ; RNA ; RNA Precursors - genetics ; RNA Precursors - metabolism ; RNA Splicing - drug effects ; RNA Splicing - genetics ; Rodents ; Splicing ; Thalassemia - blood ; Thalassemia - genetics ; Thalassemia - therapy</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2009-01, Vol.106 (4), p.1205-1210</ispartof><rights>Copyright National Academy of Sciences Jan 27, 2009</rights><rights>2009 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c616t-10af25108cc3064a2a9649db80936548bb96bb900a5173b5f7812ad0a18ccd603</citedby><cites>FETCH-LOGICAL-c616t-10af25108cc3064a2a9649db80936548bb96bb900a5173b5f7812ad0a18ccd603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/106/4.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40254707$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40254707$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19164558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Svasti, Saovaros</creatorcontrib><creatorcontrib>Suwanmanee, Thipparat</creatorcontrib><creatorcontrib>Fucharoen, Suthat</creatorcontrib><creatorcontrib>Moulton, Hong M</creatorcontrib><creatorcontrib>Nelson, Michelle H</creatorcontrib><creatorcontrib>Maeda, Nobuyo</creatorcontrib><creatorcontrib>Smithies, Oliver</creatorcontrib><creatorcontrib>Kole, Ryszard</creatorcontrib><title>RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Repair of β-globin pre-mRNA rendered defective by a thalassemia-causing splicing mutation, IVS2-654, in intron 2 of the human β-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired β-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.</description><subject>Animals</subject><subject>beta-Globins - genetics</subject><subject>Biological Sciences</subject><subject>Blood</subject><subject>Cell Shape - drug effects</subject><subject>Cells</subject><subject>DNA repair</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - pathology</subject><subject>Erythroid cells</subject><subject>Hemoglobin</subject><subject>Hemoglobins</subject><subject>Hemoglobins - genetics</subject><subject>Hemoglobins - metabolism</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>Interleukin-12 - blood</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Oligomers</subject><subject>Oligonucleotides</subject><subject>Oligonucleotides - administration & dosage</subject><subject>Oligonucleotides - adverse effects</subject><subject>Oligonucleotides - pharmacology</subject><subject>Peptides</subject><subject>Reverse transcriptase polymerase chain reaction</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA Precursors - genetics</subject><subject>RNA Precursors - metabolism</subject><subject>RNA Splicing - drug effects</subject><subject>RNA Splicing - genetics</subject><subject>Rodents</subject><subject>Splicing</subject><subject>Thalassemia - blood</subject><subject>Thalassemia - genetics</subject><subject>Thalassemia - therapy</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1v1DAQxS0EosvCmRMQ9QCntOPPOBekqqJQqQKJUq6Wk3V2vUriYCdV-e-ZaFfd0kMPY8ue3zzN0yPkLYUTCgU_HXqbTkBTJriioJ6RBYWS5kqU8JwsAFiRa8HEEXmV0hYASqnhJTmiJVVCSr0gFz-_n2XRDdZHvNIY8Mg2rgvrNlS-z9zdgD_Jhz7D1-Xva5YrKbJxY1ubkut8nWG51-RFY9vk3uzvJbm5-PLr_Ft-9ePr5fnZVV4rqsacgm2YpKDrmoMSltkSV11VGkqOsrqqSoUFYCUteCWbAq3ZFViKEysFfEk-73SHqercqnb9GG1rhug7G_-aYL35v9P7jVmHW8MU51JKFPi4F4jhz4SGTedT7drW9i5MyTBgtCiAIXj8CNyGKfZoDhkqGNdiXud0B9UxpBRdc78JBTMHZOaAzCEgnHj_0MCB3yfyAJgnD3LKCEMZzA4-PQmYZmrb0d2NSL7bkds513tUAJOiwOWW5MOu39hg7Dr6ZG6u0RwHKrUqBef_AKIptSU</recordid><startdate>20090127</startdate><enddate>20090127</enddate><creator>Svasti, Saovaros</creator><creator>Suwanmanee, Thipparat</creator><creator>Fucharoen, Suthat</creator><creator>Moulton, Hong M</creator><creator>Nelson, Michelle H</creator><creator>Maeda, Nobuyo</creator><creator>Smithies, Oliver</creator><creator>Kole, Ryszard</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20090127</creationdate><title>RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice</title><author>Svasti, Saovaros ; 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This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired β-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>19164558</pmid><doi>10.1073/pnas.0812436106</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Full-Text Journals in Chemistry (Open access); PubMed Central; Alma/SFX Local Collection; JSTOR |
| subjects | Animals beta-Globins - genetics Biological Sciences Blood Cell Shape - drug effects Cells DNA repair Erythrocytes - drug effects Erythrocytes - pathology Erythroid cells Hemoglobin Hemoglobins Hemoglobins - genetics Hemoglobins - metabolism Humans Injections, Intravenous Interleukin-12 - blood Messenger RNA Mice Mutation Mutation - genetics Oligomers Oligonucleotides Oligonucleotides - administration & dosage Oligonucleotides - adverse effects Oligonucleotides - pharmacology Peptides Reverse transcriptase polymerase chain reaction Ribonucleic acid RNA RNA Precursors - genetics RNA Precursors - metabolism RNA Splicing - drug effects RNA Splicing - genetics Rodents Splicing Thalassemia - blood Thalassemia - genetics Thalassemia - therapy |
| title | RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice |
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