Correction of DNA Protein Kinase Deficiency by Spliceosome-mediated RNA Trans-splicing and Sleeping Beauty Transposon Delivery
Spliceosome-mediated RNA trans-splicing (SMaRT) is an emerging technology for the repair of defective pre-messenger RNA (pre-mRNA) molecules. It is especially useful in the treatment of genetic disorders involving large genes. Although viral vectors have been used for achieving long-lasting expressi...
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| Veröffentlicht in: | Molecular therapy 2007-07, Vol.15 (7), p.1273-1279 |
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| creator | Zayed, Hatem Xia, Lily Yerich, Anton Yant, Stephen R Kay, Mark A Puttaraju, M McGarrity, Gerard J Wiest, David L McIvor, R Scott Tolar, Jakub Blazar, Bruce R |
| description | Spliceosome-mediated RNA trans-splicing (SMaRT) is an emerging technology for the repair of defective pre-messenger RNA (pre-mRNA) molecules. It is especially useful in the treatment of genetic disorders involving large genes. Although viral vectors have been used for achieving long-lasting expression of trans-splicing molecules, the immunogenicity and suboptimal safety profiles associated with viral-based components could limit the widespread application of SMaRT in the repair of genetic defects. Here, we tested whether the non-viral Sleeping Beauty (SB) transposon system could mediate stable delivery of trans-splicing molecules designed to correct the genetic defect responsible for severe combined immune deficiency (SCID). This immunological disorder is caused by a point mutation within the 12.4 kilobase (kb) gene encoding the DNA protein kinase catalytic subunit (DNA-PKcs) and is associated with aberrant DNA repair, defective T- and B-cell production, and hypersensitivity to radiation-induced injury. Using a novel SB-based trans-splicing vector, we demonstrate stable mRNA correction, proper DNA-PKcs protein production, and conference of a radiation-resistant phenotype in a T-cell thymoma cell line and SCID multipotent adult progenitor cells (MAPCs). These results suggest that SB-based trans-splicing vectors should prove useful in facilitating the correction of endogenous mutated mRNA transcripts, including the DNA-PKcs defect present in SCID cells. |
| doi_str_mv | 10.1038/sj.mt.6300178 |
| format | Article |
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It is especially useful in the treatment of genetic disorders involving large genes. Although viral vectors have been used for achieving long-lasting expression of trans-splicing molecules, the immunogenicity and suboptimal safety profiles associated with viral-based components could limit the widespread application of SMaRT in the repair of genetic defects. Here, we tested whether the non-viral Sleeping Beauty (SB) transposon system could mediate stable delivery of trans-splicing molecules designed to correct the genetic defect responsible for severe combined immune deficiency (SCID). This immunological disorder is caused by a point mutation within the 12.4 kilobase (kb) gene encoding the DNA protein kinase catalytic subunit (DNA-PKcs) and is associated with aberrant DNA repair, defective T- and B-cell production, and hypersensitivity to radiation-induced injury. Using a novel SB-based trans-splicing vector, we demonstrate stable mRNA correction, proper DNA-PKcs protein production, and conference of a radiation-resistant phenotype in a T-cell thymoma cell line and SCID multipotent adult progenitor cells (MAPCs). These results suggest that SB-based trans-splicing vectors should prove useful in facilitating the correction of endogenous mutated mRNA transcripts, including the DNA-PKcs defect present in SCID cells.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/sj.mt.6300178</identifier><identifier>PMID: 17457319</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Base Sequence ; Catalytic Domain ; Cell Line ; Gene therapy ; Genetic disorders ; Hematology ; Humans ; Kinases ; Mice ; Mutation ; Mutation - genetics ; Oncology ; Pediatrics ; Plasmids ; Polynucleotide 5'-Hydroxyl-Kinase - deficiency ; Polynucleotide 5'-Hydroxyl-Kinase - metabolism ; Proteins ; Radiation ; RNA, Messenger - genetics ; Spliceosomes - genetics ; Stem cells ; Trans-Splicing - genetics ; Transcription, Genetic - genetics ; Transposases - genetics ; Vectors (Biology)</subject><ispartof>Molecular therapy, 2007-07, Vol.15 (7), p.1273-1279</ispartof><rights>2007 The American Society of Gene Therapy</rights><rights>Copyright Nature Publishing Group Jul 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-5b1a0744fcb6856e9fd11572effffe33ce7e98274106397131bfe9fc3da8cb3f3</citedby><cites>FETCH-LOGICAL-c406t-5b1a0744fcb6856e9fd11572effffe33ce7e98274106397131bfe9fc3da8cb3f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1792608564?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17457319$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zayed, Hatem</creatorcontrib><creatorcontrib>Xia, Lily</creatorcontrib><creatorcontrib>Yerich, Anton</creatorcontrib><creatorcontrib>Yant, Stephen R</creatorcontrib><creatorcontrib>Kay, Mark A</creatorcontrib><creatorcontrib>Puttaraju, M</creatorcontrib><creatorcontrib>McGarrity, Gerard J</creatorcontrib><creatorcontrib>Wiest, David L</creatorcontrib><creatorcontrib>McIvor, R Scott</creatorcontrib><creatorcontrib>Tolar, Jakub</creatorcontrib><creatorcontrib>Blazar, Bruce R</creatorcontrib><title>Correction of DNA Protein Kinase Deficiency by Spliceosome-mediated RNA Trans-splicing and Sleeping Beauty Transposon Delivery</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Spliceosome-mediated RNA trans-splicing (SMaRT) is an emerging technology for the repair of defective pre-messenger RNA (pre-mRNA) molecules. 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Using a novel SB-based trans-splicing vector, we demonstrate stable mRNA correction, proper DNA-PKcs protein production, and conference of a radiation-resistant phenotype in a T-cell thymoma cell line and SCID multipotent adult progenitor cells (MAPCs). 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It is especially useful in the treatment of genetic disorders involving large genes. Although viral vectors have been used for achieving long-lasting expression of trans-splicing molecules, the immunogenicity and suboptimal safety profiles associated with viral-based components could limit the widespread application of SMaRT in the repair of genetic defects. Here, we tested whether the non-viral Sleeping Beauty (SB) transposon system could mediate stable delivery of trans-splicing molecules designed to correct the genetic defect responsible for severe combined immune deficiency (SCID). This immunological disorder is caused by a point mutation within the 12.4 kilobase (kb) gene encoding the DNA protein kinase catalytic subunit (DNA-PKcs) and is associated with aberrant DNA repair, defective T- and B-cell production, and hypersensitivity to radiation-induced injury. Using a novel SB-based trans-splicing vector, we demonstrate stable mRNA correction, proper DNA-PKcs protein production, and conference of a radiation-resistant phenotype in a T-cell thymoma cell line and SCID multipotent adult progenitor cells (MAPCs). These results suggest that SB-based trans-splicing vectors should prove useful in facilitating the correction of endogenous mutated mRNA transcripts, including the DNA-PKcs defect present in SCID cells.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17457319</pmid><doi>10.1038/sj.mt.6300178</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | Animals Base Sequence Catalytic Domain Cell Line Gene therapy Genetic disorders Hematology Humans Kinases Mice Mutation Mutation - genetics Oncology Pediatrics Plasmids Polynucleotide 5'-Hydroxyl-Kinase - deficiency Polynucleotide 5'-Hydroxyl-Kinase - metabolism Proteins Radiation RNA, Messenger - genetics Spliceosomes - genetics Stem cells Trans-Splicing - genetics Transcription, Genetic - genetics Transposases - genetics Vectors (Biology) |
| title | Correction of DNA Protein Kinase Deficiency by Spliceosome-mediated RNA Trans-splicing and Sleeping Beauty Transposon Delivery |
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