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Targeted exon skipping in transgenic hDMD mice: A model for direct preclinical screening of human-specific antisense oligonucleotides
The therapeutic potential of frame-restoring exon skipping by antisense oligonucleotides (AONs) has recently been demonstrated in cultured muscle cells from a series of Duchenne muscular dystrophy (DMD) patients. To facilitate clinical application, in vivo studies in animal models are required to de...
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| Published in: | Molecular therapy 2004-08, Vol.10 (2), p.232-240 |
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| creator | Bremmer-Bout, Mattie Aartsma-Rus, Annemieke de Meijer, Emile J Kaman, Wendy E Janson, Anneke A M Vossen, Rolf H A M van Ommen, Gert-Jan B den Dunnen, Johan T van Deutekom, Judith C T |
| description | The therapeutic potential of frame-restoring exon skipping by antisense oligonucleotides (AONs) has recently been demonstrated in cultured muscle cells from a series of Duchenne muscular dystrophy (DMD) patients. To facilitate clinical application, in vivo studies in animal models are required to develop safe and efficient AON-delivery methods. However, since exon skipping is a sequence-specific therapy, it is desirable to target the human DMD gene directly. We therefore set up human sequence-specific exon skipping in transgenic mice carrying the full-size human gene (hDMD). We initially compared the efficiency and toxicity of intramuscular AON injections using different delivery reagents in wild-type mice. At a dose of 3.6 nmol AON and using polyethylenimine, the skipping levels accumulated up to 3% in the second week postinjection and lasted for 4 weeks. We observed a correlation of this long-term effect with the intramuscular persistence of the AON. In regenerating myofibers higher efficiencies (up to 9%) could be obtained. Finally, using the optimized protocols in hDMD mice, we were able to induce the specific skipping of human DMD exons without affecting the endogenous mouse gene. These data highlight the high sequence specificity of this therapy and present the hDMD mouse as a unique model to optimize human-specific exon skipping in vivo. |
| doi_str_mv | 10.1016/j.ymthe.2004.05.031 |
| format | article |
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To facilitate clinical application, in vivo studies in animal models are required to develop safe and efficient AON-delivery methods. However, since exon skipping is a sequence-specific therapy, it is desirable to target the human DMD gene directly. We therefore set up human sequence-specific exon skipping in transgenic mice carrying the full-size human gene (hDMD). We initially compared the efficiency and toxicity of intramuscular AON injections using different delivery reagents in wild-type mice. At a dose of 3.6 nmol AON and using polyethylenimine, the skipping levels accumulated up to 3% in the second week postinjection and lasted for 4 weeks. We observed a correlation of this long-term effect with the intramuscular persistence of the AON. In regenerating myofibers higher efficiencies (up to 9%) could be obtained. Finally, using the optimized protocols in hDMD mice, we were able to induce the specific skipping of human DMD exons without affecting the endogenous mouse gene. These data highlight the high sequence specificity of this therapy and present the hDMD mouse as a unique model to optimize human-specific exon skipping in vivo.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2004.05.031</identifier><identifier>PMID: 15294170</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Dystrophin - genetics ; Dystrophin - metabolism ; Efficiency ; Exons - genetics ; Gene Targeting - methods ; Gene therapy ; Humans ; Mice ; Mice, Transgenic ; Muscle, Skeletal - chemistry ; Muscle, Skeletal - cytology ; Muscle, Skeletal - metabolism ; Muscular dystrophy ; Muscular Dystrophy, Duchenne - drug therapy ; Muscular Dystrophy, Duchenne - genetics ; Mutation ; Oligonucleotides, Antisense - analysis ; Oligonucleotides, Antisense - genetics ; Oligonucleotides, Antisense - pharmacology ; RNA, Messenger - analysis ; RNA, Messenger - metabolism ; Toxicity</subject><ispartof>Molecular therapy, 2004-08, Vol.10 (2), p.232-240</ispartof><rights>Copyright The American Society of Gene Therapy</rights><rights>Copyright Nature Publishing Group Aug 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c440t-f74eb970791ea5b809ada27df164696d7d8f76c1e0c46a2d0434758b9ee327d73</citedby><cites>FETCH-LOGICAL-c440t-f74eb970791ea5b809ada27df164696d7d8f76c1e0c46a2d0434758b9ee327d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15294170$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bremmer-Bout, Mattie</creatorcontrib><creatorcontrib>Aartsma-Rus, Annemieke</creatorcontrib><creatorcontrib>de Meijer, Emile J</creatorcontrib><creatorcontrib>Kaman, Wendy E</creatorcontrib><creatorcontrib>Janson, Anneke A M</creatorcontrib><creatorcontrib>Vossen, Rolf H A M</creatorcontrib><creatorcontrib>van Ommen, Gert-Jan B</creatorcontrib><creatorcontrib>den Dunnen, Johan T</creatorcontrib><creatorcontrib>van Deutekom, Judith C T</creatorcontrib><title>Targeted exon skipping in transgenic hDMD mice: A model for direct preclinical screening of human-specific antisense oligonucleotides</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>The therapeutic potential of frame-restoring exon skipping by antisense oligonucleotides (AONs) has recently been demonstrated in cultured muscle cells from a series of Duchenne muscular dystrophy (DMD) patients. 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To facilitate clinical application, in vivo studies in animal models are required to develop safe and efficient AON-delivery methods. However, since exon skipping is a sequence-specific therapy, it is desirable to target the human DMD gene directly. We therefore set up human sequence-specific exon skipping in transgenic mice carrying the full-size human gene (hDMD). We initially compared the efficiency and toxicity of intramuscular AON injections using different delivery reagents in wild-type mice. At a dose of 3.6 nmol AON and using polyethylenimine, the skipping levels accumulated up to 3% in the second week postinjection and lasted for 4 weeks. We observed a correlation of this long-term effect with the intramuscular persistence of the AON. In regenerating myofibers higher efficiencies (up to 9%) could be obtained. Finally, using the optimized protocols in hDMD mice, we were able to induce the specific skipping of human DMD exons without affecting the endogenous mouse gene. 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| subjects | Animals Disease Models, Animal Drug Evaluation, Preclinical Dystrophin - genetics Dystrophin - metabolism Efficiency Exons - genetics Gene Targeting - methods Gene therapy Humans Mice Mice, Transgenic Muscle, Skeletal - chemistry Muscle, Skeletal - cytology Muscle, Skeletal - metabolism Muscular dystrophy Muscular Dystrophy, Duchenne - drug therapy Muscular Dystrophy, Duchenne - genetics Mutation Oligonucleotides, Antisense - analysis Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - pharmacology RNA, Messenger - analysis RNA, Messenger - metabolism Toxicity |
| title | Targeted exon skipping in transgenic hDMD mice: A model for direct preclinical screening of human-specific antisense oligonucleotides |
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