Titre :
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Exon skipping in DMD models mediated by tricyclo-DNA analogues (poster) : Acte de colloque : 4ème colloque international de Myologie (9-13 mai 2011; Lille (France))
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contenu dans :
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Auteurs :
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Gruszczynski C ;
Gruszczynski C ;
Ziaei S ;
Leumann CJ ;
Dreyfus P ;
Garcia L
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Type de document :
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Article
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Editeur :
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AFM-TELETHON, 2011
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Pages :
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p 89
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Langues:
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Anglais
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Mots-clés :
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colloque
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dystrophie musculaire de Duchenne
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Résumé :
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RNA therapeutic approaches have proven to be very successful in cell culture and in animal experiments. Some oligonucleotides based clinical trials are currently already in progress. To be efficient, the oligonucleotides must be composed of non-natural (i.e. chemically modified) nucleotide analogues avoiding RNase H degradation of the mRNA and increasing biostability, bioavailability and affinity for the target RNA. A broad search for oligonucleotide analogues over the last two decades has yielded a series of promising candidates which can resolve some but not all of these problems.Tricyclo-DNA (tc-DNA) is a DNA analogue which belongs to the class of conformationally constrained DNA analogues which is designed to display increased RNA affinity for entropic reasons. Tc-DNA binds to RNA with higher affinity as compared to 2'-OMe-RNA, is more stable towards degradation in human sera. Given previous remarkable results in the context of splice correction obtained on b-globin, cyclophilin and anti-HIV, we decided to test whether tc-DNA can also be efficiently used for intervening in the splicing of mutant dystrophin mRNA. In the first experiments injecting as low as 5?g the tc-oligonucleotide into mdx mice muscles showed high restoration of dystrophin after 3 weeks. Moreover a 15-mer tc-oligonucleotide showed the same if not even higher activity as compared to a 20-mer 2'-OMe-RNA oligonucleotide. These results were an excellent basis to extend the study exploring the potential of tc-DNA as a therapeutic agent under systemic deliverance (IV & SC multi-mg quantities of tc-oligonucleotide in consecutive injections in mdx mice).
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