NDLI: Caractérisation du profil d'expression et des potentielles cibles off-targets d'un U7snRNA optimisé pour le traitement par saut d'exon de la Dystrophie Musculaire de Duchenne

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Caractérisation du profil d'expression et des potentielles cibles off-targets d'un U7snRNA optimisé pour le traitement par saut d'exon de la Dystrophie Musculaire de Duchenne

Content Provider	Semantic Scholar
Author	Domenger, Claire
Copyright Year	2015
Abstract	Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder characterized by progressive degeneration of whole muscle tissues. It is caused by mutations in the dmd gene encoding the dystrophin, a cytoskeleton protein. Many gene-based therapeutic strategies have recently emerged to identify a corrective treatment for DMD. Among them, exon skipping allows the restoration of the reading frame of the dmd messenger and then the production of a functional dystrophin protein. Exon skipping can be achieved using modified small nuclear RNA, U7snRNA, in which a therapeutic antisense sequence is inserted. Such U7snRNA can be packaged in vectors derived from adeno-associated virus (AAV), allowing a long-lasting repair of the dmd messenger. We recently published the high ability of an AAV8-U7 vector to transduce skeletal muscles and to restore the expression of dystrophin in GRMD dogs. These results pave the way for a phase I/II clinical trial in DMD patients treatable by skipping of the exon 53 of the dmd messenger. As part of the development of this therapeutic product, we characterized the expression profile of the U7 transgene in muscle and liver contexts (the liver being a non-targeted organ but well transduced by AAV8 in vivo). Then, we analyzed the potential off-target effects specific of the clinical U7 transgene by identifying the transcripts targeted by its antisense sequence. This study was performed in vitro on human cells models via a combined approach of RNA Sequencing and in silico analysis. The results of this study will be of particular importance to document the biosafety of this therapeutic product, before the beginning of the clinical trial, planned in 2016.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.myobase.org/doc_num.php?explnum_id=12640
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article

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