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2013-05-24 - Colloque/Présentation - poster - Français - 1 page(s)

Tassin Alexandra , Vanderplanck Céline, Ansseau Eugénie , Derenne Aline, Coppée Frédérique , Belayew Alexandra , "Different approaches to evaluate antisense strategies against the causal gene of the FSHD myopathy." in Journée de l'Institut de recherche en sciences et technologies de la santé, Mons, Belgium, 2013

  • Codes CREF : Pathologies particulières (DI3370)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Introduction. Facio-scapulo-humeral dystrophy (FSHD) is the most frequent hereditary skeletal muscle disorders in adults. It is characterized by an asymmetric muscle atrophy that gradually evolves from the upper to the lower parts of the body. It is genetically linked to the opening of the chromatin structure leading to the activation of the DoUble homeoboX 4 (DUX4) gene that our laboratory has identified within the D4Z4 repeated element long considered as “junk DNA”. There is now compelling evidence of the key role played by DUX4 in FSHD. DUX4 encodes a transcription factor expressed in few nuclei of FSHD muscle cells where it initiates a deregulation cascade of dozens of genes leading a.o. to muscle atrophy, differentiation defects and oxidative stress. Recent research activities. Using a very sensitive monoclonal antibody (Dixit et al. 2006; collaboration: Prof. O Léo and Dr. A-M. Van Acker, IBMM, ULB, Gosselies) we have studied DUX4 expression in a panel of FSHD and control primary myoblasts and on muscle biopsies (collaboration: Dr. D. Laoudj-Chenivesse, INSERM U1046, Montpellier, France). We also have studied the expression of one of its direct target gene, PITX1. These studies allow us to propose a diffusion model explaining how a very low DUX4 expression could cause a large gene deregulation affecting a whole myotube (Tassin et al., 2013). During their differentiation in vitro, FSHD myoblasts fuse to form myotubes presenting morphological abnormalities: either atrophic (very thin with aligned nuclei) or disorganized (giants, with clusters of nuclei) myotubes. In collaboration with Prof. R. Wattiez (Dpt. Proteomics and Microbiology, UMONS), we have used a differential isotopic labeling (ICPL) coupled to mass spectrometry (2DLC-MS/MS), with the aim to compare the proteome of atrophic, disorganized FSHD and control myotubes (Tassin et al., 2012). Our laboratory has developed siRNAs and specific antisense oligonucleotides (AOs) targeting the DUX4 mRNA. This study is made in collaboration with Prof. S. Wilton (Molecular Genetic Therapy Group, Murdoch University,Western Australia), an expert of this approach for the Duchenne Muscular Dystrophy (DMD). AOs restoring dystrophin expression by exon skipping on the messenger RNA have successfully gone through phase II clinical trials for children with DMD. In contrast with DMD, our AOs aim to destabilize the DUX4 messenger RNA to prevent protein synthesis. Addition of these AOs to primary FSHD myoblast cultures suppressed DUX4 protein expression and restored expression of FSHD markers to control levels as well as the normal myotube phenotype (Vanderplanck et al., 2011). Current research and prospects. No transgenic mouse model with DUX4 expression in skeletal muscle and a myopathic phenotype has been published yet, probably because of its normal function in very early embryogenesis or its toxicity. Our current research thus includes the development of mouse models (collaboration with Prof. A. Legrand, Physiology, UMONS and Prof. P. Zammit, King’s College of London, UK) which will allow the evaluation of the toxicity and efficacy of AOs targeting DUX4 in vivo. In parallel, in collaboration with Dr. L Mespouille and Prof. Ph. Dubois (Laboratory of Polymers & Composite Materials; UMONS), we plan to complex AOs to a polymeric carrier (nanoparticules), with the aim to improve their transport into the bloodstream and the specific targeting of muscle cells. Advances in this gene therapy domain will bring hope not only for patients with FSHD, but also for patients with other muscular disorders.