2013 E-Rare competition

International Rare Disease consortium (E-RARE)

Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other. Review all funded projects.

Results of the 2013 E-Rare competition

After a competitive scientific evaluation by peers, the E-Rare funding bodies recommended for funding 12 excellent scientific projects, 6 of which have a Canadian component. The funded projects cover a wide range of rare diseases including neuromuscular disorders.

Muscular Dystrophy Canada is pleased to be contributing over $380,000 towards the 2 Canadian teams that are focused on neuromuscular research.

An international effort to understand FSHD muscular dystrophy epigenetics

Project Coordinator

Davide Gabellini

Ospedale San Raffaele

Milan, Italy


F. Jeffrey Dilworth

Ottawa Hospital Research Institute

Ottawa, Canada

Evi Soutoglou

Centre Européen de Recherche en Biologie et en Médecine (CERBM-IGBMC)

Illkrich, France

Project Description

Despite the fact they constitute two thirds of the human genome, repetitive sequences are largely ignored. FSHD is an autosomal dominant disorder with a strong epigenetic component. Unlike the majority of genetic diseases, FSHD is not caused by mutation in a protein-coding gene. Instead, the disease is associated with a reduced copy number of the D4Z4 macrosatellite repeat mapping to 4q35. Despite years of intensive research, the molecular pathogenesis of FSHD remains largely unknown. We recently identified DBE-T, a chromatin-associated lncRNA produced preferentially in FSHD patients. DBE-T mediates a Polycomb to Trithorax epigenetic switch at the FSHD locus, driving chromatin remodeling and de-repression of 4q35 protein-coding genes in FSHD patients. In FSHD, up-regulation of multiple 4q35 candidate genes has been reported. Based on this, it has been suggested that FSHD could be considered a continuous gene disease in which the epigenetic alteration of multiple genes contributes to the final outcome. Since DBE-T behaves as a master regulator of the FSHD locus being required to activate all FSHD candidate genes, it is a very intriguing candidate to develop therapeutic approaches aimed at normalizing 4q35 gene expression in FSHD patients. Nevertheless, DBE-T mechanism of action is poorly understood. Here we propose to tackle these issues by addressing the following questions: – Is DBE-T responsible for the enhanced disease penetrance of FSHD in muscle? – How is DBE-T tethered to chromatin? – How does DBE-T activate FSHD candidate genes?

Stimulating Intrinsic Repair for DMD

Project Coordinator

Michael Rudnicki

Ottawa Hospital Research Institute

Ottawa, Canada


Pura Muñoz-Cánoves

UPF (Universitat Pompeu Fabra), Ciències Experimentals i de la Salut (CEXS)

Barcelona, Spain

Gillian Butler-Browne

Institut de Myologie, INSERM U974

Paris, France

Project description

Duchenne Muscular Dystrophy (DMD) is a rare and devastating genetic disease of childhood manifested by progressive debilitating skeletal muscle weakness and wasting, and ultimately death. The Rudnicki group recently identified a role for Wnt7a/Fzd7 signaling in stimulating the regeneration of muscle by acting at two levels. Wnt7a acts on satellite stem cells to drive their symmetric expansion, and also acts on myofibers to stimulate hypertrophy. Delivery of Wnt7a significantly ameliorated dystrophic changes in the mdx mouse model of DMD. The research team represents an outstanding multidisciplinary group of investigators, who are uniquely positioned to conduct the proposed basic and preclinical studies. The overall goal of the project is to assess the utility of Wnt7a and its variants as protein therapeutics for the stimulation of intrinsic regeneration for the treatment of DMD. We propose to characterize the effects of whole body treatment in mdx mice using transgenesis as well as systemic delivery of Wnt7a. We will characterize the Wnt7a/Fzd7 signaling pathway at the molecular level and identify downstream target genes to elucidate mode of action. We will investigate the basis for the suppression of the inflammatory response by Wnt7a. Finally, we will assess the activity of Wnt7a on human satellite cells and myofibers in mice carrying humanized DMD muscle. These experiments will advance our knowledge of Wnt7a signaling in muscle and illuminate the therapeutic potential of Wnt7a as a protein biologic to stimulate intrinsic repair in a muscle-wasting disease like DMD.

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