International Rare Disease Consortium (E-RARE)

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.

Preparing for therapies in autosomal recessive ataxias


Bernard Brais – Principal Investigator
Cynthia Gagnon – Co-investigator

Funding Partners:

  • Muscular Dystrophy Canada
  • Ataxia of Charlevoix-Saguenay Foundation
  • CIHR
  • National funding agencies of Germany, Italy, France, Netherlands, Turkey

Autosomal-recessive cerebellar ataxias (ARCAs) define a genetically heterogeneous group of rare degenerative disorders characterized by progressive cerebellar degeneration. Recent high-throughput sequencing techniques have allowed to identify an expanding number of novel rare ARCA genes, many identified by researchers from this consortium. However, the challenge is now to translate this genetic progress into preparing successful treatment trials. PREPARE will collate the complementary expertise from many ARCA centres and large supporting networks worldwide to facilitate the crucial translational steps from genetic fingerprinting to preclinical trials, FDA-conform outcome measures, and transnational trial-ready cohorts. To set this stage, it will establish a “translational pipeline” that will be applicable to several rare ARCAs alike. A shared prospective longitudinal registry will allow to aggregate ARCA cohorts of sufficient size and establish serial natural history data needed to launch treatment trials. Genetically still undefined ARCA patients will be screened by exome sequencing, thus maximizing the number of patients eligible for treatment trials and including definition of novel ARCA syndromes. To support causality of the novel genes and to identify pathway nodes susceptible to drug compounds, genetic fly models will be created. Trial outcome measures will be established by a stringent, FDA-conform international collaborative process, capturing the multisystemic complexity ARCA phenotypes and including extensive “„3-omics” biomarker screening. First preclinical trial protocols applicable to many ARCA types will be implemented in transgenic ARCA mice, including testing of drug compounds.

Common Pathogenic Pathways and Therapeutics for SMA and ALS motoneuron diseases


Funding partners:

  • Muscular Dystrophy Canada, Ilsa Mae Fund, $300,000
  • CIHR’s Institute of Genetics, $390,150
  • Swiss National Science Foundation $292,563

Spinal muscular atrophy (SMA) is an incurable paralytic neuromuscular disorder that mainly affects children at an incidence of 1 in 6000 to 10000 births. SMA is characterized by the selective degeneration of spinal motoneurons. About 95% of SMA cases are caused by autosomal loss-of-function mutations in the SMN1 gene. Recent work has shown that SMA and amyotrophic lateral sclerosis (ALS), another devastating motoneuron pathology, share converging aberrant pathways. The motoneuron-restricted death pathway triggered by Fas and its ligand FasL, contributes to the loss of motoneurons in ALS.

Our preliminary data shows that Fas is markedly upregulated in spinal cord motoneurons of SMA mice, suggesting that Fas may also contribute to SMA pathogenesis. Additional preliminary data demonstrates that whereas Fas undeniably induces motoneuron death, it also promotes neuronal outgrowth. Therefore, the same factor may be implicated in compensatory axonal plasticity as well as in the selective loss of neurons. Here, we propose to further dissect the functional duality of Fas and investigate the contribution of the Fas pathway in SMA pathogenesis. Activation and expression profile of the Fas pathway will be assessed in Smn depleted motoneurons, in a SMA mouse model and in human SMA spinal cord. Further, gene therapy approaches will be developed to reduce Fas activity in the spinal cord and specifically target FasL to axons in SMA mice. The ultimate goal of this collaborative endeavor is to generate common therapeutic strategies for SMA and ALS, as well as for other motoneuron diseases.

Lead Investigators

Cédric Raoul (Project Coordinator)
INM, Inserm UMR105

Rashmi Kothary
Ottawa Hospital Research Institute, Department of Regenerative Medicine
Ottawa, Canada

Patrick Aebischer
Swiss Federal Institute of Technology, Brain Mind Institute
Lausanne, Switzerland

Fast Skeletal Troponin Activation for Restoring Muscle Strength in Mouse Models of Nemaline Myopathy: a Molecular, Cellular, Metabolic and Functional Assessment


Problem to be solved: No treatment is available for nemaline myopathy (NM), a rare and fatal muscle disease.

Background: A cardinal feature of NM is muscle weakness, caused by atrophy, impaired sarcomere contractility and alterations in energy pathways. This research program builds on our recent in vitro studies, funded by E-RARE1, which suggest that muscle strength in NM might be restored by fast skeletal troponin activation. Preclinical studies with fast skeletal troponin activators in live NM mice are now warranted.

Objective: Determine the efficacy of the fast skeletal troponin activator tirasemtiv in live NM mice.

Approach: Tirasemtiv will be tested in four NM mouse models: this allows us to cover a large spectrum of the disease. We will study its effect on muscle function, energy metabolism and NM biomarkers using non-invasive magnetic resonance imaging and spectroscopy, measurements of in vivo and ex vivo muscle strength and proteomic assessments of the involved signaling pathways. This combination allows for an in-depth analysis of the efficacy of tirasemtiv in NM mice.

Innovation: The availability of (1) four NM mouse models, (2) high-end infrastructure to assess muscle – and whole body performance, and (3) a novel and promising drug, positions us ideally to tackle the problem posed.

Impact: Our research program is positioned at the level of basic science and its translation towards direct clinical application; its outcome might provide an impetus to preclinical studies in other disorders with muscle weakness.

Lead Investigators

Coen Ottenheijm

VU University Medical Center Laboratory for Physiology Institute for Cardiovascular Research
Amsterdam, The Netherlands

Roberto Bottinelli
Fondazione Salvatore Maugeri
Pavia, Italy

Julien Gondin
Aix Marseille University
Marseille, France

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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