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.
After a competitive scientific evaluation by peers, the E-Rare funding bodies recommended for funding 13 excellent scientific projects on innovative therapeutic approaches for rare diseases, including projects focused on Spinal Muscular Atrophy and Nemaline Myopathy.
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.
Cédric Raoul (Project Coordinator)
INM, Inserm UMR105
Ottawa Hospital Research Institute, Department of Regenerative Medicine
Swiss Federal Institute of Technology, Brain Mind Institute
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.
VU University Medical Center Laboratory for Physiology Institute for Cardiovascular Research
Amsterdam, The Netherlands
Fondazione Salvatore Maugeri
Aix Marseille University