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 European 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.

Modulation of Neuregulin signaling as an effective strategy to treat hereditary neuropathies (Charcot-Marie-Tooth disease)

Project Coordinator

University Medical Center Göttingen


Nicolas Tricaud INSERM U1051 Monpellier, France
Alessandra Bolino San Raffaele Scientific Institute Milan, Italy

Hypo- or hypermyelination are key features of a subgroup of hereditary neuropathies, referred to as Charcot-Marie-Tooth disease (CMT). At present, no cure is available. In the peripheral nervous system, the interaction of axonal NRG1 type III with ErbB2/B3 receptor tyrosine kinases regulates myelin sheath thickness. We previously demonstrated that treatment with soluble NRG1 in rodent models of hypomyelinating CMT1A, the most common CMT subtype, increased myelin formation and improved the clinical phenotype via modulation of PI3K signaling. Vice versa, we downregulated NRG1 type III signaling with recombinant TACE treatment in models of hypermyelinating neuropathy which decreased the excess of myelin and also ameliorated the clinical phenotype. Modulation of NRG1 activity may therefore constitute a promising therapeutic rational for CMT forms characterized by altered level of myelination Thus, we here propose to increase the NRG1-PI3K/AKT activity in hypomyelinating CMT forms by soluble NRG1 administration and by direct delivery of NRG1 by means of viral transgenesis. In hypermyelinating CMT forms, we will downregulate NRG1-PI3K/AKT signaling by administration of Niaspan-a FDA approved TACE activator- and of novel drugs known to modulate PI3K/AKT signaling. Importantly, the combined in vivo and in vitro approaches of the CMT-NRG consortium will shed light into the molecular mechanisms of NRG1 signaling in CMT. This may be translated to a common therapeutic target for CMT subforms in the future.

E-Rare 2012 - Created by Toussaint Biger