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

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.

Acronym CMT-NRG
Duration 01/01/2016 - 01/12/2018
Network E-Rare-3
Call E-Rare-3 JTC 2015

Project partner

Number Name Role Country
1 University Medical Center Göttingen Coordinator Germany
2 San Raffaele Scientific Institute Partner Italy
3 INSERM U1051 Partner France