Genetic modulation to rescue Charcot-Marie-Tooth peripheral neuropathy – CMT-GM

Peripheral neuropathies, also called Charcot-Marie-Tooth (CMT) or Hereditary Sensory motor neuropathies (HSMN), is a group of inherited disorders that affects the peripheral nervous system and has a prevalence as high as 1:2,500 world-wide. Main signs include motor dysfunction, muscle weakness and atrophy, and sensory defects. There is no curative therapy.
Among the implicated genes, DNM2 encodes the large GTPase dynamin 2, a main regulator of membrane and cytoskeleton remodeling. Preliminary data identified DNM2 activity is dysregulated in DNM2-CMT. Here, to validate our hypothesis that normalizing DNM2 activity can rescue DNM2-CMT, we propose to modulate DNM2 activity in vivo in 2 faithful and complementary mouse models of DNM2-CMT previously characterized. The efficacy of this novel approach will be analyzed through monitoring of motor and sensory functions, and muscle and peripheral nerves structures.
The success of this project will provide a first therapeutic strategy for DNM2-CMT forms, and is an essential step towards clinical trials. As other genetic forms of CMT are due to mutations in proteins that are part of cellular pathways controlled by DNM2, this work may be beneficial for the treatment of these other forms.