Rescue of Nav1.2 Sodium Channel Functions in Severe Neurodevelopmental Disorders – Nav12RESCUE

Mutations that reduce Nav1.2/SCN2A sodium channel function are major players in a large spectrum of severe untreatable neurodevelopmental disorders, but specific pathological mechanisms are not clear yet. Importantly, there are no treatments available that can target Nav1.2 loss of function. Our preliminary work has identified negative dominance (NegD, >50% reduction of function in heterozygosis, induced by the interaction between mutant and wild type Nav1.2) as the mechanism of Nav1.2 mutations associated to severe autistic spectrum disorder: a novel pathological mechanism for Nav1.2 mutations and a thus far undisclosed therapeutic target. Also, we are identifying compounds that can selectively enhance Nav1.2 activity. Moreover, we have developed a novel cutting-edge technique to optically measure Na+ currents in neuronal sub-compartments, which can overcome the limits of classical electrophysiological techniques.

The objectives of Nav1.2RESCUE are to:
1. develop drugs and strategies for counteracting reduced NaV1.2 function and NegD (novel therapeutic target completely unexplored thus far), which are unavailable and could be used to treat severe neurodevelopmental disorders;
2. exploit established and develop new gene targeted animal models of NaV1.2 loss of function and NegD, studying pathological mechanisms and effects of treatments;
3. use novel cutting-edge imaging techniques for studying detailed mechanisms and evaluate effects of treatments, optically measuring Na+ currents in neuronal sub-compartments.

In addition to these objectives, Nav1.2RESCUE will generate several products, in particular:
I. NaV1.2 enhancers, unavailable thus far and that could be used for therapies as well as for basic research;
II. tools for studying negative dominance of Na+ channels and their molecular interactions;
III. the validation of the first gene targeted mouse model carrying an actual human NaV1.2 loss of function mutation, which will be available to the scientific community at the end of the project;
IV. the validation and exploitation of a novel cutting edge Na+ imaging technique that can have numerous applications in basic and preclinical research.

Overall, Nav1.2RESCUE will disclose mechanisms and exploit therapeutic targets for untreatable severe neurodevelopmental disorders. Our work can be important also to provide information that may be exploitable for early diagnosis, prevention, stratification of patients and selection of already available therapies (including avoiding treatments that could worsen phenotypes).