Patients with Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene exhibit postnatal neurological regression leading to motor and cognitive impairments, respiratory and autonomic dysregulation, seizures and autism-like behaviors. Preclinical studies have demonstrated that a sub-anesthetic dose of the non-selective NMDA antagonist ketamine acutely reverses cortical hypofunction in Mecp2 null and heterozygous mice (Kron et al., 2012), suggesting the potential utility of NMDA antagonists for treatment of RTT. Ketamine and glutamate antagonists as a class represent a therapeutically challenging target both from a safety and tolerability perspective but also from target engagement perspective. We have now examined a number of NMDA channel blockers previously in clinical development for the treatment of epilepsy, major depression and ischemic brain damage for behavioral and physiological effects in a mouse model of Rett syndrome. Mecp2 null and heterozygous mice were treated with these compounds and were analyzed for effects on EEG, breathing and locomotor function. Our preliminary studies suggest that some NMDA antagonists reverse key phenotypic deficits of the model at clinically achievable exposures and may be of therapeutic value for the treatment of RTT patients.<br/>

Utility of NMDA antagonists for the treatment of Rett syndrome

249th National Meeting (2015)

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