We conducted a double blind crossover trial to investigate whether ganaxolone can ameliorate clinical symptoms of patients with Fragile X syndrome. In a crossover trial, each patient acts as his own control, receiving placebo for part of the trial, and active drug during a different part of the trial. This clinical trial will include 30 patients with Fragile X syndrome in Antwerp, Belgium, and is expected to be complete within two years.
GABA-A in Fragile X
Proper function of the nervous system requires both excitatory neurons and counterbalancing inhibitory neurons. Glutamate is the major excitatory neurotransmitter in the brain, and Fragile X is closely associated with abnormalities at metabotropic glutamate receptors (mGluRs). However, inhibition is also clearly abnormal.
GABA-A receptors, the main inhibitory receptors in the brain, are implicated in processes disturbed in Fragile X patients, including excessive neuronal excitability, leading to enhanced seizures susceptibility, anxiety, sleep, and learning and memory problems. The Kooy lab is studying the function of GABA (gamma-amino butyric acid) in Fragile X, with a goal of developing treatments based on enhancement of inhibitory neurotransmission.
The Kooy lab previously showed that part of the clinical symptoms of the Fragile X syndrome is due to a dysfunctional GABAergic system. Subsequent experiments showed that drugs that restore the GABAergic function can reduce symptoms of the disorder in animal models.
Ganaxolone is an investigational new drug under development by Marinus Pharmaceuticals and is one of a class of drugs known as neurosteroids. It is a positive modulator of the GABA-A receptor and thus it can enhance the GABA neurotransmitter system. Ganaxolone protects against seizures in diverse animal models. Unlike for benzodiazepines, there is no tolerance to the anticonvulsant effects of ganaxolone.
Ganaxolone is being investigated for potential medical use in the treatment of epilepsy. Trials in adults with partial seizures and in infantile spasms have been completed. See http://en.wikipedia.org/wiki/Ganaxolone