With a $90,000 grant from FRAXA Research Foundation funded during 2014-2015, Dr. Frank Kooy and colleagues at the University of Antwerp are conducting a double blind crossover trial of ganaxolone in patients with fragile X syndrome. Results of this study were mixed (see Marinus: Results from Phase 2 Exploratory Clinical Study Support Continued Development of Ganaxolone in Fragile X Syndrome.
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
Previous Grants to this Team
$45,000 in 2010
$100,000 in 2007-8
$65,000 in 1999-2000
Absence of a single protein, FMRP, in fragile X patients leads to a cascade of molecular events in brain cells. To find out which other genes are involved the clinical symptoms, we have been looking for genes that are differentially expressed in fragile X syndrome.
One of the genes specifically underexpressed is part of the GABAA receptor. As GABA-A receptors are the main inhibitory receptors in the brain, involved in processes like anxiety, mood swings, sleep and cognition, processes also disturbed in fragile X patients, we followed up on this finding. In subsequent studies, we demonstrated abnormalities in expression levels of multiple parts of the GABA-A receptor, both in the mouse model and in the fly model, indicating underexpression is an evolutionary conserved hallmark of fragile X syndrome. Our case for involvement of the GABAergic system in fragile X is supported by independent findings from other groups.
During the first years of our study, we analyzed the relative expression of many genes that are responsible for GABA synthesis, transport, clustering and degradation. Essentially all of these genes were under expressed in the fragile X syndrome, strengthening our hypothesis that the entire GABA system is down regulated in the disorder. We then verified that GABAergic drugs such as the neurosteroid alphaxolone are effective in the knockout mice.
We then moved our studies to patients with fragile X syndrome, by performing a clinical study of position emission tomography (PET), a functional imaging technology that is able to provide non-invasive in vivo assessment and quantification of GABA-A receptor binding through injections of labelled flumazenil. We found a difference in GABA-A receptor distribution between fragile X patients and controls. This reenforces our hypothesis that a dysfunction of the GABAergic system is responsible for the neurologic and behavioral problems seen in fragile X patients. Our research strongly encourages drug trials on fragile X patients.