Pharmacological Approach

Neurotransmission is the process by which signaling molecules, called neurotransmitters, are released by a presynaptic neuron, travel over the synaptic space and bind to and interact with receptors on a postsynaptic neuron. Depending on the nature of the neurotransmitter and receptor, this interaction results in excitation, inhibition or modulation of the receiving neuron's behavior. An agonist is an agent that binds the receptor to increase the function of the neurotransmitter. An antagonist is an agent that binds the receptor to decrease the function of the neurotransmitter.

GABA, or gamma-aminobutyric acid, the most prominent inhibitory neurotransmitter in the CNS, binds to the GABA receptor, a well-established target for drug development. Recent advances in research have shown that excess GABAergic inhibition likely underlies the pervasive sedation in a number of rare primary hypersomnias and also the manifestations of learning and memory deficits in some intellectual disabilities. There are a number of GABA agonist products on the market including barbiturates, benzodiazepines and sleep aids. These GABA agonists increase the activity of GABA, resulting in sedation at varying degrees depending on agent and dose. Recent research at Emory University has shown that the pervasive sedation observed in IH and Na-2 likely results from the GABA agonist activity of an endogenous peptide or small protein present in the CNS of these patients. We believe the pharmacological approach to address this unwanted GABA agonism is to treat these patients with a GABA antagonist like BTD-001 that counters the endogenous agonist and its sedative effects.

Research at Stanford University and elsewhere has shown that neural over-inhibition may be the molecular basis for cognitive impairment in Down syndrome and other intellectual disabilities. Excessive inhibitory tone reduces synaptic plasticity, which interferes with information processing and memory formation, consolidation, retrieval and extinction. Excess inhibitory signaling at synapses in the brain, or over-inhibition, can be achieved through chemical or pharmacological means, resulting in cognitive impairment. For example, alcohol, benzodiazepines, barbiturates and certain sleep aids are GABA agonists that have been shown to cause cognitive impairment when taken chronically. Research from Stanford, UCLA and others have demonstrated that excess inhibitory tone may also result from genetic abnormalities such as an extra chromosome in Down syndrome. Our pharmacological approach to these conditions is to restore the proper balance between inhibition and excitation in neural circuits by antagonizing excessive inhibitory tone with a GABA antagonist like BTD-001.