MICA: Exploring GABAAalpha2,3 receptor signalling as novel therapy for focal dystonias and peripheral neuropathies

Skilled hand functions are impaired in a variety of neurological diseases. Patients unintentionally drop objects and have difficulties in fine motor coordination. This occurs when there is a loss of tactile and motor functions as in peripheral nerve diseases which affect 2-3% of the general population or when there is uninhibited motor activity as in dystonia. In a series of proof of concept studies we want to test the possibility that a new medicine AZD7235 (a positive modulator of GABAAalpha2,3 receptors) can help to normalise the impaired hand function.
The compound positively enhances the function of GABA (gamma-aminobutyric acid), the chief inhibitory signalling neurotransmitter in the CNS. GABA signals though a variety of receptors expressed by nerve cells of the brain and medicines that enhance this signalling pathway are in common clinical use to treat conditions such as insomnia, epilepsy and anxiety. However, currently available drugs notably benzodiazepines (e.g. diazepam/Valium) affect rather non-selectively most GABA receptors. Drugs of this class therefore cause a number of unwanted side effects such as sedation or addiction which limits more widespread clinical use. The new compound is one of the first from a new class which affects only a subtype of GABA receptors that has been developed to have an attenuated side effects profile. It is therefore important to establish whether these compounds are efficacious in clinical conditions where sedation is unwanted.
We will use three groups of tests to study the effectiveness of this new compound: 1.) a sensitive neurophysiological biomarkers which can non-invasively detect changes in GABA receptor signalling in the brain. 2.) sophisticated object manipulation tasks that quantifies the way subjects handle objects and which replicates many of the tasks in daily living, like holding a glass or writing. 3.) a battery of psychophysical tasks to test the performance of the sensory system mediating touch
Researchers have previously shown that a better performance in tactile detection and motor tasks in humans is predicted by a higher GABA concentration in specific brain areas. We will therefore study whether further enhancement through AZD7235 improves this function in healthy volunteers. Prior research has also shown that GABA signalling is impaired in dystonia and we consequently want to test whether symptoms can be ameliorated with a GABA enhancing treatment. We will then ask whether we can harness this strategy to centrally compensate for the peripheral loss in patients with neuropathy.
If the studies have the expected positive outcome they will provide a rationale for investigating the clinical utility of this new class of medicines in larger proof of principal clinical trials.

This is a series of proof of concept studies to establish the use of a novel, safe and orally bioavailable positive modulator of GABAAalpha2,3 receptor AZD7235 for new clinical indications on sensory and motor performance tasks in humans. Three cohorts of study participants will be studied in double blind, placebo controlled, 3-way cross-over studies: healthy volunteers, and patients with two neurological conditions representing the abnormal gain (primary focal dystonia) or loss (peripheral neuropathy) of somatosensory function.

The rationale is to use enhanced central GABAAalpha2,3 receptor signalling to ameliorate conditions characterised by a loss of central GABAA receptor activity (dystonia) or to compensate centrally for a peripheral deficit (neuropathy). The expected outcomes include: 1.) Changes of short-interval intracortical inhibition (SICI), a sensitive neurophysiological biomarkers of GABAA receptor function in sensorimotor control of the CNS. 2.) Improvement in the performance of standardised skilled object manipulation tasks. 3.) Improvement in the performance of psychophysical tests of cutaneous mechanosensation of the hand

The expected positive outcome will provide the rationale for future proof of principle studies in larger clinical cohorts and open the possibility for new therapeutic strategies in these difficult to treat conditions.

The outcome of this research will impact on:
1.) Patients. Hand function is fundamental to human existence. Disintegration of sensorimotor control of hand function is relative common and leads to significant impairment and an area of large unmet clinical need for effective therapies. A recent survey demonstrated that quadriplegic individuals ranked regaining hand as 5 times more important than sexual function, bowel and bladder control and absence of pain (Anderson,K.D., Targeting recovery: priorities of the spinal cord-injured population, J. Neurotrauma 21 (2004) 1371-1383). Even though impairment of hand function in dystonia and neuropathy is much milder, because of the larger prevalence it has significant direct costs to the National Health Service and indirect costs to society because the impairment will often results in patients not achieving their full potential in society. Dramatic improvements in our understanding of sensorimotor control is therefore expected to improve clinical management of these patients.
2.) Researchers and pharmaceutical companies working in drug development of medicines targeting GABA signalling. The better definition of the role of biomarkers which functionally monitor target engagement will be of great benefit for future design of proof of concept studies.
3.) Expanding the spectrum of indications for these medicines will lead to further drug developments and generate intelectual property rights for academia and income for the pharmaceutical industry.