Adenosine kinase, glutamine synthetase and EAAT2 as gene therapy targets for temporal lobe epilepsy

Young D, Fong DM, Lawlor PA, Wu A, Mouravlev A, McRae M, Glass M, Dragunow M, During MJ.

Contributed by Sloka Iyengar

Gene Therapy September 2014 doi:10.1038/gt.2014.82

Objective – Anti-epileptic drugs (AEDs) manage seizures reasonably well, but they can be associated with refractoriness and side-effects. AEDs work via only a few known mechanisms, hence it is worthwhile putting in the effort to find additional targets for drug action. New drugs hold the promise of not only being more effective in stopping seizures, but also having fewer side effects. A novel target in the field of epilepsy is adenosine – a molecule that has anticonvulsant effects. The authors of a recent study investigated whether gene therapy targeting adenosine kinase (ADK) would be effective in an experimental model of seizures in rats. ADK is the enzyme that causes breakdown of adenosine; the thought being, blockade of the enzyme would allow more adenosine to be available for action

Results – The scientists first confirmed that the gene therapy approach did what it was meant to do – i.e. a substantial reduction in expression of ADK. Drugs used to simulate seizures in the lab are known as chemoconvulsants – one such drug is kainate. Using the gene therapy approach, the scientists found that rats with a reduction in ADK (and hence more adenosine) showed a reduction in seizures caused by kainate. Rats that experience kainate-induced seizures show a loss of neurons in a part of the hippocampus known as the hilus (as do people with epilepsy). Rats that had an increase in ADK showed that these neurons were protected.

Interpretation – This preclinical study has possible implications for discovery of newer AEDs. Gene therapy could be of special importance in a chronic disorder like epilepsy because of the potential to provide long-term beneficial effects with minimal side-effects. This study shows preliminary evidence that gene therapy targeting of adenosine may be beneficial in epilepsy.

Summary for specialists