Epilepsy

Novel biomarkers and drug targets for pharmacoresistant epilepsy

Funded by a $2 million NHMRC (National Health and Medical Research Council) Ideas Grant (2023-2026)

Hypothesis
Genetic studies of risk and AED response in pharmacoresistant epilepsy will identify new genetic biomarkers & drug targets.

Aims

  1. Identify and contact epilepsy patients prescribed a second-line AED during the past 5 years.
  2. Collect and assess symptom and prescription information from responding participants and collect DNA from 10,000 pharmacoresistant epilepsy patients.
  3. Genotype common DNA sequence variants in the collected epilepsy patient samples.
  4. Perform pharmacogenetic association and bioinformatic analysis of DNA sequence variants.

Outcomes and Significance
The benefits of this research will include i) insight into epilepsy biology and AED mechanisms of action; ii) elucidation of a profile associated with efficacy and tolerability of AED response in pharmacoresistant epilepsy (personalised medicine); and iii) discovery of novel targets to develop new AEDs for pharmacoresistant epilepsy.

Media / Lay summary
In one-third of epilepsy patients, currently available antiepileptic drugs (AEDs) do not control seizures. Recurrent seizures threaten life and impair its quality; hence, there is a clear need to discover new AEDs. In addition, there is currently no way to accurately predict which and how individuals will respond to a specific or any AED. The proposed research aims identify new AED targets and predict the right (and wrong) drugs for an epilepsy patient from the outset.

Research Team
CIA Prof Dale R Nyholt, CIB AsPro Wendyl D’Souza, CIC AsPro Bobby Koeleman; AIs: Prof Nicholas Martin, Prof Ingrid Scheffer, Prof Arn van den Maagdenberg, Prof Melanie Bahlo; Research Staff: Senior Project Coordinator, Laboratory Co-ordinator, Sample collection Co-ordinator, Recruitment Officer 1, Recruitment Officer 2, Recruitment Officer 3, Statistical/Bioinformatic Analyst.

Participate in the study
The Genetics of Pharmacoresistant Epilepsy (GenPhEp) Study is a collaborative project conducted by researchers from the Queensland University of Technology, QIMR Berghofer Medical Research Institute, and the University of Melbourne.
We are seeking adults who have a diagnosis of Epilepsy or recurrent seizures to participate in our study. We are looking for participants with any type of Epilepsy, including from a brain tumour, injury or whether the diagnosis is related to another condition, to help us find out how to predict the right (and wrong) medications for an epilepsy patient from the beginning.
Please visit https://www.qimrberghofer.edu.au/epilepsy/ to learn how you can participate in the study.

 

Epilepsy – what is it and why research is needed

Epilepsy―an umbrella term for the tendency to have recurrent seizures―affects around 1 in 26 people at some stage in their life.1 This definition can be pragmatically dichotomised into generalised or focal epilepsies encompassing genetic generalised epilepsy (GGE) comprising childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, GGE with generalised tonic clonic seizures only, and GGE unspecified; and the established genetic focal epilepsies (FE) comprising autosomal dominant nocturnal frontal lobe epilepsy, lateral temporal lobe epilepsy with auditory features, uncertain genetic FEs of benign epilepsy with centrotemporal spikes, and acquired FE. Although the basic neurophysiological mechanisms of some epileptic activity are now understood, many important issues remain elusive, in particular the mechanisms of how epilepsy arises from a specific insult, why some epilepsies are responsive or resistant to medical treatment, and the precise combinations of cellular pathophysiologies in epilepsy.2

Epilepsy is associated with significantly increased morbidity, including a high risk of premature death. For example, uncontrolled seizures lead directly to the death of ~300 Australians3 and over 12,000 Europeans each year. Over 20 antiepileptic drugs (AEDs) are licensed for treatment.4,5 However, in one-third of patients, currently-available AEDs do not control seizures.6 Recurrent seizures threaten life and impair its quality, and account for much of the €15.5 billion annual cost of epilepsy in Europe alone.7-9 Thus, there is a clear need to discover new AEDs. In addition, there is currently no way to accurately predict which patients will respond to a specific or any AED, and how well; and even in the two-thirds who do respond, only 47% respond to the first AED, only a further 13% respond to the second AED, and only 4% respond to the third or more AED; while the correct drug is being sought, risks from seizures continue.6 Indeed, for some patients, positive response does not occur until prescription of their fourth or fifth (or more) AED—these occurrences need to be identifiable from the outset. Furthermore, and unrelated to responder (seizure control) status, AEDs can cause serious adverse drug reactions (ADRs), and no robust predictors of such response currently exist. A primary motivation of this project is the need to be able to predict the wrong and tailor the right drugs for an epilepsy patient from the outset.

References

  1. England, M.J., Liverman, C.T., Schultz, A.M. & Strawbridge, L.M. Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav 25, 266-76 (2012).
  2. Koeleman, B.P.C. What do genetic studies tell us about the heritable basis of common epilepsy? Polygenic or complex epilepsy? Neurosci Lett 667, 10-16 (2018).
  3. Australian Bureau of Statistics (ABS). 3303.0 Causes of death, Australia, 2012. ABS, Canberra (2014).
  4. Sirven, J.I., Noe, K., Hoerth, M. & Drazkowski, J. Antiepileptic drugs 2012: recent advances and trends. Mayo Clin Proc 87, 879-89 (2012).
  5. Golyala, A. & Kwan, P. Drug development for refractory epilepsy: The past 25 years and beyond. Seizure 44, 147-156 (2017).
  6. Kwan, P. & Brodie, M.J. Early identification of refractory epilepsy. N Engl J Med 342, 314-9 (2000).