MicroRNA Biofluid Profiles as Molecular Diagnostics for Response to the Antiepileptic Drug Leveteracitam

'MicroRNA Biofluid Profiles as Molecular Diagnostics for Response to the Antiepileptic Drug Leveteracitam' image

Investigator:
Dr Sinead Heavin, Royal College of Surgeons. Dr Gianpiero Cavalleri will act as Primary Academic Mentor on the project.

Investment:
€101,790 over two years, of which €30,596 is provided by Epilepsy Ireland. The project is co-funded by the Irish Research Council through its Enterprise Partnership Scheme.

About Dr. Heavin
Dr Heavin is a post-doctoral researcher at the RCSI. Following her PhD, she moved into the field of epilepsy genetics, working at the Epilepsy Research Centre at the University of Melbourne as a Clinical Research Scientist, where she trained in epileptology and the genetics of epilepsy with the world-renowned Prof. Ingrid Scheffer and Prof. Sam Berkovic She has been a co-author on a number of articles in top-tier scientific journals, including two publications in Nature Genetics. As part of this research she was involved in the discovery of the first causative gene for Alternating Hemiplegia of Childhood, a rare but severe, neurodevelopmental disorder. She was also involved in the discovery of novel genes as causative agents for the epileptic encephalopathies, a group of severe epilepsies with poor prognosis.

About the project
Introduction:
Epilepsy is a serious, chronic neurological disorder caused by recurring seizures which affects over six million people in Europe. Epilepsy is typically treated with anti-epileptic drugs (AEDs). Levetiracetam (LEV) is a highly effective AED, response to which can be dramatic in that some patients, who previously were refractory to treatment, respond well to LEV. As yet, there is no way of predicting these unexpectedly responsive patients. Biomarkers to identify responders would allow more personalised treatment of the condition.

MicroRNAs (miRNAs) are small molecules made in all cells that control gene expression. Emerging data show miRNA levels are altered in the brain in experimental and human epilepsy. In addition, miRNAs also appear in the blood following injury to the brain including seizures where they are stable and readily detectable, making them ideal potential diagnostic biomarkers.

Hypothesis:
Biofluid levels of miRNAs differ between patients with drug-responsive versus pharmacoresistant epilepsy. We aim to determine if a patient's miRNA profile can help predict whether they will be a responder to LEV.

Methodology:
This is a retrospective case:control study, comparing miRNA profiles across three categories of patients: i) Previously refractory patients that are 'late responders' to LEV (n=20), ii) Refractory patients that also fail LEV (n=20), iii) Patients seizure free on any drug (n=20). Plasma samples from patients in each group will be analysed to obtain comprehensive miRNA profiles. Comparison across these groups will allow us to identify profiles that are unique to LEV response.

Significance:
Through this project we will identify microRNA biomarkers for responsiveness to LEV. The identification of a microRNA signature of drug response would represent the first such molecular diagnostic for epilepsy, tailoring treatment to an individual's genetic and molecular make-up and ensuring greatly improved treatment response.