UQCCR Seminar Series With Associate Professor John O'Sullivan and Dr Selin Pars

Huntington’s disease – clinical research update with Associate Professor John O'Sullivan 
Bio: After completing neurology training at the Royal Brisbane & Women’s Hospital (RBWH) in 1995, A/Prof O’Sullivan completed Fellowships in Movement Disorders at the Austin & Repatriation Medical Centre, Melbourne then the National Hospital for Neurology and Neurosurgery, and Middlesex Hospital in London, UK. He was awarded a doctorate in Medicine from Melbourne University in 2000 for studies into surgery for Parkinson’s disease. He returned to the RBWH in 2001 and set up the Movement Disorders Clinical Service including botulinum toxin and later Friedreich's ataxia clinics, and co-ordinating the Huntington's disease multidisciplinary clinic. Through these clinics he has established collaborations with local, interstate and international researchers in the fields of Parkinson's disease, and other movement disorders and neurodegenerative diseases. He is currently Associate Professor of Medicine and Principal Research Fellow at UQ Centre for Clinical Research, previously Royal Brisbane and Uniting Care Health Clinical Units in UQ School of Clinical Medicine. A/Prof O'Sullivan past President of the Movement Disorders Society of Australia and New Zealand (MDSANZ), having previously served as Chair of the MDSANZ Clinical Trials and Research Group. He is on the Council of the Australian and New Zealand Association of Neurologists (ANZAN) and previously chaired the ANZAN Scientific Program Committee. 

Anti-seizure medication screening in epilepsy patient-derived brain organoids with Dr Selin Pars  
Bio: Dr. Selin Pars is a postdoctoral researcher (1.5 years post PhD) working at the Australian Institute for Bioengineering and Nanotechnology (AIBN), the University of Queensland in Wolvetang group. She specialises in stem cell research and neuroscience. Her research interests lay in disease modelling of neurological diseases that employ the human induced pluripotent stem cell technology and human brain organoids. 
Overview: Epilepsy is a heterogenous neurological disorder that globally affects more than 50 million people, and is characterized by seizures. More than one third of people with epilepsy will be resistant to anti-seizure medication (ASM). The impacts of epilepsy include economic and societal burdens, psychological co-morbidities, and an increased risk of sudden unexplained death. The current treatment approach is a trial-and-error method. The medication odyssey that people with drug-resistant epilepsy endure, often for years to improve seizure control, adds to the disease burden.

To date, animal models have been limited for screening ASMs. Limitations of this approach include inability to recapitulate human-specific neuronal development, lack of patient-specificity, and are hard to scale-up for high-throughput drug screening.
In our work, we established a patient-derived drug screening platform using brain organoids from epilepsy patients. Cortical organoids (COs) derived from patient PBMCs were used as an in vitro drug screening platform.

COs from 6 patients (3 drug resistant and 3 drug-responsive) had their cellular subtypes assessed by immunocytochemistry and scRNAseq. Next, using high-density microelectrode assay (HD-MEA), we quantified the changes in mean firing rate (MFR) and burst frequency (BF) in response to various ASMs in patient COs. Drug-responsive patient lines have been subject to their prescribed ASMs (lamotrigine, levetiracetam, and zonisamide). Lamotrigine (70µM) and zonisamide (400µM) significantly decreased MFR and BF, however, levetiracetam has not been effective in changing neuronal firing, possibly due to its mechanism of action. Drug-resistant patient lines have been tested with novel ASMs. Out of 4 drugs tested each, perampanel (1µM) have significantly reduced MFR and BF, whereas cannabidiol (3µM) and fenfluramine (5µM) showed partial effectiveness.

Overall, our results demonstrate applicability of a patient-derived brain organoid platform for in vitro ASM screening. The future potential of this novel approach include utility for drug predictions and drug discovery.