Focusing on epilepsy –a kaleidoscopic approach

Globally,

The Florey is home to a team of 40 medical researchers dedicated to understanding the full spectrum of epilepsies with a particular emphasis on very young children. They look into the causes of genetic epilepsies, design and test new medications, and study large populations in an efort to test their discoveries in the lab. Our imaging team creates detailed images of the brain to reveal electrical activity and guide surgeons in theatre when surgical intervention is possible.

The goal? Improved treatments to control abnormal brain activity and seizures.

Dravet syndrome is a particular focus of our team. Children afected by this genetic dysfunction of the brain experience severe developmental disabilities and rely on a range of specialists and combinations of inefective medications to limit the impact of this devastating disease. Our scientists hope that by identifying and targeting the efects of the underlying mutations they will make a meaningful diference to these children’s lives.

Unique treatments using stem cells

A growing collection of patient samples from all over the world are being used to study severe genetic epilepsies in children using a stem cell “brain-in-a-dish” technique.

The team in the Ion Channels and Human Disease laboratory works closely with the families and clinicians of afected children. In parallel, valuable and detailed clinical information has been collected by clinicians from Austin Health and the Murdoch Children’s Research Institute to help understand the natural history of the disease, and the specific features of each patient’s condition.

Starting from patient biopsies, individual skin cells are ‘sent backwards’ through development, and turned into stem cells, which can then be instructed to turn into brain cells. This provides an opportunity to investigate the underlying genetic basis of each patient’s condition, and to screen the safety and efectiveness of diferent therapies. The ultimate aim is to translate labbased discoveries into targeted therapies for individual patients, providing hope to the families and health carers battling the severe and incurable early onset epileptic disorders.

No2 Modelling epilepsy in mice

A collaborative approach across the Florey and hospitals ensures clinical and geneticist colleagues identify mutations that cause devastating epilepsies in children. This has important implications for diagnosis but is really just the start of trying to understand why these children have seizures. Florey researchers are using this human genetic information to mimic epilepsy in mice that closely resembles the human disease - using CRISPR technology. The science is exciting Florey researchers for a few reasons. Firstly, they can more easily interrogate the brain mechanisms that cause seizures and gain a better understating of the underlying disease process. The CRISPR technique is already allowing them to screen new or existing ‘precision’ medicines that are targeted to a particular genetic cause of epilepsy. The new medicines are rapidly trialled on the animal model in a way that would be impossible in humans. Medicines that work in the mice are likely to be helpful in the patients because the underlying genetic mutations are exactly the same as the human disease.

No3 Spider toxin and cannabinoids to treat Dravet syndrome

Dravet syndrome is a devastating neurological disease which presents in a child’s first year of life and there is no efective treatment, driving our researchers and clinicians to find answers. Children have multiple seizures and experience severe intellectual and learning delays. They also have a high risk of premature death. In collaboration with national and international experts, Florey researchers are exploring new therapies from surprising sources. When given to a mouse with a human-like Dravet syndrome, a tarantula venom protein can precisely act on the faulty neurons and rescue normal function, stopping seizures and preventing premature death.

The team is also exploring the efect of medicinal cannabinoids as a potential therapy. Clinical trials of medicinal cannabis show promise in the treatment of Dravet syndrome, which has led to their approved use in the USA. The Florey’s goal is to optimise safe and efective cannabinoid therapeutics for paediatric epilepsies here in Australia.

No4

Watching epilepsy brain cell activity

Developmental epileptic encephalopathies (cumulative brain damage caused by severe epileptic seizures) are serious treatment-resistant disorders that usually appear in infancy or early childhood. Florey scientists have found that mutations in ion channels – the ‘gatekeepers’ in brain cells that allow them to be electrically active - are usually the underlying cause.

The Ion Channels and Human Diseases team is using a novel approach to predict how ion channel mutations, and potential drug therapies, afect brain cell excitability.

Understanding the mechanisms causing these encephalopathies will help clinicians decide how to ofer personalised treatment to each of these very sick patients.

Pictured above: Dr Snezana Maljevic, a Senior Research Fellow with the Ion Channels and Human Diseases team.

No5 Brainoids

Our brains are complicated three dimensional objects. Typically, scientists study the brain’s wiring in a flat, 2D environment rather than in 3D, limiting their capacity to see how the brain behaves naturally. Enter the mini-brain. Also known as a brainoid, scientists can now study how cells develop and communicate in a 3D environment. Florey scientists are watching neurons freely self-organise and form networks as they would in our brains. Researchers look inside the mini-brains at their organisation and wiring patterns using state-of-the art laser microscopy. They are watching the way the brain’s wiring behaves when afected by a genetic disease and then comparing this with healthy controls. The electrical signalling between the cells can even be recorded using flashes of light instead of spikes of electricity.