Murdoch Children's Stem Cell Medicine has several exceptional laboratories that focus on the brain using a combination of cutting-edge stem cell, gene editing and genomic technologies to make a difference in the lives of children and patients with brain disorders.  

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Brain disorders caused by genetic variation are a major and growing problem throughout the world, often with devastating effects. Many neurological disorders are chronic and debilitating; they span all age groups, from infants with brain malformations or fatal encephalopathies, to children with Autism Spectrum Disorder to the elderly with neurodegenerative disease. Identification of the genetic basis of disease in an affected individual is critical for diagnosis, prognosis and effective management. However, for many brain disorders, treatment approaches are ineffective, often because of the intrinsic difficulty in accessing human brain tissues for research purposes.

Our laboratories use stem cells to grow neurons and other types of cell found in the brain to aid in diagnosis of brain disorders, to understand disease causes and pathways, and to devise and trial targeted treatment approaches.

Our research uses genomic and other technologies to identify the genetic causes of brain disorders, either in genes already linked to the condition or by discovery of new or novel disease genes. Our labs use human stem cell brain tissue models to test and confirm whether specific genes suspected of causing disease are malfunctioning  (this process is known as functional validation).  Stem cell based models have advantages for functional validation in enabling us to study the function of neural cell lines that are affected in the patient. Similarly, stem cell models typically provide the best model system to better understand disease mechanisms in order to devise and trial new treatment approaches.


Understanding how the brain develops

Correct development of the brain is critically dependent on genetic and environmental cues and signals. However, when the process goes wrong it can result in a malformation of brain development (MBD) and usually neurodevelopmental disorders such as intellectual disability and epilepsy. MBD are relatively common and are a heavy burden for families, as affected individuals often require lifelong multidisciplinary care from health and community services.

There are over 100 new patients seen every year at The Royal Children’s Hospital. To better understand and treat MBD we have established a multidisciplinary clinical and laboratory research program at Murdoch Children's Stem Cell Medicine. We utilise genomic technologies to identify changes in both known and novel genes that are causing the disorder – such a genetic diagnosis provides important information for prognosis, genetic counselling and prenatal testing.

Our work has led to the discovery of over 15 new genes for neurodevelopmental disorders and has provided the evidence base for improvements in the surgical treatments of drug resistant epilepsies. We also collect patient tissue and generate stem cells to undertake disease modelling. The goal of our stem cell research is to identify and develop targeted medical therapies for paediatric brain disorders to then take back to the patient in the form of clinical trials.

Brain cells in a dish to study Rett syndrome (and related disorders).

The second most common cause of severe intellectual disability in females (after Down syndrome) is known as Rett syndrome.  It is a rare and devastating neurological disease, with symptoms including stunted brain growth, problems with muscle coordination, language difficulties and seizures – most women with Rett syndrome never lead independent lives and rarely reach middle-age. 

The fundamental biology of Rett syndrome disease is poorly understood, however, we do know that in most cases, it is caused by mutations in a gene called MECP2. In addition, we have found that mutations in another gene, CDKL5 cause a neurological disorder with features that overlap with Rett syndrome.  Using stem cells derived from patients with mutations in these two genes, we have been able to generate their brain tissues in our lab to better explore their functions and processes. 

Using cutting-edge technology, we can now also correct the “mistake/mutation” in the gene using CRISPR/Cas9 gene editing technologies, and can grow them side by side with the patient cells with the mistake/mutation for comparative research. Uncovering the biological mechanisms of these gene mutations will be of significant importance in understanding its cause, and disease pathways, and in finding a cure for patients with Rett syndrome.

Creating a panel of stem cells lines covering the range of mitochondrial disease mechanisms

Mitochondrial energy generation disorders can cause severe symptoms in any organ or tissue - particularly the brain and heart - which have the highest energy demands in the body. Many patients die in infancy or childhood as there are no treatments proven to be effective.  We now know of more than 300 genes in which mutations can cause mitochondrial disease, and these disorders affect at least 1 in 5000 births, with at least 60 new cases born each year in Australia.

At Murdoch Children's Stem Cell Medicine, we are generating a bank of patient-derived and gene-edited stem cell lines for more than 20 distinct types of mitochondrial disease. This panel covers the major types of mitochondrial disease mechanisms, which we can then use to investigate cell types relevant to the disease. There is unlikely to be a single “silver bullet” therapy that will work for 300 different disease genes. Thus, having this panel means we can perform preclinical treatment studies of specific drugs and drug combinations in neural cell lines to identify which treatment approach is likely to be the best for each category of mitochondrial disease.

Our goals are to identify and validate disease mechanisms and to identify personalised treatment strategies that restore proper mitochondrial function in patients.

Stem cell models of a novel neurodegenerative disorder exacerbated by febrile illness

We recently identified a group of unrelated families with a previously unknown syndrome in which affected children developed normally until an episode of mild fever or a common infection triggered a fatal neurodegenerative disorder. We used genomics to identify mutations in each patient in a gene called NAXD, required for proper recycling of vitamin B3. When the gene is not working, a toxic version of vitamin B3 accumulates in cells and interferes with normal cellular functions. Skin cells from these children had severely compromised energy production and a massive accumulation of damaged vitamin B3.

We plan to use gene editing technology to convert skin cells from NAXD patients into neuronal cells in culture that will then be used to further dissect the neurological consequences of NAXD deficiency. We expect that this may provide avenues for the development of protective therapies.

Undiagnosed Diseases Program - Victoria

Some children thought to have rare genetic disorders have highly unique symptoms that appear to be unlike any known inherited disorder, and are thus said to have an ‘orphan disease’. Our expertise with genomics gives us a great opportunity to uncover the genetic answer for these unique families, and we often identify genetic changes in a gene that has never been previously linked to a disease. In order to prove that changes in such genes are truly causing the patient’s symptoms, further studies of disease mechanisms need to be performed. This can involve collaboration with researchers anywhere around the world but one of the ongoing challenges for validating novel brain disorder genes is the need to be able to study cells that reflect the behaviour of brain cells.

Murdoch Children's Stem Cell Medicine provides the opportunity to trick skin or blood cells from a patient into becoming stem cells that can then be differentiated into brain cells. This means we can perform detailed studies targeting the function of any gene in a model system that should reflect the patient’s underlying problem. The ability to perform such studies is an increasingly important way for us to solve the most complicated causes of undiagnosed orphan diseases, opening up the opportunity for better diagnosis, prevention and treatment of novel disorders.

Understanding the neurobiology of autism spectrum disorder

Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition that presents in early childhood. Over 300,000 Australians have ASD, with a significant impact on affected individuals and their families. ASD is a lifelong developmental condition that affects the way an individual relates to their environment and interacts with people, and at the severe end of the spectrum can be highly debilitating and stressful for the patient and their families.  While many studies have shown that autism has a strong genetic basis, we do not know the cause of the condition in about two-thirds of individuals.

Therefore, we are combining clinical, neuropsychological and genomic approaches to study large families, allowing us to identify both genes that cause ASD and additional genes that can moderate the outcome, leading to less severe features. We know that changes in the way the brain handles and processes information are very important in ASD. Ultimately, therapies for ASD will need to target the nerve cells in the brain and help them function and talk to each other more effectively.

Using patient-derived stem cells, we can now make brain cells and brain cell networks in the laboratory and begin to understand why cells in the brain are not working properly in an individual with ASD. These studies will allow us to develop treatments that may improve the function of nerve cells. This means we can test drugs and other therapeutic agents to find compounds that can correct the problems in the patient-derived cells. We hope that these compounds will eventually translate to patients, providing treatments to help mitigate or prevent challenging behavioural features associated with ASD.

Novel stem cell models to understand Parkinson’s disease.

Parkinson’s disease (PD) is a complex neurological condition affecting 100,000 Australians. The primary clinical features of PD, tremor and unstable gait, result from the selective loss of a specific type of neuron. It is currently unclear why these neurons are preferentially lost. We have identified a novel gene that causes early onset PD and have generated stem cells from affected individuals.

We have been converting these stem cells into different neuron types that are present in the brain and are specifically interested in the type of neurons (dopaminergic neurons) that are lost in PD. We have shown that these neurons do not function as well as similar cells generated from unaffected individuals. In particular, the dopaminergic neurons do not seem to be able to dispose of proteins that are no longer needed or have become damaged.

These defective proteins accumulate in the cell and compromise its ability to communicate with other neurons and target cells. We are now investigating if we can identify compounds that can correct this problem in our model neurons, with the ultimate aim of using these compounds to treat individuals with PD.

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